The 28-days-to-diagnosis pathway is the current expected standard of care for women with symptoms of ovarian cancer in the UK. However, the anticipated conversion rate of symptoms to cancer is only 3%, and use of the pathway is increasing. A rapid triage at the moment of receipt of the referral might allow resources to be allocated more appropriately. In secondary care, multidisciplinary teams (MDTs) use the risk of malignancy index (RMI) score, (multiply menopausal status pre = 1 or post = 3 × ultrasound score = 0 − 3 × the CA 125 level), using a score of >200, to triage urgency and management in possible ovarian cancer cases. The most powerful determinant of the RMI score variables is CA 125 level, an objective number. Could a simple modification of the RMI score retain a high sensitivity for cancer whilst improving specificity and, consequently, decrease the morbidity of false-positive classification? To test this hypothesis, a retrospective evaluation of an ovarian two-week-wait telephone clinic of one consultant gynaecological oncologist was undertaken. Enquiry re menopause status was scored as one for pre- and three for postmenopausal or uncertain. CA 125 levels of >67 u/mL for premenopausal and >23 u/mL for postmenopausal women were used to precipitate urgent cross-sectional imaging requests and MDT opinions. These CA 125 cut thresholds were calculated using an assumption that the RMI imaging score, regardless of whether the result was available, could be three. We contemplate that women who did not exceed a provisional RMI score of >200 might be informed they are extremely unlikely to have cancer, removed from the malignancy tracker and appropriate follow-up arranged. One hundred and forty consecutive cases were analysed; 43% were deemed premenopausal and 57% postmenopausal. Twenty of the women had cancer, eighteen (90%) of whom had an RMI > 200. One hundred and twenty were benign, and only twenty-three (19%) classified as urgent cases in need of accelerated referral to imaging. In contrast, CA 125 > 35 u/mL, whilst retaining the sensitivity of 90%, misclassified 36 (30%) of the benign cases. It is possible that a telephone triage via a questionnaire determining menopausal status and the CA 125 result could offer a sensitivity for cancer of 90% and urgent expert review of under 20% of benign cases. This rapid initial telephone assessment could be presented by a trained pathway navigator, physician associate or nurse specialist. Substantial savings in NHS cancer services resources, anxieties all around and reduced patient morbidity may occur as a result.

Objective. UKCTOCS provides an opportunity to explore symptoms in preclinical invasive epithelial ovarian cancer (iEOC). We report on symptoms in women with pre-clinical (screen-detected) cancers (PC) compared to clinically diagnosed (CD) cancers. Methods. In UKCTOCS, 202638 postmenopausal women, aged 50-74 were randomly allocated (April 17, 2001-September 29, 2005) 2:1:1 to no screening or annual screening till Dec 31,2011, using a multimodal or ultrasound strategy. Follow-up was through national registries. An outcomes committee adjudicated on OC diagnosis, histotype, stage. Eligible women were those diagnosed with iEOC at primary censorship (Dec 31, 2014). Symptom details were extracted from trial clinical-assessment forms and medical records. Descriptive statistics were used to compare symptoms in PC versus CD women with early (I/II) and advanced (III/IV/unable to stage) stage high-grade-serous (HGSC) cancer. ISRCTN-22488978; ClinicalTrials.gov-NCT00058032. Results. 1133 (286PC; 847CD) women developed iEOC. Median age (years) at diagnosis was earlier in PC compared to CD (66.8PC, 68.7CD, p = 0.0001) group. In the PC group, 48% (112/234; 90%, 660/730CD) reported symptoms when questioned. Half PC (50%, 13/26PC; 36%, 29/80CD; p = 0.213) women with symptomatic HGSC had >1symptom, with abdominal symptoms most common, both in early (62%, 16/26, PC; 53% 42/80, CD; p = 0.421) and advanced (57%, 49/86, PC; 74%, 431/580, CD; p = 0.001) stages. In symptomatic early stage HGSC, compared to CD, PC women reported more gastrointestinal (change in bowel habits and dyspepsia) (35%, 9/26PC; 9%, 7/80CD; p = 0.001) and systemic (mostly lethargy/tiredness) (27%, 7/26PC; 9%, 7/80CD; p = 0.017) symptoms. Conclusions. Our findings, add to the growing evidence, that we should reconsider what constitutes alert symptoms for early tubo-ovarian cancer. We need a more nuanced complex of key symptoms which is then evaluated and refined in a prospective trial.(c) 2023 The Authors. Published by Elsevier Inc.

Background In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy.Methods UKCTOCS was a 13-centre randomised controlled trial of screening postmenopausal women from the general population, aged 50-74 years, with intact ovaries. The trial management system randomly allocated (2:1:1) eligible participants (recruited from April 17, 2001, to Sept 29, 2005) in blocks of 32 using computer generated random numbers to no screening or annual screening (multimodal screening or ultrasound screening) until Dec 31, 2011. Follow-up was through national registries until June 30, 2020. An outcome review committee, masked to randomisation group, adjudicated on ovarian cancer diagnosis, histotype, stage, and cause of death. In this study, analyses were intention-to -screen comparisons of women with high-grade serous cancer at censorship (Dec 31, 2014) in multimodal screening versus no screening, using descriptive statistics for stage and treatment endpoints, and the Versatile test for survival from randomisation. This trial is registered with the ISRCTN Registry, 22488978, and ClinicalTrials.gov, NCT00058032.Findings 202 562 eligible women were recruited (50 625 multimodal screening; 50 623 ultrasound screening; 101 314 no screening). 259 (0 center dot 5%) of 50 625 participants in the multimodal screening group and 520 (0 center dot 5%) of 101 314 in the no screening group were diagnosed with high-grade serous cancer. In the multimodal screening group compared with the no screening group, fewer were diagnosed with advanced stage disease (195 [75%] of 259 vs 446 [86%] of 520; p=0 center dot 0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0 center dot 0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0 center dot 0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0 center dot 0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0 center dot 69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9 center dot 51 years (IQR 6 center dot 04-13 center dot 00). At censorship (June 30, 2020), survival from randomisation was longer in women with high-grade serous cancer in the multimodal screening group than in the no screening group with absolute difference in survival of 6 center dot 9% (95% CI 0 center dot 4-13 center dot 0; p=0 center dot 042) at 18 years (21% [95% CI 15 center dot 6-26 center dot 2] vs 14% [95% CI 10 center dot 5-17 center dot 4]).Interpretation To our knowledge, this is the first evidence that screening can detect high-grade serous cancer earlier and lead to improved short-term treatment outcomes compared with no screening. The potential survival benefit for women with high-grade serous cancer was small, most likely due to only modest gains in early detection and treatment improvement, and tumour biology. The cumulative results of the trial suggest that surrogate endpoints for disease-specific mortality should not currently be used in screening trials for ovarian cancer.Funding National Institute for Health Research, Medical Research Council, Cancer Research UK, The Eve Appeal.Copyright (c) 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Background: To address the disparity in UKCTOCS between decrease in advanced stage disease and lack of mortality reduction in tubo-ovarian cancer (OC) in the multimodal screening (MMS) compared to no screening (C) group, we undertook exploratory analyses by histotype. Methods: In UKCTOCS, 202562(50625 MMS;50623 USS;101314C) eligible women were randomised (2001-5) and followed up till 30June2020. Screening group participants underwent annual screening till 31Dec2011. An outcomes committee adjudicated on OC diagnosis, histotype, stage and cause of death. Treatment details were extracted from hospital records. In women diagnosed with cancer (high-grade serous, HGSC; non-high-grade serous, non-HGSC) at censorship (31Dec2014), we compared descriptive statistics(p-values) and survival from randomisation (Versatile test) in MMS and USS group separately to the C group.Findings: In both the MMS(259/50625) and C(520/101314) groups, 0.51% developed HGSC. In HGSC, on an intention-to-screen analysis, there was a reduction in advanced(III/IV/unable to stage) stage disease(MMS75%195/259; C86%,446/520;p=0·0003), higher rates of primary surgery(MMS61%,158/259; C42%,219/520;p<0·0001), zero residual disease(MMS 46%,119/259; C30%,157/520;p<0·0001) and treatment including surgery and chemotherapy(MMS74%,192/259; C64%,331/520;p=0·003) in the MMS compared to C group. There was no difference in those receiving first line combination chemotherapy(MMS55%, 142/259; C56%, 293/520;p=0·687). There was evidence of improvement in survival from randomisation in HGSC in MMS(MMS21%,54/259; C14%,74/520;p=0·042) in the case only analysis. No differences were observed in the comparisons in USS or non-HGSC in the MMS versus C group.Interpretation: Our findings provide robust evidence for the first time that screening can detect HGSC earlier and result in improved treatment outcomes. The lack of overall mortality benefit is likely related to the magnitude of early detection and treatment improvement as well as tumour biology. The findings do not support use of surrogate end points in place of disease-specific mortality.Funding National Institute for Health Research, MRC, Cancer Research UK, The Eve Appeal.Trial Registration: This trial is registered with ISRCTN number 22488978; ClinicalTrials.gov number NCT00058032.Funding: The Long Term Follow Up (LFTU) UKCTOCS is supported by National Institute for Health Research (NIHR HTA grant 16/46/01), Cancer Research UK (CRUK) and The Eve Appeal. UKCTOCS was funded by Medical Research Council (G9901012 and G0801228), CRUK (C1479/A2884), and the Department of Health, with additional support from The Eve Appeal. Researchers at UCL are supported by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre and MRC CTU at UCL core funding (MR_UU_12023).Declaration of Interest: UM has stock ownership awarded by University College London (UCL) in Abcodia, which holds the licence for ROCA (between 1 April 2011 and 30 October 2021). She has received grants from the Medical Research Council (MRC), Cancer Research UK, the National Institute for Health Research (NIHR), and The Eve Appeal. She holds patent number EP10178345.4 for Breast Cancer Diagnostics. MP has received grants and AG-M, MB, and AR, have been funded by grants from MRC, CRUK, NIHR, and The Eve Appeal. UM, SA and AG-M received research funding from iLOF (intelligent Lab on Fiber), Micronoma, Imperial College London, QIMR Berghofer Medical Research Institute, Innovate UK, Mercy Bioanalytics, University of Innsbruck, NHMRC and MRC Proximity to Discovery Industrial Connectivity Award. UM has received an honorarium from NY Obstetrical Society and reimbursements for invited talks from NY Obstetrical Society (USA), National Cancer Policy Forum (USA), and Robinson College, Cambridge. She is a member of ACED (International Alliance for Cancer Early Detection) Gynaecological Cancers Working Group, and a member of Advisory Boards or Committees for Tina’s Wish, Mixed COVID Vaccines study, India, Yorkshire Cancer Research, GEM3, NOVEL, and PROTECTOR. UM and SA received research funding from RNA Guardian and Dana Faber. MP was a member of the EME funding committee while the project was active. MB reports funding from NIHR UCL Hospitals Biomedical Research Centre. SA received funding from Abcodia. AG-M is a member of ACED (International Alliance for Cancer Early Detection) Gynaecological Cancers Working Group, and Co-Director Research Domain Trials for ACED. RM has received grants from The Eve Appeal, Rosetrees Charity, and Barts Charity, Yorkshire Cancer Research, Ovacure, BGCS, GSK, personal fees from AstraZeneca and consulting fees from Everything Genetics Limited. AMcG was a member of NIHR HTA and EME Editorial Board from 1 April 2012 to 31 March 2022. LJF received a grant form MRC for the psycho-social arm of the UKCTOCS study 2001-2013. SJS holds the (expired) patent for ROCA, patented and owned by Massachusetts General Hospital and Queen Mary University of London, licenced to Abcodia. He reports personal fees from Abcodia, Guardant Health, and Freenome, outside the submitted work, funding from NIHR, NCI and Mercy Bioanalytics and consulting fees from Guardant Health. He participates on Board of SISCAPA Assay Technologies and has stock ownership for this. IJJ reports grants from Eve Appeal Charity, Medical Research Council, Cancer Research UK, and NIHR during the conduct of the study. He co-invented the ROCA in 1995, it was patented by Massachusetts General Hospital and Queen Mary University of London and is owned by these universities. Massachusetts General Hospital and Queen Mary University of London granted a licence to ROCA to Abcodia in 2014. IJJ is a board member, shareholder, and consultant to Abcodia and has rights to royalties from sales of the ROCA. He founded (1985), was a trustee of (2012–14), and is now an Emeritus trustee (2015–present) of The Eve Appeal, one of the funding agencies for UKCTOCS. NS received an honorarium from Astra-Zeneca-MSD and GlaxoSmithKline for participation in Advisory board. All other authors declare no competing interests.Ethical Approval: Approved by the UK North West MREC (00/8/34) on June 23, 2000.

Randomised controlled trials of ovarian cancer (OC) screening have not yet demonstrated an impact on disease mortality. Meanwhile, the screening data from clinical trials represents a rich resource to understand the performance of modalities used. We report here on incidence screening in the ultrasound arm of UKCTOCS. 44,799 of the 50,639 women who were randomised to annual screening with transvaginal ultrasound attended annual incidence screening between 28 April 2002 and 31 December 2011. Transvaginal ultrasound was used both as the first and the second line test. Participants were followed up through electronic health record linkage and postal questionnaires. Out of 280,534 annual incidence screens, 960 women underwent screen-positive surgery. 113 had ovarian/tubal cancer (80 invasive epithelial). Of the screen-detected invasive epithelial cancers, 37.5% (95% CI: 26.9–49.0) were Stage I/II. An additional 52 (50 invasive epithelial) were diagnosed within one year of their last screen. Of the 50 interval epithelial cancers, 6.0% (95% CI: 1.3–16.5) were Stage I/II. For detection of all ovarian/tubal cancers diagnosed within one year of screen, the sensitivity, specificity, and positive predictive values were 68.5% (95% CI: 60.8–75.5), 99.7% (95% CI: 99.7–99.7), and 11.8% (95% CI: 9.8–14) respectively. When the analysis was restricted to invasive epithelial cancers, sensitivity, specificity and positive predictive values were 61.5% (95% CI: 52.6–69.9); 99.7% (95% CI: 99.7–99.7) and 8.3% (95% CI: 6.7–10.3), with 12 surgeries per screen positive. The low sensitivity coupled with the advanced stage of interval cancers suggests that ultrasound scanning as the first line test might not be suitable for population screening for ovarian cancer. Trial registration: ISRCTN22488978. Registered on 6 April 2000.

Background There is a trend to increasing use of routinely collected health data to ascertain outcome measures in trials. We report on the completeness and accuracy of national ovarian cancer and death registration in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Methods Of the 202,638 participants, 202,632 were successfully linked and followed through national cancer and death registries of Northern Ireland, Wales and England. Women with registrations of any of 19 pre-defined ICD-10 codes suggestive of tubo-ovarian cancer or notification of ovarian/tubal/peritoneal cancer from hospital episode statistics or trial sites were identified. Copies of hospital and primary care notes were retrieved and reviewed by an independent outcomes review committee. National registration of site and cause of death as ovarian/tubal/peritoneal cancer (C56/C57/C48) obtained up to 3 months after trial censorship was compared to that assigned by outcomes review (reference standard). Results Outcome review was undertaken in 3110 women on whom notification was received between 2001 and 2014. Ovarian cancer was confirmed in 1324 of whom 1125 had a relevant cancer registration. Sensitivity and specificity of ovarian/tubal/peritoneal cancer registration were 85.0% (1125/1324; 95% CI 83.7–86.2%) and 94.0% (1679/1786; 95% CI 93.2–94.8%), respectively. Of 2041 death registrations reviewed, 681 were confirmed to have a tubo-ovarian cancer of whom 605 had relevant death registration. Sensitivity and specificity were 88.8% (605/681; 95% CI 86.4–91.2%) and 96.7% (1482/1533, 95% CI 95.8–97.6%), respectively. When multiple electronic health record sources were considered, sensitivity for cancer site increased to 91.1% (1206/1324, 95% CI 89.4–92.5%) and for cause of death 94.0% (640/681, 95% CI 91.9–95.5%). Of 1232 with cancer registration, 8.7% (107/1232) were wrongly designated as ovarian/tubal/peritoneal cancers by the registry and 4.0% (47/1172) of confirmed tubo-ovarian cancers were mis-registered. In 656 with death registrations, 7.8% (51/656) were wrongly assigned as due to ovarian/tubal/peritoneal cancers while 6.2% (40/645) of confirmed tubo-ovarian cancer deaths were mis-registered. Conclusion Follow-up of trial participants for tubo-ovarian cancer using national registry data will result in incomplete ascertainment, particularly of the site due in part to the latency of registration. This can be reduced by using other routinely collected data such as hospital episode statistics. Central adjudication by experts though resource intensive adds value by improving the accuracy of diagnoses. Trial registration ISRCTN: ISRCTN22488978 . Registered on 6 April 2000

Background During trials that span decades, new evidence including progress in statistical methodology, may require revision of original assumptions. An example is the continued use of a constant-effect approach to analyse the mortality reduction which is often delayed in cancer-screening trials. The latter led us to re-examine our approach for the upcoming primary mortality analysis (2020) of long-term follow-up of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (LTFU UKCTOCS), having initially (2014) used the proportional hazards (PH) Cox model. Methods We wrote to 12 experts in statistics/epidemiology/screening trials, setting out current evidence, the importance of pre-specification, our previous mortality analysis (2014) and three possible choices for the follow-up analysis (2020) of the mortality outcome: (A) all data (2001–2020) using the Cox model (2014), (B) new data (2015–2020) only and (C) all data (2001–2020) using a test that allows for delayed effects. Results Of 11 respondents, eight supported changing the 2014 approach to allow for a potential delayed effect (option C), suggesting various tests while three favoured retaining the Cox model (option A). Consequently, we opted for the Versatile test introduced in 2016 which maintains good power for early, constant or delayed effects. We retained the Royston-Parmar model to estimate absolute differences in disease-specific mortality at 5, 10, 15 and 18 years. Conclusions The decision to alter the follow-up analysis for the primary outcome on the basis of new evidence and using new statistical methodology for long-term follow-up is novel and has implications beyond UKCTOCS. There is an urgent need for consensus building on how best to design, test, estimate and report mortality outcomes from long-term randomised cancer screening trials. Trial registration ISRCTN22488978 . Registered on 6 April 2000.

(Abstracted from Lancet 2021;397:2182–2193) Ovarian cancer is most commonly diagnosed at an advanced stage (3 or 4) and remains the deadliest gynecologic malignancy. When diagnosed at stage 1, a survival rate of greater than 90% has been demonstrated, compared with a 5-year survival rate of 27% and 13% for stage 3 and stage 4 disease, respectively.

Objective. There are widespread efforts to increase symptom awareness of 'pelvic/abdominal pain, increased abdominal size/bloating, difficulty eating/feeling full and urinary frequency/urgency' in an attempt to diagnose ovarian cancer earlier. Long-term survival of women with these symptoms adjusted for known prognostic factors is yet to be determined. This study explored the association of symptoms, routes and interval to diagnosis and long-term survival in a population-based cohort of postmenopausal women diagnosed with invasive epithelial tubo-ovarian cancer (iE0C) in the 'no screen' (control) UKCTOCS arm. Methods. Of 101,299 women in the control arm. 574 were confirmed on outcome review to have iE0C between randomisation (2001-2005) and 31 December 2014. Data was extracted from medical notes and electronic records. A multivariable model was fitted for individual symptoms, time interval from symptom onset to diagnosis, route to diagnosis, speciality, morphological Type, age at diagnosis, year of diagnosis (period effect), stage, primary treatment, and residual disease. Results. Women presenting with symptoms listed in the NICE guidelines (HR1.48, 95%CI 1.16-1.89, p = 0.001) or the modified Goff Index (HR1- 68, 95%CI 1.32-2.13, p < 0.0001) had significantly worse survival than those who did not. Each additional presenting symptom decreased survival (HR1.20, 95%CI 1.12-1.28, p < 0.0001). In multivariable analysis, in addition to advanced stage, increasing residual disease and inadequate primary treatment, abdominal pain and loss of appetite/feeling full were significantly associated with increased mortality. Conclusions. The ovarian cancer symptom indices identify postmenopausal women with a poorer prognosis. This study however cannot exclude the possibility of better outcomes in those who are aware and act on their symptoms. (C) 2020 The Authors. Published by Elsevier Inc.

Objective There has been considerable interest in the impact of reproductive factors on health but there are little data on how these have varied over time. We explore trends in reproductive/lifestyle factors of postmenopausal British women by analysing self-reported data from participants of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Design Prospective birth cohort analysis. Setting Population cohort invited between 2001 and 2005 from age-sex registers of 27 Primary Care Trusts in England, Wales and Northern Ireland and recruited through 13 National Health Service Trusts. Participants 202 638 postmenopausal women aged 50–74 years at randomisation to UKCTOCS between April 2001 and October 2005. Interventions Women were stratified into the following six birth cohorts (1925–1929, 1930–1934, 1935–1939, 1940–1944, 1945–1949, 1950–1955) based on year of birth. Self-reported data on reproductive factors provided at recruitment were explored using tabular and graphical summaries to examine for differences between the birth cohorts. Outcome measures Trends in mean age at menarche and menopause, use of oral contraceptives, change in family size, infertility treatments, tubal ligation and hysterectomy rates. Results Women born between 1935 and 1955 made up 86% of the cohort. Median age at menarche decreased from 13.4 for women born between 1925 and 1929 to 12.8 for women born between 1950 and 1955. Increased use of the oral contraceptives, infertility treatments and smaller family size was observed in the younger birth cohorts. Tubal ligation rates increased for those born between 1925 and 1945, but this increase did not persist in subsequent cohorts. Hysterectomy rates (17–20%) did not change over time. Conclusions The trends seen in this large cohort are likely to reflect the reproductive history of the UK female postmenopausal population of similar age. Since these are risk factors for hormone-related cancers, these trends are important in understanding the changing incidence of these cancers. Trial registration number International Standard Randomised Controlled Trial Number: 22488978.

Background: To assess the within-trial cost-effectiveness of an NHS ovarian cancer screening (OCS) programme using data from UKCTOCS and extrapolate results based on average life expectancy. Methods: Within-trial economic evaluation of no screening (C) vs either (1) an annual OCS programme using transvaginal ultrasound (USS) or (2) an annual ovarian cancer multimodal screening programme with serum CA125 interpreted using a risk algorithm (ROCA) and transvaginal ultrasound as a second-line test (MMS), plus comparison of lifetime extrapolation of the no screening arm and the MMS programme using both a predictive and a Markov model. Results: Using a CA125–ROCA cost of £20, the within-trial results show USS to be strictly dominated by MMS, with the MMS vs C comparison returning an incremental cost-effectiveness ratio (ICER) of £91 452 per life year gained (LYG). If the CA125–ROCA unit cost is reduced to £15, the ICER becomes £77 818 per LYG. Predictive extrapolation over the expected lifetime of the UKCTOCS women returns an ICER of £30 033 per LYG, while Markov modelling produces an ICER of £46 922 per QALY. Conclusion: Analysis suggests that, after accounting for the lead time required to establish full mortality benefits, a national OCS programme based on the MMS strategy quickly approaches the current NICE thresholds for cost-effectiveness when extrapolated out to lifetime as compared with the within-trial ICER estimates. Whether MMS could be recommended on economic grounds would depend on the confirmation and size of the mortality benefit at the end of an ongoing follow-up of the UKCTOCS cohort.

Atypical endometrial hyperplasia shows a high propensity to progress to endometrioid adenocarcinoma. Hysteroscopic biopsy represents a valid method for detection of this pre-neoplastic disease. This study assesses the accuracy of histological diagnosis of endometrial atypia in hysteroscopy with blind biopsy, in postmenopausal women with an endometrial thickness (ET) greater than 5 mm. In order, to determine the relationship between ET and atypia more precisely, ET was subdivided in three categories of 5–7 mm, ≥7–9 mm and >9 mm. Ninety-nine postmenopausal patients, aged 51–79 years, with abnormal uterine bleeding and an endometrial thickness >5 mm in whom a diagnosis of endometrial hyperplasia, with or without atypia, was established with hysteroscopy with biopsy, underwent subsequent hysterectomy. Hysteroscopy and biopsy were carried out using a blind endometrial biopsy guided by hysteroscopic findings. The results of biopsies and hysterectomy histology, for the presence of atypia, were compared. Sensitivity and likelihood ratio of hysteroscopic biopsy, as a diagnostic tool for detecting atypia, were calculated. The sensitivity in detecting atypia was 93.3 % corresponding to a negative likelihood ratio equal to 0.06. Univariate analysis did not show a significant association between atypia, age and/or endometrial thickness. The high sensitivity of hysteroscopic biopsy, corresponding to a strong negative likelihood ratio, made it a valid diagnostic tool for detecting atypia in postmenopausal women with abnormal uterine bleeding, hyperplasia and endometrial thickness >5 mm. There was no association between atypia and increase of endometrial thickness from 5 to >9 mm.

Background Ovarian and tubal cancers are lethal gynaecological cancers, with over 50% of the patients diagnosed at advanced stage. Trial design Randomised controlled trial involving 27 primary care trusts adjacent to 13 trial centres based at NHS Trusts in England, Wales and Northern Ireland. Methods Participants Postmenopausal average-risk women, aged 50–74, with intact ovaries and no previous ovarian or current non-ovarian cancer. Interventions One of two annual screening strategies: (1) multimodal screening (MMS) using a longitudinal CA125 algorithm with repeat CA125 testing and transvaginal scan (TVS) as second line test (2) ultrasound screening (USS) using TVS alone with repeat scan to confirm any abnormality. The control (C) group had no screening. Follow-up was through linkage to national registries, postal follow-up questionnaires and direct communication with trial centres and participants. Objective To assess comprehensively risks and benefits of ovarian cancer screening in the general population. Outcome Primary outcome was death due to ovarian or tubal cancer as assigned by an independent outcomes review committee. Secondary outcomes included incidence and stage at diagnosis of ovarian and tubal cancer, compliance, performance characteristics, harms and cost-effectiveness of the two screening strategies and a bioresource for future research. Randomisation The trial management system confirmed eligibility and randomly allocated participants using computer-generated random numbers to MMS, USS and C groups in a 1:1:2 ratio. Blinding Investigators and participants were unblinded and outcomes review committee was masked to randomisation group. Analyses Primary analyses were by intention to screen, comparing separately MMS and USS with C using the Versatile test. Results Recruitment 1,243,282 women were invited and 205,090 attended for recruitment between April 2001 and September 2005. Randomised 202,638 women: 50,640 MMS, 50,639 USS and 101,359 C group. Numbers analysed for primary outcome 202,562 (>99.9%): 50,625 (>99.9%) MMS, 50,623 (>99.9%) USS, and 101,314 (>99.9%) C group. Outcome Women in MMS and USS groups underwent 345,570 and 327,775 annual screens between randomisation and 31 December 2011. At median follow-up of 16.3 (IQR 15.1–17.3) years, 2055 women developed ovarian or tubal cancer: 522 (1.0% of 50,625) MMS, 517 (1.0% of 50,623) USS, and 1016 (1.0% of 101314) in C group. Compared to the C group, in the MMS group, the incidence of Stage I/II disease was 39.2% (95% CI 16.1 to 66.9) higher and stage III/IV 10.2% (95% CI –21.3 to 2.4) lower. There was no difference in stage in the USS group. 1206 women died of the disease: 296 (0.6%) MMS, 291 (0.6%) USS, and 619 (0.6%) C group. There was no significant reduction in ovarian and tubal cancer deaths in either MMS (p = 0.580) or USS (p = 0.360) groups compared to the C group. Overall compliance with annual screening episode was 80.8% (345,570/420,047) in the MMS and 78.0% (327,775/420,047) in the USS group. For ovarian and tubal cancers diagnosed within one year of the last test in a screening episode, in the MMS group, the sensitivity, specificity and positive predictive values were 83.8% (95% CI 78.7 to 88.1), 99.8% (95% CI 99.8 to 99.9), and 28.8% (95% CI 25.5 to 32.2) and in the USS group, 72.2% (95% CI 65.9 to 78.0), 99.5% (95% CI 99.5 to 99.5), and 9.1% (95% CI 7.8 to 10.5) respectively. The final within-trial cost-effectiveness analysis was not undertaken as there was no mortality reduction. A bioresource (UKCTOCS Longitudinal Women’s Cohort) of longitudinal outcome data and over 0.5 million serum samples including serial annual samples in women in the MMS group was established and to date has been used in many new studies, mainly focused on early detection of cancer. Harms Both screening tests (venepuncture and TVS) were associated with minor complications with low (8.6/100,000 screens MMS; 18.6/100,000 screens USS) complication rates. Screening itself did not cause anxiety unless more intense repeat testing was required following abnormal screens. In the MMS group, for each screen-detected ovarian or tubal cancer, an additional 2.3 (489 false positives; 212 cancers) women in the MMS group had unnecessary false-positive (benign adnexal pathology or normal adnexa) surgery. Overall, 14 (489/345,572 annual screens) underwent unnecessary surgery per 10,000 screens. In the USS group, for each screen-detected ovarian or tubal cancer, an additional 10 (1630 false positives; 164 cancers) underwent unnecessary false-positive surgery. Overall, 50 (1630/327,775 annual screens) women underwent unnecessary surgery per 10,000 screens. Conclusions Population screening for ovarian and tubal cancer for average-risk women using these strategies should not be undertaken. Decreased incidence of Stage III/IV cancers during multimodal screening did not translate to mortality reduction. Researchers should be cautious about using early stage as a surrogate outcome in screening trials. Meanwhile the bioresource provides a unique opportunity to evaluate early cancer detection tests. Funding Long-term follow-up UKCTOCS (2015–2020) – National Institute for Health and Care Research (NIHR HTA grant 16/46/01), Cancer Research UK, and The Eve Appeal. UKCTOCS (2001–2014) – Medical Research Council (MRC) (G9901012/G0801228), Cancer Research UK (C1479/A2884), and the UK Department of Health, with additional support from The Eve Appeal. Researchers at UCL were supported by the NIHR UCL Hospitals Biomedical Research Centre and by MRC Clinical Trials Unit at UCL core funding (MR_UU_12023).

Background: Adenomyosis is defined as aberrant endometrial glands and stroma in the myometrium.It is a benign gynecologic disorder that occurs in late reproductive years.Malignant transformation of Adenomyosis is rare with only 51 cases reported in International literature.Case Description: A case of a 46 year-old, nullipara, complaining of progressive severe dysmenorrhea without abnormal uterine bleeding is hereby presented.She has a strong family history of cancer (sister with ovarian carcinoma and mother with liver cancer).The patient underwent Total Hysterectomy with Bilateral Salpingooophorectomy for a preoperative diagnosis of Adenomyosis.A bulging area on the posterior wall measuring 3 x 2 cm was noted exhibiting multicystic to slit-like lesions filled with blood clots on cut section.The endometrial stripe measured 0.1 cm.Histopathologic results showed Adenocarcinoma, moderately differentiated, arising from Adenomyosis with microscopic seeding on the serosa of the left fallopian tube and right mesovarium ligament.The focus of Adenocarcinoma was noted 10 mm from the base of the endometrium.The active endometrium is intact, tumor-free and in the proliferative phase, no focus of carcinoma was found. Conclusion:The exact pathogenesis of carcinoma arising from adenomyosis is unknown but theories on the histogenesis of Adenomyosis may explain its malignant transformation.There is no established treatment protocol for managing such disease.We advised the patient adjuvant therapy with Paclitaxel and Carboplatin.

Purpose Cancer screening strategies have commonly adopted single-biomarker thresholds to identify abnormality. We investigated the impact of serial biomarker change interpreted through a risk algorithm on cancer detection rates. Patients and Methods In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 46,237 women, age 50 years or older underwent incidence screening by using the multimodal strategy (MMS) in which annual serum cancer antigen 125 (CA-125) was interpreted with the risk of ovarian cancer algorithm (ROCA). Women were triaged by the ROCA: normal risk, returned to annual screening; intermediate risk, repeat CA-125; and elevated risk, repeat CA-125 and transvaginal ultrasound. Women with persistently increased risk were clinically evaluated. All participants were followed through national cancer and/or death registries. Performance characteristics of a single-threshold rule and the ROCA were compared by using receiver operating characteristic curves. Results After 296,911 women-years of annual incidence screening, 640 women underwent surgery. Of those, 133 had primary invasive epithelial ovarian or tubal cancers (iEOCs). In all, 22 interval iEOCs occurred within 1 year of screening, of which one was detected by ROCA but was managed conservatively after clinical assessment. The sensitivity and specificity of MMS for detection of iEOCs were 85.8% (95% CI, 79.3% to 90.9%) and 99.8% (95% CI, 99.8% to 99.8%), respectively, with 4.8 surgeries per iEOC. ROCA alone detected 87.1% (135 of 155) of the iEOCs. Using fixed CA-125 cutoffs at the last annual screen of more than 35, more than 30, and more than 22 U/mL would have identified 41.3% (64 of 155), 48.4% (75 of 155), and 66.5% (103 of 155), respectively. The area under the curve for ROCA (0.915) was significantly (P = .0027) higher than that for a single-threshold rule (0.869). Conclusion Screening by using ROCA doubled the number of screen-detected iEOCs compared with a fixed cutoff. In the context of cancer screening, reliance on predefined single-threshold rules may result in biomarkers of value being discarded.

Background. Robotic surgery in gynaecological oncology is a rapidly developing field as it offers several technical advantages over conventional laparoscopy. An audit was performed on the outcome of robotic surgery during our learning curve and compared with recent well-established laparoscopic procedure data. Method. Following acquisition of the da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, California, USA), we prospectively analysed all cases performed over the first six months by one experienced gynaecologist who had been appropriately trained and mentored. Data on age, BMI, pathology, surgery type, blood loss, morbidity, return to theatre, hospital stay, and readmission rate were collected and compared with a consecutive series over the preceding 6 months performed laparoscopically by the same team. Results. A comparison of two consecutive series was made. The mean age was somewhat different, 55 years in the robotic versus 69 years in the laparoscopic group, but obesity was a feature of both groups with a mean of BMI 29.3 versus 28.06, respectively. This difference was not statistically significant (P = 0.54). Three subgroups of minimal access surgical procedures were performed: total hysterectomy and bilateral salpingooophorectomy (TH + BSO), total hysterectomy and bilateral salpingooophorectomy plus bilateral pelvic lymphadenectomy (TH + BSO + BPLND), and radical hysterectomy plus bilateral pelvic lymphadenectomy (RH + BPLND). The mean time taken to perform surgery for TH + BSO was longer in the robotic group, 151.2 min compared to 126.3 min in the laparoscopic group. TH + BSO + BPLND surgical time was similar to 178.3 min in robotic group and 176.5 min in laparoscopic group. RH + BPLND surgical time was similar, 263.6 min (robotic arm) and 264.0 min (laparoscopic arm). However, the numbers in this initial analysis were small especially in the last two subgroups and do not allow for statistical analysis. The rate of complications necessitating intervention (Clavien-Dindo classification grade 2/3) was higher in the robotic arm(22.7%) compared to the laparoscopic approach (4.5%). The readmission rate was higher in the robotic group (18.2%) compared to the laparoscopic group (4.5%). The return to theatre in the robotic group was 18.2% and 4.5% in laparoscopic group. Uncomplicated robotic surgery hospital stay appeared to be shorter, 1.3 days compared to the uncomplicated laparoscopic group, 2.5 days. There was no conversion to the open procedure in either arm. Estimated blood loss in all cases was less than 100 mL in both groups. Conclusion. Robotic surgery is comparable to laparoscopic surgery in blood loss; however, the hospital stay in uncomplicated cases appears to be longer in the laparoscopic arm. Surgical robotic time is equivalent to laparoscopic in complex cases but may be longer in cases not requiring lymph node dissection. The robotic surgery team learning curve may be associated with higher rate of morbidity. Further research on the benefits to the surgeon is needed to clarify the whole picture of this versatile novel surgical approach.

Background The increase in the worldwide incidence of endometrial cancer relates to rising obesity, falling fertility, and the ageing of the population. Transvaginal ultrasound (TVS) is a possible screening test, but there have been no large-scale studies. We report the performance of TVS screening in a large cohort.Methods We did a nested case-control study of postmenopausal women who underwent TVS in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) following recruitment between April 17, 2001, and Sept 29, 2005. Endometrial thickness and endometrial abnormalities were recorded, and follow-up, through national registries and a postal questionnaire, documented the diagnosis of endometrial cancer. Our primary outcome measure was endometrial cancer and atypical endometrial hyperplasia (AEH). Performance characteristics of endometrial thickness and abnormalities for detection of endometrial cancer within 1 year of TVS were calculated. Epidemiological variables were used to develop a logistic regression model and assess a screening strategy for women at higher risk. Our study is registered with ClinicalTrials.gov, number NCT00058032, and with the International Standard Randomised Controlled Trial register, number ISRCTN22488978.Findings 48 230 women underwent TVS in the UKCTOCS prevalence screen. 9078 women were ineligible because they had undergone a hysterectomy and 2271 because their endometrial thickness had not been recorded; however, 157 of these women had an endometrial abnormality on TVS and were included in the analysis. Median follow-up was 5.11 years (IQR 4.05-5.95). 136 women with endometrial cancer or AEH within 1 year of TVS were included in our primary analysis. The optimum endometrial thickness cutoff for endometrial cancer or AEH was 5.15 mm, with sensitivity of 80.5% (95% CI 72.7-86.8) and specificity of 86.2% (85.8-86.6). Sensitivity and specificity at a 5 mm or greater cutoff were 80.5% (72.7-86.8) and 85.7% (85.4-86.2); for women with a 5 mm or greater cutoff plus endometrial abnormalities, the sensitivity and specificity were 85.3% (78.2-90.8) and 80.4% (80.0-80.8), respectively. For a cutoff of 10 mm or greater, sensitivity and specificity were 54.1% (45.3-62.8) and 97.2% (97.0-97.4). When our analysis was restricted to the 96 women with endometrial cancer or AEH who reported no symptoms of postmenopausal bleeding at the UKCTOCS scan before diagnosis and had an endometrial thickness measurement available, a cutoff of 5 mm achieved a sensitivity of 77.1% (67.8-84.3) and specificity of 85.8% (85.7-85.9). The logistic regression model identified 25% of the population as at high risk and 39.5% of endometrial cancer or AEH cases were identified within this high risk group. In this high-risk population, a cutoff at 6.75 mm achieved sensitivity of 84.3% (71.4-93.0) and specificity of 89.9% (89.3-90.5).Interpretation Our findings show that TVS screening for endometrial cancer has good sensitivity in postmenopausal women. The burden of diagnostic procedures and false-positive results can be reduced by limiting screening to a higher-risk group. The role of population screening for endometrial cancer remains uncertain, but our findings are of immediate value in the management of increased endometrial thickness in postmenopausal women undergoing pelvic scans for reasons other than vaginal bleeding.

Background Participants in trials evaluating preventive interventions such as screening are on average healthier than the general population. To decrease this 'healthy volunteer effect' (HVE) women were randomly invited from population registers to participate in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and not allowed to self refer. This report assesses the extent of the HVE still prevalent in UKCTOCS and considers how certain shortfalls in mortality and incidence can be related to differences in socioeconomic status. Methods Between 2001 and 2005, 202 638 postmenopausal women joined the trial out of 1 243 312 women randomly invited from local health authority registers. The cohort was flagged for deaths and cancer registrations and mean follow up at censoring was 5.55 years for mortality, and 2.58 years for cancer incidence. Overall and cause-specific Standardised Mortality Ratios (SMRs) and Standardised Incidence Ratios (SIRs) were calculated based on national mortality (2005) and cancer incidence (2006) statistics. The Index of Multiple Deprivation (IMD 2007) was used to assess the link between socioeconomic status and mortality/cancer incidence, and differences between the invited and recruited populations. Results The SMR for all trial participants was 37%. By subgroup, the SMRs were higher for: younger age groups, extremes of BMI distribution and with each increasing year in trial. There was a clear trend between lower socioeconomic status and increased mortality but less pronounced with incidence. While the invited population had higher mean IMD scores (more deprived) than the national average, those who joined the trial were less deprived. Conclusions Recruitment to screening trials through invitation from population registers does not prevent a pronounced HVE on mortality. The impact on cancer incidence is much smaller. Similar shortfalls can be expected in other screening RCTs and it maybe prudent to use the various mortality and incidence rates presented as guides for calculating event rates and power in RCTs involving women. Trial Registration This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978 . Medical Research Council (grant no. G990102), Cancer Research UK (grant no. C1479/A2884) and Department of Health