Why Did Downstaging in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) Not Result in a Mortality Benefit: Exploratory Analysis of a Randomised Controlled Trial

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.