title: Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial.
abstract: BACKGROUND
  Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality.
  
  
  METHODS
  In this randomised controlled trial, we recruited postmenopausal women aged 50-74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032.
  
  
  RESULTS
  Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202,638 women: 50,640 (25·0%) to MMS, 50,639 (25·0%) to USS, and 101,359 (50·0%) to no screening. 202,546 (>99·9%) women were eligible for analysis: 50,624 (>99·9%) women in the MMS group, 50,623 (>99·9%) in the USS group, and 101,299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345,570 MMS and 327,775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0-12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0-14 of 15% (95% CI -3 to 30; p=0·10) with MMS and 11% (-7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (-20 to 31) in years 0-7 and 23% (1-46) in years 7-14, and in the USS group, of 2% (-27 to 26) in years 0-7 and 21% (-2 to 42) in years 7-14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (-2 to 40) and a reduction of 8% (-27 to 43) in years 0-7 and 28% (-3 to 49) in years 7-14 in favour of MMS.
  
  
  CONCLUSIONS
  Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7-14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening.
  
  
  BACKGROUND
  Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal.
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK; University of New South Wales, Sydney, NSW, Australia; Centre for Women's Health, Institute of Human Development, University of Manchester, Manchester, UK. Electronic address: i.jacobs@unsw.edu.au.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Jacobs
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK. Electronic address: u.menon@ucl.ac.uk.
authors.forename: Usha
authors.initials: U
authors.lastname: Menon
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
authors.forename: Andy
authors.initials: A
authors.lastname: Ryan
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
authors.forename: Aleksandra
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authors.lastname: Gentry-Maharaj
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
authors.forename: Matthew
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authors.lastname: Burnell
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
authors.forename: Jatinderpal K
authors.initials: JK
authors.lastname: Kalsi
authors.affiliation: Obstetrics and Gynaecology, School of Medicine, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK.
authors.forename: Nazar N
authors.initials: NN
authors.lastname: Amso
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
authors.forename: Sophia
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authors.lastname: Apostolidou
authors.affiliation: Research Department of Pathology, Cancer Institute, University College London Hospital, London, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Benjamin
authors.affiliation: Department of Gynaecological Oncology, James Cook University Hospital, Middlesbrough, UK.
authors.forename: Derek
authors.initials: D
authors.lastname: Cruickshank
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
authors.forename: Danielle N
authors.initials: DN
authors.lastname: Crump
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Davies
authors.affiliation: Clinical Biochemistry, University College London Hospital, London, UK.
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authors.lastname: Dawnay
authors.affiliation: Department of Gynaecological Oncology, Belfast City Hospital, Belfast, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Dobbs
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
authors.forename: Gwendolen
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authors.lastname: Fletcher
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK; Malomatia (Information, Communication and Technology QATAR) Qatari Shareholding Company, Qatar.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Ford
authors.affiliation: Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Gateshead, Tyne and Wear, UK.
authors.forename: Keith
authors.initials: K
authors.lastname: Godfrey
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Gunu
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK; Medical Research Council Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Mariam
authors.initials: M
authors.lastname: Habib
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK; School of Medical Sciences, Bangor University, Bangor, Gwynedd, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Hallett
authors.affiliation: Department of Gynaecology, Liverpool Women's Hospital, Liverpool, UK; Women's Hospital, Hamad Medical Corporation, Doha, Qatar.
authors.forename: Jonathan
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authors.lastname: Herod
authors.affiliation: Department of Gynaecological Oncology, Royal Derby Hospital, Derby, UK.
authors.forename: Howard
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authors.lastname: Jenkins
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
authors.forename: Chloe
authors.initials: C
authors.lastname: Karpinskyj
authors.affiliation: Department of Gynaecological Oncology, Llandudno Hospital, Gwynedd, UK.
authors.forename: Simon
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authors.lastname: Leeson
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Lewis
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
authors.forename: William R
authors.initials: WR
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authors.affiliation: Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Gateshead, Tyne and Wear, UK; Derriford Hospital, Plymouth, Devon, UK.
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authors.affiliation: Department of Gynaecological Oncology, University College London Hospital, London, UK; Department of Gynaecological Oncology, Royal Free Hospital, London.
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authors.affiliation: Department of Gynaecological Oncology, St Michael's Hospital, Bristol, UK.
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authors.affiliation: Department of Gynaecological Oncology, St Bartholomew's Hospital, London, UK.
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authors.affiliation: Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA.
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authors.affiliation: Department of Gynaecological Oncology, St Bartholomew's Hospital, London, UK.
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authors.affiliation: Department of Gynaecological Oncology, Royal Derby Hospital, Derby, UK.
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authors.affiliation: Central Manchester Foundation Trust, St Mary's Hospital, Manchester, UK; Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors.forename: Mourad W
authors.initials: MW
authors.lastname: Seif
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK; Department of Gynaecological Oncology, University Hospital of Wales, Heath Park, Cardiff, UK.
authors.forename: Aarti
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Pathology, Barts Health National Health Service Trust, London, UK.
authors.forename: Naveena
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authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
authors.forename: Julie
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authors.lastname: Taylor
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK; Public Health England, London, UK.
authors.forename: Fiona
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authors.lastname: Warburton
authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
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authors.affiliation: Department of Gynaecological Oncology, Nottingham City Hospital, Nottingham, UK.
authors.forename: Karin
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authors.affiliation: Department of Women's Cancer, Institute for Women's Health, University College London, London, UK; Department of Gynaecological Oncology, Queen Alexandra Hospital, Portsmouth, Hampshire, UK.
authors.forename: Robert
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authors.affiliation: Sussex Health Outcomes Research and Education in Cancer, Brighton and Sussex Medical School, University of Sussex, Sussex, UK.
authors.forename: Lesley
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authors.affiliation: Department of Social Policy, London School of Economics, London, UK.
authors.forename: Alistair J
authors.initials: AJ
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authors.affiliation: Create Health Clinic, London, UK.
authors.forename: Stuart
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authors.lastname: Campbell
authors.affiliation: Medical Research Council Clinical Trials Unit at University College London, London, UK.
authors.forename: Mahesh
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authors.affiliation: Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
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mesh_terms: D000368:Aged; D000465:Algorithms; D018394:CA-125 Antigen / Q000097:blood; D055088:Early Detection of Cancer; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000097:blood; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000401:mortality*; D016016:Proportional Hazards Models; D006113:United Kingdom
chemical_list: D018394:CA-125 Antigen; C451759:MUC16 protein, human; D008565:Membrane Proteins