Randomized Controlled Trial

.2016 Mar 5;387(10022):945-956.

doi: 10.1016/S0140-6736(15)01224-6. Epub 2015 Dec 17.

Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial

Ian J Jacobs¹, Usha Menon², Andy Ryan³, Aleksandra Gentry-Maharaj³, Matthew Burnell³, Jatinderpal K Kalsi³, Nazar N Amso⁴, Sophia Apostolidou³, Elizabeth Benjamin⁵, Derek Cruickshank⁶, Danielle N Crump³, Susan K Davies³, Anne Dawnay⁷, Stephen Dobbs⁸, Gwendolen Fletcher³, Jeremy Ford⁹, Keith Godfrey¹⁰, Richard Gunu³, Mariam Habib¹¹, Rachel Hallett¹², Jonathan Herod¹³, Howard Jenkins¹⁴, Chloe Karpinskyj³, Simon Leeson¹⁵, Sara J Lewis³, William R Liston³, Alberto Lopes¹⁶, Tim Mould¹⁷, John Murdoch¹⁸, David Oram¹⁹, Dustin J Rabideau²⁰, Karina Reynolds¹⁹, Ian Scott¹⁴, Mourad W Seif²¹, Aarti Sharma²², Naveena Singh²³, Julie Taylor³, Fiona Warburton²⁴, Martin Widschwendter³, Karin Williamson²⁵, Robert Woolas²⁶, Lesley Fallowfield²⁷, Alistair J McGuire²⁸, Stuart Campbell²⁹, Mahesh Parmar³⁰, Steven J Skates³¹

Affiliations

¹ 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.
² Department of Women's Cancer, Institute for Women's Health, University College London, London, UK. Electronic address: u.menon@ucl.ac.uk.
³ Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
⁴ Obstetrics and Gynaecology, School of Medicine, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK.
⁵ Research Department of Pathology, Cancer Institute, University College London Hospital, London, UK.
⁶ Department of Gynaecological Oncology, James Cook University Hospital, Middlesbrough, UK.
⁷ Clinical Biochemistry, University College London Hospital, London, UK.
⁸ Department of Gynaecological Oncology, Belfast City Hospital, Belfast, UK.
⁹ 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.
¹⁰ Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Gateshead, Tyne and Wear, UK.
¹¹ 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.
¹² Department of Women's Cancer, Institute for Women's Health, University College London, London, UK; School of Medical Sciences, Bangor University, Bangor, Gwynedd, UK.
¹³ Department of Gynaecology, Liverpool Women's Hospital, Liverpool, UK; Women's Hospital, Hamad Medical Corporation, Doha, Qatar.
¹⁴ Department of Gynaecological Oncology, Royal Derby Hospital, Derby, UK.
¹⁵ Department of Gynaecological Oncology, Llandudno Hospital, Gwynedd, UK.
¹⁶ Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Gateshead, Tyne and Wear, UK; Derriford Hospital, Plymouth, Devon, UK.
¹⁷ Department of Gynaecological Oncology, University College London Hospital, London, UK; Department of Gynaecological Oncology, Royal Free Hospital, London.
¹⁸ Department of Gynaecological Oncology, St Michael's Hospital, Bristol, UK.
¹⁹ Department of Gynaecological Oncology, St Bartholomew's Hospital, London, UK.
²⁰ Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA.
²¹ Central Manchester Foundation Trust, St Mary's Hospital, Manchester, UK; Institute of Cancer Sciences, University of Manchester, Manchester, UK.
²² 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.
²³ Department of Pathology, Barts Health National Health Service Trust, London, UK.
²⁴ Department of Women's Cancer, Institute for Women's Health, University College London, London, UK; Public Health England, London, UK.
²⁵ Department of Gynaecological Oncology, Nottingham City Hospital, Nottingham, UK.
²⁶ 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.
²⁷ Sussex Health Outcomes Research and Education in Cancer, Brighton and Sussex Medical School, University of Sussex, Sussex, UK.
²⁸ Department of Social Policy, London School of Economics, London, UK.
²⁹ Create Health Clinic, London, UK.
³⁰ Medical Research Council Clinical Trials Unit at University College London, London, UK.
³¹ Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.

PMID:26707054
PMCID: PMC4779792
DOI: 10.1016/S0140-6736(15)01224-6

Randomized Controlled Trial

Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial

Ian J Jacobs et al. Lancet.2016.

.2016 Mar 5;387(10022):945-956.

doi: 10.1016/S0140-6736(15)01224-6. Epub 2015 Dec 17.

Authors

Affiliations

¹ 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.
² Department of Women's Cancer, Institute for Women's Health, University College London, London, UK. Electronic address: u.menon@ucl.ac.uk.
³ Department of Women's Cancer, Institute for Women's Health, University College London, London, UK.
⁴ Obstetrics and Gynaecology, School of Medicine, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK.
⁵ Research Department of Pathology, Cancer Institute, University College London Hospital, London, UK.
⁶ Department of Gynaecological Oncology, James Cook University Hospital, Middlesbrough, UK.
⁷ Clinical Biochemistry, University College London Hospital, London, UK.
⁸ Department of Gynaecological Oncology, Belfast City Hospital, Belfast, UK.
⁹ 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.
¹⁰ Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Gateshead, Tyne and Wear, UK.
¹¹ 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.
¹² Department of Women's Cancer, Institute for Women's Health, University College London, London, UK; School of Medical Sciences, Bangor University, Bangor, Gwynedd, UK.
¹³ Department of Gynaecology, Liverpool Women's Hospital, Liverpool, UK; Women's Hospital, Hamad Medical Corporation, Doha, Qatar.
¹⁴ Department of Gynaecological Oncology, Royal Derby Hospital, Derby, UK.
¹⁵ Department of Gynaecological Oncology, Llandudno Hospital, Gwynedd, UK.
¹⁶ Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Gateshead, Tyne and Wear, UK; Derriford Hospital, Plymouth, Devon, UK.
¹⁷ Department of Gynaecological Oncology, University College London Hospital, London, UK; Department of Gynaecological Oncology, Royal Free Hospital, London.
¹⁸ Department of Gynaecological Oncology, St Michael's Hospital, Bristol, UK.
¹⁹ Department of Gynaecological Oncology, St Bartholomew's Hospital, London, UK.
²⁰ Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA.
²¹ Central Manchester Foundation Trust, St Mary's Hospital, Manchester, UK; Institute of Cancer Sciences, University of Manchester, Manchester, UK.
²² 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.
²³ Department of Pathology, Barts Health National Health Service Trust, London, UK.
²⁴ Department of Women's Cancer, Institute for Women's Health, University College London, London, UK; Public Health England, London, UK.
²⁵ Department of Gynaecological Oncology, Nottingham City Hospital, Nottingham, UK.
²⁶ 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.
²⁷ Sussex Health Outcomes Research and Education in Cancer, Brighton and Sussex Medical School, University of Sussex, Sussex, UK.
²⁸ Department of Social Policy, London School of Economics, London, UK.
²⁹ Create Health Clinic, London, UK.
³⁰ Medical Research Council Clinical Trials Unit at University College London, London, UK.
³¹ Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.

PMID:26707054
PMCID: PMC4779792
DOI: 10.1016/S0140-6736(15)01224-6

Erratum in

Lancet. 2016 Mar 5;387(10022):944
Department of Error.
[No authors listed][No authors listed]Lancet. 2016 Mar 5;387(10022):944. doi: 10.1016/S0140-6736(16)00228-2. Epub 2016 Jan 30.Lancet. 2016.PMID:28832000Free PMC article.No abstract available.

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, numberNCT00058032.

Findings: 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.

Interpretation: 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.

Funding: Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal.

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Figures

**Figure 1**
Trial profile MMS=multimodal screening. USS=ultrasound screening. *Events occurred before recruitment, but discovered after randomisation.

**Figure 2**
(A) Cumulative ovarian cancer and (B) ovarian and peritoneal cancer deaths The Royston-Parmar model is shown in the appendix (p 12, 13). HR=hazard ratio. MMS=multimodal screening. USS=ultrasound screening.

**Figure 3**
Rates of ovarian cancer The figure including confidence limits is in the appendix (p 14). MMS=multimodal screening. USS=ultrasound screening.

**Figure 4**
(A) Cumulative ovarian cancer and (B) ovarian and peritoneal deaths in MMS and no screening groups after exclusion of prevalent cases HRs and mortality reductions for 0–7 years and 7–14 years calculated from the Royston-Parmar model. Cumulative mortality curves from the Royston-Parmar model are overlaid onto Kaplan-Meier curves. HR=hazard ratio. MMS=multimodal screening.

See this image and copyright information in PMC

Comment in

Whether screening for ovarian cancer saves lives is still unclear despite large trial.
Kmietowicz Z.Kmietowicz Z.BMJ. 2015 Dec 18;351:h6876. doi: 10.1136/bmj.h6876.BMJ. 2015.PMID:26684480No abstract available.
Screening to improve ovarian cancer prognosis?
Verheijen RHM, Zweemer RP.Verheijen RHM, et al.Lancet. 2016 Mar 5;387(10022):921-923. doi: 10.1016/S0140-6736(15)01236-2. Epub 2015 Dec 17.Lancet. 2016.PMID:26707055No abstract available.
Ovarian cancer: Multimodal screening - keeping mortality at bay?
Hutchinson L.Hutchinson L.Nat Rev Clin Oncol. 2016 Mar;13(3):133. doi: 10.1038/nrclinonc.2016.10. Epub 2016 Jan 27.Nat Rev Clin Oncol. 2016.PMID:26813936No abstract available.
Ovarian Cancer Screening There May Be Light at the End of the Tunnel?
Manchanda R, Cibula D.Manchanda R, et al.Int J Gynecol Cancer. 2016 May;26(4):608-9. doi: 10.1097/IGC.0000000000000706.Int J Gynecol Cancer. 2016.PMID:27101522No abstract available.
Two large randomised trials show ovarian cancer screening has minimal impact on survival.
Johnson N.Johnson N.BJOG. 2018 Apr;125(5):524-525. doi: 10.1111/1471-0528.14052. Epub 2016 May 13.BJOG. 2018.PMID:27173436No abstract available.
Ovarian cancer screening: UKCTOCS trial.
Thornton JG, Bewley S.Thornton JG, et al.Lancet. 2016 Jun 25;387(10038):2601-2602. doi: 10.1016/S0140-6736(16)30846-7.Lancet. 2016.PMID:27353818No abstract available.
Ovarian cancer screening: UKCTOCS trial.
Sasieni PD, Duffy SW, Cuzick J.Sasieni PD, et al.Lancet. 2016 Jun 25;387(10038):2602. doi: 10.1016/S0140-6736(16)30847-9.Lancet. 2016.PMID:27353820No abstract available.
Ovarian cancer screening: UKCTOCS trial.
Hoskins P, Gotlieb W.Hoskins P, et al.Lancet. 2016 Jun 25;387(10038):2602-2603. doi: 10.1016/S0140-6736(16)30848-0.Lancet. 2016.PMID:27353821No abstract available.
Ovarian cancer screening: UKCTOCS trial - Authors' reply.
Jacobs IJ, Parmar M, Skates SJ, Menon U.Jacobs IJ, et al.Lancet. 2016 Jun 25;387(10038):2603-2604. doi: 10.1016/S0140-6736(16)30849-2.Lancet. 2016.PMID:27353822No abstract available.
Large ovarian cancer screening trial shows modest mortality reduction, but does not justify population-based ovarian cancer screening.
Wentzensen N.Wentzensen N.Evid Based Med. 2016 Aug;21(4):159. doi: 10.1136/ebmed-2016-110411. Epub 2016 Jul 22.Evid Based Med. 2016.PMID:27450366No abstract available.
Ovarian cancer screening effectiveness: A realization from the UK Collaborative Trial of Ovarian Cancer Screening.
Pavlik EJ.Pavlik EJ.Womens Health (Lond). 2016 Sep;12(5):475-479. doi: 10.1177/1745505716666096. Epub 2016 Sep 5.Womens Health (Lond). 2016.PMID:27595999Free PMC article.

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References

1. Cancer Research UK. Ovarian cancer survival statistics. One-, five- and ten-year survival for ovarian cancer.http://www.cancerresearchuk.org/health-professional/cancer-statistics/st... (accessed Nov 3, 2015)
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Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial

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Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial

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