Title: Long term impact of screening on ovarian cancer mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)
Funder: Department of Health and Social Care

Abstract: Ovarian cancer continues to kill more women than any other gynaecological cancer. A key reason is diagnosis at advanced stage. The 30% diagnosed in Stage I have 5-year survival rates of 90%. This has led to sustained efforts to improve early detection. A key part of the latter has been UKCTOCS, the largest randomised controlled trial of ovarian cancer screening. UKCTOCS is one of the world’s largest multicentre randomised controlled trials and has involved 202,638 women from the general population, 673,765 annual screens and 2.2 million women-years of follow-up. At censorship on 31st December 2014, in women with invasive epithelial ovarian/tubal/peritoneal cancers, a significant stage shift was noted in the multimodal screening (MMS) arm compared to no screening control (C) arm but not in the ultrasound screening (USS) arm. Compared to the C arm, the reduction in OC deaths was not conventionally significant with ‘average’ estimated relative mortality reductions of 15% (p=0.10) MMS and 11% (p=0.21) USS on the primary Cox analysis. But it was significant (p=0.021) in the MMS versus C pre-specified analysis excluding prevalent cases and in a single post-hoc weighted log rank analysis (p=0.023). As noted in other screening trials, the mortality reduction was delayed and only apparent after about 7 years. The issue is that with the current length of follow-up, 45% (157/347) of OC deaths in the C arm occur before 7 years where there is no evidence of a difference. Long term follow-up till 2018 would result in approximately 73% (420/547) of estimated OC deaths in the C arm occurring after 7 years. This would allow us to assess whether the observed stage shift in the MMS arm translates into a difference in mortality. In support of this possibility, we note that at censorship, the C group OC mortality rate continuing to rise linearly, whereas the rates in MMS and USS groups appear to be plateauing. We propose to continue follow-up of the participants to 31st Dec 2018 to determine whether ovarian cancer screening (1) improves disease-specific mortality and (2) is cost effective. In addition we will (3) undertake further more detailed analysis of the data to improve our understanding of ovarian cancer diagnosis, treatment and management and the cost-effectiveness of screening. The primary outcome for the mortality and cost-effectiveness analysis will continue to be ovarian cancer death. Ovarian cancer will be defined by WHO 2014 criteria and include malignant neoplasms of the ovary, fallopian tube and undesignated malignancies of the ovaries/tube/peritoneum. Cases previously designated as primary peritoneal cancer by WHO 2003 criteria are likely to be reclassified as ovarian or tubal cancers. The primary analysis will continue to be a modified intention-to-screen comparison using the Cox proportional hazards model of MMS versus C and USS versus C separately. Additional analysis will include fitting Royston-Parmar models for a delayed effect and estimating the long term screening effect by excluding prevalent cases. A cost-effectiveness analysis will involve both within trial analysis and modelling of screening in the NHS screening over a longer timeframe using the primary mortality endpoint. We will also undertake data analysis to explore in this unbiased population cohort OC management in the UK, trends with time, novel epidemiological risk factors and symptoms/routes to diagnosis (in the C arm). In addition to publication in scientific journals, our final results will be disseminated through UKCTOCS website, sponsor/funder websites, media and via ovarian cancer charities.

Lay abstract: Ovarian cancer is the leading cause of death from gynaecological cancers in the UK. This is related to diagnosis at advanced stage. When women are diagnosed earlier, they have a much better survival – over 90% of Stage I patients are alive five years after diagnosis compared to 4% of Stage IV patients. This suggests that screening may help save lives by detecting the disease earlier. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) was designed to test this hypothesis. Between April 2001-Sept 2005, 202,638 postmenopausal women, aged 50-74 years were recruited through 13 trial centres in England, Wales and Northern Ireland. Women were randomly allocated to one of three groups:- (i) control (C) - no screening (ii) multimodal screening (MMS) - annual blood test for serum CA125 measurement. The results were interpreted using the ‘Risk of Ovarian Cancer Algorithm’, with transvaginal ultrasound as a second line test in case of abnormality (iii) ultrasound screening (USS) - annual and second line tests were transvaginal scans. Women in the screen arms underwent a total of 673,765 annual screens till 31st December 2011. On 31st Dec 2014 at a median follow-up of 11.1 years per woman the initial mortality analysis was undertaken. Compared to the control group there was significant increase in proportion of women diagnosed with early stage ovarian cancer in the multimodal but not in the ultrasound group. The average reduction in ovarian cancer deaths was 15% in multimodal group and 11% in ultrasound group compared to control but this was not definitive. The final extent of reduction remains to be determined as the ovarian cancer death rates were increasing in the control group and levelling off in the multimodal and ultrasound groups. Women are linked via their individual NHS numbers to national cancer and death registries in England, Wales and Northern Ireland as well as administrative databases such as Hospital Episode Statistics and National Cancer Intelligence Network. Records of women identified as having a possible ovarian cancer based on a specified list of disease codes will be retrieved and reviewed by an independent outcomes committee who will confirm final outcome. Data from other national databases such as Hospital Episodes statistics will be used to calculate the cost of screening. Follow-up will continue till 31st Dec 2018 when a second mortality and cost effectiveness analysis will be undertaken.

Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS