Two large randomised trials show ovarian cancer screening has minimal impact on survival

The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) represents a magnificent achievement. It was a 30-year project costing close to £50 million. A fifth of a million women freely refrained from ovarian cancer screening or had regular intrusive investigations according to random allocation, so that we could know how effective the screening was. The organisation and reporting of this randomised trial was to the highest standard, and is testament to the advancement of medical science. The media reported that ovarian cancer screening may reduce death by a fifth (www.bbc.co.uk/news/health-35111 443; http://www.abc.net.au/news/2015-12-18/screening-maycut-ovarian-cancer-deaths-study-finds/7039738). The paradox is that the data tell a conflicting story that is even more profound than the headline. The subgroup responsible for the headline only concerns the biologically unlikely impact of benefit exclusively limited to women after 7 years of screening. These data are affected by the exclusion of more deaths attributed to peritoneal cancer in the screening arm and the exclusion of screening-detected cancers at entry to the trial. These selected data are then supported with a post-hoc weighted proportional statistical test (the provocative slang for this is a fiddle factor) outside the protocol. The quoted headline probability value also lacks the appropriate statistical corrections for multiple tests. It is also curious that the benefit seems to be most impressive when the ultrasound was delayed by waiting for the CA125 trend. It is a credit to the authors that they present all of this and also provide data that allow for interpretation beyond the media headline. The raw data are not complete because uterine cancer deaths have not been given, but it seems that survival from Mullerian adenocarcinoma is similar whether you are or are not screened. Survival is similar if you have an ultrasound each year or a CA125 test each year, with the proviso that an ultrasound is initiated according to the Risk of Ovarian Cancer Algorithm (ROCA) (http:// www.therocatest.co.uk/). The crucial data are that screening was associated with 35 fewer deaths from ovarian, fallopian tube, and peritoneal cancer at the time of censorship, and the survival curves begin to separate after about 10 years. The trial headline figure is actually 45 more survivors with screening, but this is restricted to the label of ovarian cancer. The selective use of this data is unhelpful because there were double (ten more) deaths from peritoneal cancer in the groups who were screened (n = 11 versus 21). A diagnosis shift seems more plausible than a phenomenon where screening doubles the number of deaths from peritoneal cancer. It seems immaterial if death is attributed to peritoneal or ovarian cancer, so the mortality difference from both cancers is 35. A difference of 35/101 000 suggests an absolute risk reduction of 0.03% (with a 95% confidence interval for this difference ranging from 0.02% to 0.08%). This equates to a need to screen about 3000 women for more than 10 years to prevent one death. This result is not statistically significant, and it seems biologically unlikely that screening is only effective if started 10 years before death from ovarian cancer. A small benefit is plausible, and it is tempting to accept that an operation that removed a coincidental and unexpected cancer confined to the inside of the ovary could serendipitously save a woman from a small cancer before it has spread. It also seems plausible to think that surgery is simpler for earlier stage cancers, and it seems obvious that some women will be harmed if a screening test puts her though an operation to remove a nodule that turns out to be irrelevant, and she risks developing cancer if she chooses screening with minimal efficacy instead of prophylactic surgery for her BRCA mutation. The breakthrough from UKCTOCS is that we can now add UK data to the very