December 17, 2015
4 min read

CA125-concentration screening may improve ovarian cancer detection, OS

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Annual multimodal screening with serum cancer antigen 125-concentration testing may reduce ovarian cancer mortality, according to the results of a randomized controlled trial conducted by the U.K. Collaborative Trial of Ovarian Cancer Screening.

However, additional follow-up is needed to fully assess mortality reduction and cost-effectiveness of the screening method in the general population, according to the researchers.

“Our report on the mortality data from the U.K. Collaborative Trial of Ovarian Cancer Screening is the first evidence from a randomized controlled trial that screening can reduce ovarian cancer deaths,” Usha Menon, MD, FRCOG, professor of gynecological cancer at the Institute for Women’s Health, University College London, said in a press release. “The findings are of importance given the limited progress in treatment outcomes for ovarian cancer over the last 30 years.”

Ovarian cancer is often diagnosed at a late stage, corresponding with a poor prognosis, according to study background. The 5-year OS rate of patients with ovarian cancer is 40%.

Thus, Menon and colleagues sought to establish the effect of early detection from screening on ovarian cancer mortality.

The researchers enrolled 202,546 postmenopausal women aged 50 years to 74 years from medical centers in England, Wales and Northern Ireland. They excluded women with previous bilateral oophorectomy or ovarian malignancy, familial ovarian cancer risk, or active non-ovarian malignancy.

Women underwent annual multimodal screening (MMS) with serum cancer antigen 125 (CA125)-concentration testing (n = 50,624), annual transvaginal ultrasound screening (USS; n = 50,623) or no screening (n = 101,299).

Ovarian cancer risk was identified in the MMS group based on significant rises in CA125. Based on CA125 levels, women continued annual screening, repeated CA125 concentration testing in 3 months (intermediate risk) or repeated CA125 concentration testing and transvaginal USS as a second-line test in 6 weeks (elevated risk).

In the USS group, women with normal results continued annual screening, whereas women with unsatisfactory results repeated testing in 3 months, and women with abnormal results received a scan from a senior ultrasonographer within 6 weeks.

Death due to ovarian cancer served as the primary endpoint.

The median follow-up was 11.1 years (interquartile range, 10-12). By the end of the screening period in December 2011, 345,570 MMS and 327,775 USS episodes occurred.

Overall, 1,282 women (0.6%) received an ovarian cancer diagnosis, which included 338 women (0.7%) in the MMS arm, 314 (0.6%) in the USS arm and 630 (0.6%) in the no screening arm.

Of the patients with ovarian cancer, deaths due to ovarian cancer occurred in 148 women (0.29%) in the MMS arm, 154 (0.3%) in the USS arm and 347 (0.34%) in the no screening arm.

Based on results of the primary analysis using a Cox proportional hazards model, MSS conferred a 15% (95% CI, –3 to 30) mortality reduction and USS conferred an 11% (95% CI, –7 to 27) mortality reduction over years 0-14. However, these reductions did not reach statistical significance.

Based on data from a Royston-Parmar flexible parametric model, the mortality reduction in the MSS group appeared driven by an 8% (95% CI, –20 to 31) relative reduction during the first 7 years and a 23% (95% CI, 1-46) relative reduction years 7 through 14 compared with no screening.

For the USS arm, the relative reduction rates were 2% (95% CI, –27 to 26) years 0 through 7 and 21% (95% CI, –2 to 42) years 7 through 14 compared with no screening.

However, after the exclusion of women with undiagnosed ovarian cancer at the start of screening, the reduction in ovarian cancer death rate reached statistical significance (P = .021). In this analysis, MMS appeared to confer an overall average mortality reduction of 20% (95% CI, –2 to 40), with an 8% (95% CI, –27 to 43) reduction years 0 through 7 and 28% (95% CI, –3 to 49) years 7 through 14.

Screening complications occurred in less than 1% of women in the MSS and USS groups, resulting in a screening-related complication rate of 8.6 per 100,000 women in the MSS group and 18.6 per 100,000 women in the USS group.

Further, 14 false-positive surgeries per 10,000 screens occurred in the MMS group and 50 false-positive surgeries per 10,000 screens occurred in the USS group.

The researchers acknowledged their failure to anticipate the late effect of screening as a study limitation.

“Further follow-up will provide greater confidence about the precise reduction in mortality which is achievable,” Ian J. Jacobs, MD, professor of gynecologic cancer at University of Manchester and University College London, said in a press release. “It is possible that the mortality reduction after follow-up for an additional 2 to 3 years will be greater or less than these initial estimates.”

In an accompanying editorial, René H.M. Verheijen, MD, and Ronald P. Zweemer, MD, both of the department of gynecological oncology in the division of surgical oncology at University Medical Center Utrecht Cancer Center in the Netherlands, questioned the efficacy and usefulness of screening modalities for ovarian cancer.

“Awareness and symptom recognition for diagnosis of ovarian cancer at an early stage will be difficult to improve upon,” Verheijen and Zweemer wrote. “Screening will not be warranted until the outcome has been validated in daily practice. But careful studies as that of Jacobs and colleagues show that we must and can focus on mechanisms of early cancer detection.” – by Cameron Kelsall

Disclosure: Menon reports stock ownership in and research funding from Abcodia, as well as grant support from Cancer Research U.K., The Eve Appeal, Medical Research Council and the National Institute for Health Research. Jacobs reports personal fees from Abcodia and Women’s Health Specialists, as well as a patent agreement with Abcodia for intellectual property related to this study. He further reports grants from Medical Research Council and a trustee role with The Eve Appeal. Please see the full study for a list of all other researchers’ relevant financial disclosures. Verheijen and Zweemer report no relevant financial disclosures.