Normal Risk Ovarian Screening Study: 21-Year Update

Abstract

Purpose: The Normal Risk Ovarian Screening Study (NROSS) tested a two-stage screening strategy in postmenopausal women at conventional hereditary risk where significantly rising cancer antigen (CA)-125 prompted transvaginal sonography (TVS) and abnormal TVS prompted surgery to detect ovarian cancer.

Methods: A total of 7,856 healthy postmenopausal women were screened annually for a total of 50,596 woman-years in a single-arm study (ClinicalTrials.gov identifier: NCT00539162). Serum CA125 was analyzed with the Risk of Ovarian Cancer Algorithm (ROCA) each year. If risk was unchanged and <1:2,000, women returned in a year. If risk increased above 1:500, TVS was undertaken immediately, and if risk was intermediate, CA125 was repeated in 3 months with a further increase in risk above 1:500 prompting referral for TVS. An average of 2% of participants were referred to TVS annually.

Results: Thirty-four patients were referred for operations detecting 15 ovarian cancers and two borderline tumors with 12 in early stage (I-II). In addition, seven endometrial cancers were detected with six in stage I. As four ovarian cancers and two borderline tumors were diagnosed with a normal ROCA, the sensitivity for detecting ovarian and borderline cancer was 74% (17 of 23), and 70% of ROCA-detected cases (12 of 17) were in stage I-II. NROSS screening reduced late-stage (III-IV) disease by 34% compared with UKCTOCS controls and by 30% compared with US SEER values. The positive predictive value (PPV) was 50% (17 of 34) for detecting ovarian cancer and 74% (25 of 34) for any cancer, far exceeding the minimum acceptable study end point of 10% PPV.

Conclusion: While the NROSS trial was not powered to detect reduced mortality, the high specificity, PPV, and marked stage shift support further development of this strategy.

FIG 1.

Diagram of participant flow including referral to TVS, study indicated surgeries, and outcomes of study indicated surgeries and clinically detected ovarian cancers and borderline tumors. Averages per year over 21 years are provided for screening encounters—CA125 tests and TVSs. The average number of CA125 tests per year was the total CA125 blood draws performed in the study divided by 21 years, percentage ROCA recommendations are the number of recommendations for each category divided by the total number of CA125 blood draws, and percentage ultrasound recommendations computed by combining a physician ultrasound impression and a final physician recommendation. CA125, cancer antigen-125; ROCA, Risk of Ovarian Cancer Algorithm; TVS, transvaginal sonography.

FIG 2.

CA125 values over time before operations prompted by the ROCA. (A) Early-stage cases. (B) Late-stage cases. (C) Other cancers. (D) Benign pelvic masses (the red line indicates conventional cutoff of CA125 measurement as >35 U/mL). CA125, cancer antigen-125; ROCA, Risk of Ovarian Cancer Algorithm.