Identifying the best diagnostic test for Ovarian cancer in premenopausal women with non-specific symptoms – results from the ROCkeTS prospective, multicentre, cohort study

Objective

Diagnosing ovarian cancer in premenopausal women is challenging due to the rarity of cancer and the ubiquity of symptoms, ovarian cysts on ultrasound, and raised serum CA125 tumour marker levels. We investigated the accuracy of risk prediction models and scores for diagnosing ovarian cancer in premenopausal women presenting to secondary care with symptoms and abnormal tests.

Methods

A cohort of premenopausal women presenting with non-specific symptoms, and raised CA125 or abnormal imaging, were prospectively recruited in 23 hospitals in the UK between June 2015 and March 2023, predominantly referred through the NHS urgent suspected cancer pathway from primary to secondary care. A head-to-head comparison of the accuracy of the six risk prediction models and scores was conducted using donated blood and ultrasound scans performed by NHS staff trained in the use of IOTA imaging terminology. Index tests (at pre-stated thresholds) were: RMI1 (200, 250); ROMA (7.4%, 11.4%, 12.5%, 13.1%); IOTA ADNEX (3%, 10%); IOTA SRRisk (3%, 10%); IOTA simple rules; and CA125 (87 IU/ml). Participants were classified as having primary invasive ovarian cancer versus having benign or normal pathology according to the reference standard determined from surgical specimens, biopsies or cytology, by histology if undertaken, or else by 12-month follow-up. After June 2018, because of COVID restrictions and concerns about sample size, ongoing recruitment was restricted to only women undergoing surgery within 3 months of presentation (a selected group in whom ovarian cancer was more likely).

Results

Of 1,211 premenopausal recruited women 88 were diagnosed with primary OC, 857 in the pre-June 2018 cohort (prevalence of 5.7% (49/857)) and 354 in the post-June 2018 cohort 11.0% (39/354). For the diagnosis of primary ovarian cancer, (n=799 women after exclusion of n=58 other diagnoses), RMI1 at the 250 threshold had a sensitivity of 42.6%, 95% confidence interval 28.3 to 57.8, and specificity of 96.5%, 94.7 to 97.8. Compared to RMI1/250, CA125 and all other models had higher sensitivity (CA125: 55.1%, 40.2 to 69.3, p=0.06; ROMA/11.4%: 79.2%, 65.0 to 89.5, p<0.0001; IOTA ADNEX/10%: 89.1%, 76.4 to 96.4, p<0.0001; IOTA SRRisk/10%: 83.0%, 69.2 to 92.4, p<0.0001; IOTA simple rules: 75.0%, 56.6 to 88.5, p=0.01) and lower specificity (CA125: 89.0%, 86.5 to 91.2, p<0.0001; ROMA/11.4%: 73.1%, 69.6 to 76.3, p<0.0001; IOTA ADNEX/10%: 75.1%, 71.4 to 78.6, p<0.0001; IOTA SRRisk/10%: 76.0%, 72.4 to 79.3, p<0.0001; IOTA simple rules 95.2%, 93.0 to 96.9, p=0.06). IOTA simple rules have inconclusive results in 120/799 of the participants. Analysis of the complete cohort (n=1,211) including the 354 premenopausal women with a higher likelihood of ovarian cancer, yielded similar results.

Conclusions

Compared to RMI 250, the current test used in NHS secondary care to triage women to tertiary care, most tests improve sensitivity but reduce specificity. Ultrasound triage with the IOTA ADNEX model at 10% in secondary care demonstrated the highest sensitivity gain with a comparable decline in specificity to other comparator tests. Ultrasound with the IOTA ADNEX model at 10% should be considered the new standard of care triage test for premenopausal women in secondary care; implementation in practice should incorporate staff training and quality assurance.

Trial registration – ROCkeTS is registered ISRCTN17160843