Katie Scandrett

Identifying the best diagnostic test for ovarian cancer – synopsis of Refining Ovarian Cancer Test accuracy Scores (ROCkeTS) research

Background Ovarian cancer survival is stage-dependent: Stage I patients have 90% 5-year survival versus 15% for stage IV. Over 70% of patients worldwide are diagnosed at advanced stages. Ovarian cancer presents with non-specific symptoms (abdominal bloating, early satiety, discomfort/pain, bowel/urinary changes). Current National Institute for Health and Care Excellence guidelines recommend that symptomatic women presenting to primary care are tested with cancer antigen 125 and ultrasound, then referred to secondary care for further triage if these tests are abnormal. Current standard of care risk prediction model used to triage women in National Health Service secondary care is Risk of Malignancy Index 1 combining cancer antigen 125 and simple ultrasound features, which at 250 threshold has 70% sensitivity and 90% specificity. Newer models offer potential for improved sensitivity, earlier diagnosis and better survival outcomes. Objectives To evaluate diagnostic strategies for ovarian cancer in women with non-specific symptoms through systematic review, United Kingdom Collaborative Trial of Ovarian Cancer Screening data set analysis, prospective studies and health economic evaluation comparing Risk of Malignancy Index 1 against newer approaches including Risk of Ovarian Malignancy Algorithm, Ovarian-Adnexal Reporting and Data System and International Ovarian Tumour Analysis models, including International Ovarian Tumour Analysis Assessment of Different NEoplasias in the adneXa. Methods Four concurrent work packages: (1) Cochrane systematic review; (2) United Kingdom Collaborative Trial of Ovarian Cancer Screening data set model development; (3) prospective multicentre diagnostic accuracy study (ROCkeTS) with parallel pre/postmenopausal cohorts; and (4) cost–consequence analysis. Allied analyses investigated psychological impact and cancer outcomes from symptom-triggered pathways. ROCkeTS recruited 2453 women across 23 hospitals (2015–23) with symptoms, raised cancer antigen 125 and/or abnormal imaging. Women completed questionnaires, donated blood and underwent transvaginal ultrasound scored by International Ovarian Tumour Analysis terminology by certified National Health Service sonographers with quality assurance. Reference standard was histology for surgical cases or 12-month wellbeing ascertainment. Primary outcome: primary invasive ovarian cancer versus benign or normal. Results The Cochrane systematic review (58 studies, 30,121 patients and 9061 ovarian cancer cases) demonstrated that most published diagnostic test accuracy studies failed to differentiate between pre- and postmenopausal women, and all were conducted in high-prevalence settings, limiting applicability to routine practice. In the ROCkeTS prospective study in premenopausal women, in the initial cohort recruited prior to protocol change ( n  = 857), Risk of Malignancy Index 1 at threshold 250 showed poor sensitivity (42.6%, 95% confidence interval 28.3 to 57.8) but high specificity (96.5%, 95% confidence interval 94.7 to 97.8). All other tests improved sensitivity but dropped specificity. International Ovarian Tumour Analysis Assessment of Different NEoplasias in the adneXa at 10% threshold achieved significantly higher sensitivity (89.1%, 95% confidence interval 76.4 to 96.4), higher than all other tests with acceptable specificity (73.2%, 95% confidence interval 69.9 to 76.4). In the ROCkeTS prospective cohort study in postmenopausal women ( n  = 1242), Risk of Malignancy Index 1 at 250 demonstrated better performance (82.9%, 95% confidence interval 76.7 to 88.0), but International Ovarian Tumour Analysis Assessment of Different NEoplasias in the adneXa at 10% had the best sensitivity at 96.1% (95% confidence interval 92.2 to 98.4) compared to Risk of Malignancy Index 1 with the least drop of specificity. Risk of Ovarian Malignancy Algorithm at manufacturer recommended threshold and Ovarian-Adnexal Reporting and Data System did not improve on Risk of Malignancy Index 1 sensitivity in postmenopausal women. Cancer prevalence differed between premenopausal (5.7%) and postmenopausal (17%) cohorts. Early-stage cancer (I/II) were diagnosed in 60.2% of premenopausal and 41% of postmenopausal cohorts. Cancer diagnosis rates were very low (1.6%) in women under 40 years. High anxiety and distress were noted, particularly in younger women. One in four women with high-grade serous ovarian cancers were diagnosed at early stage (I/II). Complete cytoreduction was achieved in 61.3% of cases, with optimal cytoreduction (≤ 1 cm residual disease) in an additional 15.1%. Cost–consequence analysis demonstrated that a two-step strategy deployed at the same ultrasound sitting, initially triaging out benign looking tumours on ultrasound, then calculating ovarian cancer risk with International Ovarian Tumour Analysis Assessment of Different NEoplasias in the adneXa ultrasound model at 10% demonstrated the best balance across cost, diagnostic yield and cancer deaths compared to other diagnostic strategies. Limitations Cohort study required key changes to protocol and post-pandemic recruitment was slow. Conclusions International Ovarian Tumour Analysis Assessment of Different NEoplasias in the adneXa ultrasound at 10% threshold, delivered by trained National Health Service sonographers demonstrated superior diagnostic performance compared to Risk of Malignancy Index 1 and should be considered as new standard of care for suspected ovarian cancer in pre- and postmenopausal women. A two-step strategy using International Ovarian Tumour Analysis Assessment of Different NEoplasias in the adneXa offers optimal balance across cost, diagnostic yield and cancer death reduction. Implementation requires sonographer training investment and quality assurance. Future research International Ovarian Tumour Analysis Assessment of Different NEoplasias in the adneXa implementation in primary care/community settings, artificial intelligence-enabled quality assurance, reconfiguration of referral pathways in primary care to reduce unnecessary referrals in younger women and consequent harm are important research areas. Systematic symptom elicitation capitalising on routine health interactions to reach underserved communities warrants further research. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 13/13/01.

Diagnostic tests for ovarian cancer in premenopausal women with non-specific symptoms (ROCkeTS): prospective, multicentre, cohort study

Abstract Objective To investigate the accuracy of risk prediction models and scores for diagnosing ovarian cancer in premenopausal women presenting to secondary care with symptoms and abnormal test results. Design Prospective cohort study. Setting Secondary care in 23 hospitals in the UK between June 2015 and March 2023. Participants Premenopausal women presenting with non-specific symptoms, and raised serum levels of cancer antigen 125 or abnormal imaging results, were prospectively recruited, predominantly referred through the NHS urgent suspected cancer pathway from primary 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 International Ovarian Tumour Analysis (IOTA) imaging terminology. The index tests used were Risk of Malignancy Index 1 (with pre-stated thresholds of 200, 250), Risk of Malignancy Algorithm (7.4%, 11.4%, 12.5%, 13.1%), IOTA Assessment of Different Neoplasias in the adnEXa (ADNEX) (3%, 10%), IOTA simple rules risk model (3%, 10%), IOTA simple rules, and cancer antigen 125 (CA 125, 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 or biopsies by histology or cytology, if undertaken, or else at 12 month follow-up. After June 2018, because of covid restrictions and concerns about sample size, recruitment was restricted to only women undergoing surgery within three months of presentation to clinic (in whom ovarian cancer was more likely). Main outcome measures Diagnostic accuracy at predicting primary invasive ovarian cancer versus benign or normal histology, assessed by analysing the sensitivity, specificity, C index, area under receiver operating characteristic curve, positive and negative predictive values, and calibration plots in participants with conclusive reference standard results and available index test data. Results 88 of 1211 premenopausal women received diagnoses of primary ovarian cancer: 49 of 857 women in the pre-June 2018 cohort (prevalence of 5.7%) and 39 of 354 women in the post-June 2018 cohort (11.0%). For the diagnosis of primary ovarian cancer (n=799 women, after exclusion of 58 other diagnoses), Risk of Malignancy Index 1 at the 250 threshold had a sensitivity of 42.6% (95% confidence interval (CI) 28.3 to 57.8; specificity 96.5%, 94.7 to 97.8). Compared with Risk of Malignancy Index 1 at the 250 threshold, CA 125 and all other tests had higher sensitivity (CA 125 at 87 IU/mL threshold: 55.1%, 40.2 to 69.3, P=0.06; Risk of Malignancy Algorithm at 11.4% threshold: 79.2%, 65.0 to 89.5, P<0.001; IOTA ADNEX at 10% threshold: 89.1%, 76.4 to 96.4, P<0.001; IOTA simple rules risk at 10% threshold: 83.0%, 69.2 to 92.4, P<0.001; IOTA simple rules: 75.0%, 56.6 to 88.5, P=0.01) and lower specificity (CA 125 at 87 IU/mL threshold: 89.0%, 86.5 to 91.2, P<0.001; Risk of Malignancy Algorithm at 11.4% threshold: 73.1%, 69.6 to 76.3, P<0.001; IOTA ADNEX at 10% threshold: 75.1%, 71.4 to 78.6, P<0.001; IOTA simple rules risk at 10% threshold: 76.0%, 72.4 to 79.3, P<0.001; IOTA simple rules: 95.2%, 93.0 to 96.9, P=0.06). Results for IOTA simple rules were inconclusive in 120 of 799 participants. Analysis of the complete cohort (n=1211), including the 354 premenopausal women with a higher likelihood of developing ovarian cancer, yielded similar results. Conclusions Compared to Risk of Malignancy Index 1 at 250 threshold—the test currently 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 test for triaging premenopausal women in secondary care. Implementation should incorporate staff training and quality assurance. Trial registration ISRCTN17160843 .