Pan Birmingham Gynaecological Cancer Centre, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
Lancet Oncol. 2024 Oct;25(10):1371-1386. doi: 10.1016/S1470-2045(24)00406-6.
Multiple risk-prediction models are used in clinical practice to triage patients as being at low risk or high risk of ovarian cancer. In the ROCkeTS study, we aimed to identify the best diagnostic test for ovarian cancer in symptomatic patients, through head-to-head comparisons of risk-prediction models, in a real-world setting. Here, we report the results for the postmenopausal cohort.
In this multicentre, prospective diagnostic accuracy study, we recruited newly presenting female patients aged 16-90 years with non-specific symptoms and raised CA125 or abnormal ultrasound results (or both) who had been referred via rapid access, elective clinics, or emergency presentations from 23 hospitals in the UK. Patients with normal CA125 and simple ovarian cysts of smaller than 5 cm in diameter, active non-ovarian malignancy, or previous ovarian malignancy, or those who were pregnant or declined a transvaginal scan, were ineligible. In this analysis, only postmenopausal participants were included. Participants completed a symptom questionnaire, gave a blood sample, and had transabdominal and transvaginal ultrasounds performed by International Ovarian Tumour Analysis consortium (IOTA)-certified sonographers. Index tests were Risk of Malignancy 1 (RMI1) at a threshold of 200, Risk of Malignancy Algorithm (ROMA) at multiple thresholds, IOTA Assessment of Different Neoplasias in the Adnexa (ADNEX) at thresholds of 3% and 10%, IOTA SRRisk model at thresholds of 3% and 10%, IOTA Simple Rules (malignant vs benign, or inconclusive), and CA125 at 35 IU/mL. In a post-hoc analysis, the Ovarian Adnexal and Reporting Data System (ORADS) at 10% was derived from IOTA ultrasound variables using established methods since ORADS was described after completion of recruitment. Index tests were conducted by study staff masked to the results of the reference standard. The comparator was RMI1 at the 250 threshold (the current UK National Health Service standard of care). The reference standard was surgical or biopsy tissue histology or cytology within 3 months, or a self-reported diagnosis of ovarian cancer at 12 month follow-up. The primary outcome was 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. This study is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN17160843).
Between July 13, 2015, and Nov 30, 2018, 1242 postmenopausal patients were recruited, of whom 215 (17%) had primary ovarian cancer. 166 participants had missing, inconclusive, or other reference standard results; therefore, data from a maximum of 1076 participants were used to assess the index tests for the primary outcome. Compared with RMI1 at 250 (sensitivity 82·9% [95% CI 76·7 to 88·0], specificity 87·4% [84·9 to 89·6]), IOTA ADNEX at 10% was more sensitive (difference of -13·9% [-20·2 to -7·6], p<0·0001) but less specific (difference of 28·5% [24·7 to 32·3], p<0·0001). ROMA at 29·9 had similar sensitivity (difference of -3·6% [-9·1 to 1·9], p=0·24) but lower specificity (difference of 5·2% [2·5 to 8·0], p=0·0001). RMI1 at 200 had similar sensitivity (difference of -2·1% [-4·7 to 0·5], p=0·13) but lower specificity (difference of 3·0% [1·7 to 4·3], p<0·0001). IOTA SRRisk model at 10% had similar sensitivity (difference of -4·3% [-11·0 to -2·3], p=0·23) but lower specificity (difference of 16·2% [12·6 to 19·8], p<0·0001). IOTA Simple Rules had similar sensitivity (difference of -1·6% [-9·3 to 6·2], p=0·82) and specificity (difference of -2·2% [-5·1 to 0·6], p=0·14). CA125 at 35 IU/mL had similar sensitivity (difference of -2·1% [-6·6 to 2·3], p=0·42) but higher specificity (difference of 6·7% [4·3 to 9·1], p<0·0001). In a post-hoc analysis, when compared with RMI1 at 250, ORADS achieved similar sensitivity (difference of -2·1%, 95% CI -8·6 to 4·3, p=0·60) and lower specificity (difference of 10·2%, 95% CI 6·8 to 13·6, p<0·0001).
In view of its higher sensitivity than RMI1 at 250, despite some loss in specificity, we recommend that IOTA ADNEX at 10% should be considered as the new standard-of-care diagnostic in ovarian cancer for postmenopausal patients.
UK National Institute of Heath Research.
多种风险预测模型被用于临床实践，以对卵巢癌患者进行低危或高危分层。在 ROCkeTS 研究中，我们旨在通过比较风险预测模型，在真实环境中确定用于有症状患者的最佳卵巢癌诊断测试。在这里，我们报告绝经后队列的结果。
在这项多中心前瞻性诊断准确性研究中，我们招募了来自英国 23 家医院的新出现的、年龄在 16-90 岁之间的、有非特异性症状且 CA125 升高或超声结果异常（或两者兼有）的女性患者。CA125 正常且单纯卵巢囊肿直径小于 5cm、有活动性非卵巢恶性肿瘤或既往卵巢恶性肿瘤、或妊娠或拒绝经阴道超声检查的患者不符合入组条件。在本分析中，仅纳入绝经后参与者。参与者完成症状问卷，采集血样，并由国际卵巢肿瘤分析协会（IOTA）认证的超声医师进行经腹和经阴道超声检查。索引测试为风险评估 1（RMI1）阈值为 200、风险评估算法（ROMA）多个阈值、附件中的不同肿瘤评估（ADNEX）阈值为 3%和 10%、IOTA 风险评估模型（SRRisk）阈值为 3%和 10%、IOTA 简单规则（恶性与良性或不确定）和 CA125 为 35IU/mL。在事后分析中，使用既定方法从 IOTA 超声变量中衍生出卵巢附件和报告数据系统（ORADS）的 10%，因为 ORADS 是在招募完成后描述的。索引测试由对参考标准结果设盲的研究人员进行。比较组为 RMI1 阈值为 250（英国国家卫生服务标准护理的当前标准）。参考标准为 3 个月内的手术或活检组织病理学或细胞学，或 12 个月随访时的自我报告的卵巢癌诊断。主要结局是在有明确参考标准结果和可用索引测试数据的参与者中，预测原发性浸润性卵巢癌与良性或正常组织学的诊断准确性，通过分析灵敏度、特异性、C 指数、受试者工作特征曲线下面积、阳性和阴性预测值以及校准图来评估。这项研究在国际随机对照试验编号注册中心（ISRCTN17160843）注册。
2015 年 7 月 13 日至 2018 年 11 月 30 日，共招募了 1242 名绝经后患者，其中 215 名（17%）患有原发性卵巢癌。166 名参与者的参考标准结果缺失、不确定或其他结果；因此，使用最多 1076 名参与者的数据来评估主要结局的索引测试。与 RMI1 阈值为 250 相比（灵敏度 82.9%[76.7-88.0]，特异性 87.4%[84.9-89.6]），IOTA ADNEX 阈值为 10%的敏感性更高（差异为-13.9%[-20.2-7.6]，p<0.0001），但特异性更低（差异为 28.5%[24.7-32.3]，p<0.0001）。ROMA 阈值为 29.9 的灵敏度相似（差异为-3.6%[-9.1-1.9]，p=0.24），但特异性较低（差异为 5.2%[2.5-8.0]，p=0.0001）。RMI1 阈值为 200 的灵敏度相似（差异为-2.1%[-4.7-0.5]，p=0.13），但特异性较低（差异为 3.0%[1.7-4.3]，p<0.0001）。IOTA SRRisk 模型阈值为 10%的灵敏度相似（差异为-4.3%[-11.0-2.3]，p=0.23），但特异性较低（差异为 16.2%[12.6-19.8]，p<0.0001）。IOTA 简单规则的灵敏度相似（差异为-1.6%[-9.3-6.2]，p=0.82），特异性相似（差异为-2.2%[-5.1-0.6]，p=0.14）。CA125 阈值为 35IU/mL 的灵敏度相似（差异为-2.1%[-6.6-2.3]，p=0.42），但特异性较高（差异为 6.7%[4.3-9.1]，p<0.0001）。在事后分析中，与 RMI1 阈值为 250 相比，ORADS 达到相似的灵敏度（差异为-2.1%，95%CI-8.6-4.3，p=0.60）和较低的特异性（差异为 10.2%，95%CI 6.8-13.6，p<0.0001）。
鉴于其比 RMI1 阈值为 250 更高的敏感性，尽管特异性略有下降，我们建议将 IOTA ADNEX 阈值为 10%作为绝经后患者卵巢癌的新的标准护理诊断测试。
英国国家卫生研究院。
