Tests in secondary care to identify people at high risk of ovarian cancer

The assessment of different neoplasias in the adnexa (ADNEX) model

3.1 The ADNEX model was developed by the International Ovarian Tumor Analysis (IOTA) group to assess people with an adnexal mass who are considered to need surgery. The model uses 3 clinical predictors and 6 ultrasound-derived predictors to estimate the probability that a pelvic tumour is benign or malignant (see table 1). Also, the model estimates probabilities that a tumour is borderline, stage I cancer, stage II to IV cancer or secondary metastatic cancer. The ADNEX model formulas are available in published literature (Van Calster et al. 2014) and the model is further described on the IOTA website. The terminology used in the model is as defined in a publication by the IOTA group (Timmerman et al. 2000), and the group run courses that teach the terms, definitions and measurement techniques needed to assess pelvic masses for the ADNEX model. An online training tool for NHS practitioners is also currently in development.

Table 1 Criteria included in the ADNEX model

3.2 The ultrasound variables for the ADNEX model need B mode imaging and the IOTA group states that any modern ultrasound machine with a high-frequency (more than 6 Hz) transvaginal probe can be used. The ADNEX model has not been validated for use in people who are pregnant.

Overa (MIA2G) serum test (Vermillion)

3.3 The Overa (MIA2G) is a CE-marked qualitative serum test that combines the results of 5 immunoassays into a single numeric result (the Overa Risk Score). The 5 biomarkers included in the test are: follicle-stimulating hormone (FSH), human epididymis protein 4 (HE4), apolipoprotein A‑1 (Apo A‑1), transferrin (TRF), and cancer antigen 125 (CA125). The serum levels of these biomarkers are determined using immunoassays run on the Roche cobas 6000 system. The Overa Risk Score is generated by the company's OvaCalc software, with results ranging between 0.0 and 10.0. A risk score of less than 5.0 indicates a low probability of malignancy and a score of 5.0 or more indicates a high probability of malignancy. The assay is for use in people over 18 years with a pelvic mass for whom surgery may be considered. It is intended to be part of preoperative assessment to help decide if a person presenting with a pelvic mass has a high or low risk of ovarian malignancy.

3.4 The company states that test results must be interpreted in conjunction with an independent clinical and imaging evaluation, and that the test is not intended for use in screening or as a stand-alone assay. The Overa (MIA2G) is available to the NHS through a private laboratory which tests samples and provides Overa Risk scores.

Risk of malignancy index 1 (RMI I) with thresholds other than 250

3.5 The RMI I tool combines 3 pre-surgical features (measured serum CA125 levels [CA125], ultrasound imaging [U] and menopausal status [M]) to create an index score: RMI I score = U×M×CA125. Definitions of these terms from the NICE guideline on ovarian cancer are in table 2.

Table 2 Definitions of RMI I terms

3.6 The NICE guideline on ovarian cancer recommends that people with an RMI I score of 250 or more should be referred to a specialist MDT (the RMI I at this threshold is the comparator for this assessment, see section 3.15). However, this guideline also includes a research recommendation stating that further research should be done to determine the optimum RMI I threshold that should be applied in secondary care to guide the management of suspected ovarian cancer. The subsequently published Scottish Intercollegiate Guidelines Network (SIGN) guideline on the management of epithelial ovarian cancer (SIGN 135) recommends referring people with an RMI I score of more than 200 to a gynaecological oncology multidisciplinary team.

Risk of ovarian malignancy algorithm (ROMA)

3.7 The ROMA combines serum CA125 and HE4 levels with a person's menopausal status to estimate the probability that they have epithelial ovarian cancer. Different equations are used depending on whether the person is pre- or postmenopausal (Moore et al. 2009). Cut-off values for the ROMA score stratify individuals as being at a high or low risk of having epithelial ovarian cancer. Cut-off values vary depending on which manufacturers' HE4 and CA125 assays are being used. The ROMA has not been validated in people under 18 years old, people being treated with chemotherapy and people who have previously been treated for a malignancy.

3.8 Three assays that measure HE4 serum levels using automated immunoassay analysers, and that are available to the NHS, are described in the following sections.

Simple Rules ultrasound classification system

3.12 Simple Rules was developed by the IOTA group to assess people with a pelvic mass who are considered to need surgery. It is a scoring system based on the presence of ultrasound features, to characterise an ovarian tumour before surgery as benign or malignant. No specific make or model of ultrasound device is needed to use the Simples Rules system. A transvaginal probe is needed and image quality must be of sufficient quality to allow the ultrasound features specified by the Simple Rules system to be seen.

3.13 Terms and definitions used in the classification system are as defined by the IOTA group. The group run courses that teach the terms, definitions and measurement techniques needed to assess pelvic masses for the Simple Rules. An online training tool for NHS practitioners is also currently under development. Simple Rules has not been validated for use in people who are pregnant.

3.14 There are 5 rules that predict a malignant tumour (M‑rules) and 5 rules that predict a benign tumour (B‑rules), as described in table 3. If any M‑rules apply (and no B‑rules) then the mass is classified as malignant. If any B‑rules apply (and no M‑rules) then the mass is classified as benign. However, if both M- and B‑rules apply, or neither, then the result is inconclusive, and is either classed as malignant or further criteria are needed to assess whether the mass is likely to be malignant; for example, further expert subjective assessment of the ultrasound images.

Table 3 Simple Rules ultrasound classification system