Ovarian cancer screening in high-risk women

Over the past two decades a number of OC screening trials have been undertaken in women at high risk. Whether screening is of benefit in this group of women is yet to be determined. The initial strategy was annual screening using both serum CA125 and TVS as first-line tests. However, this was not effective in detecting early stage disease (Stirling et al., 2005). Results of annual screening from Phase I of the UK Familial Ovarian Cancer Screening Study (UKFOCSS) further confirm this. This study involved 3563 women who underwent annual screening with serum CA125 and TVS. Sensitivity for detection of incident OC/FT cancer within a year of the last screening was 81.3-87.5%, depending on whether occult cancers were classified as interval cancers or true positives. However, only 30.8% of screen-detected OC/FTCs were Stage I/II. There was preliminary evidence that advanced stage disease defined as >IIIC was more likely (85.7% versus 26.1%; P = 0.009) in those who had not been screened in the year before diagnosis compared with those who had (Rosenthal et al., 2013). As most cancers detected in this group of women are high-grade serous epithelial OCs which progress rapidly, a shorter screening interval is being investigated in UKFOCSS Phase II (Manchanda et al., 2009). Recent data suggest that high-risk women participating in frequent ovarian screening who are recalled for an abnormal result may experience transient cancer-specific distress but there is no significant effect on general anxiety/depression or overall reassurance.

UKFOCSS Phase II is using a sophisticated time-series algorithm to interpret serum CA125. An individual’s age-specific incidence of OC and serial CA125 profile are used to estimate the ‘risk of OC’ (ROC) (Skates et al., 2003). Based on the ROC results, women are triaged into low, intermediate and elevated-risk. Those at intermediate risk have repeat CA125 test; those with elevated risk are referred for CA125 testing and TVS, and if either is positive, women are referred for clinical assessment by a gynaecological oncologist with a view to surgery (Menon et al., 2009). In the general population, for a target specificity of 98% for pre-clinical detection of OC, the ROC calculation achieved a sensitivity of 86%

(Skates et al., 2003). Four-monthly screening using ROC is being evaluated in UKFOCSS Phase II involving 5700 women. The ROC is also being evaluated prospectively in screening trials in women at high risk in the United States (Cancer Genetics Network, CGN, and Gynecologic Oncology Group, GOG). Addition of human epididymis protein 4 (HE4) to CA125 in screening may reduce false positives as its levels are lower in many of the benign conditions that elevate CA125, such as endometriosis.

In the UK there is currently no screening of high-risk women on the NHS. The recommendation for such women is referral for genetic counselling, OC symptom awareness National Institute for Health and Care Excellence (NICE) guidelines (NICE, 2011) and risk-reducing bilateral salpingo-oopherectomy in their early 40s on completion of their families. While surgery is the primary recommendation in the United States as well, screening using 6-monthly serum CA125 and TVS is still considered a reasonable approach for those who do not opt for risk-reducing salpingo-oophorectomy according to the guidelines of the National Comprehensive Cancer Network (NCCN, 2014).

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