Ovarian cancer screening
By Dr Stuart SalďŹ nger, Gynaecologic Oncologist, KEMH & SJOG Hospitals
cancer disease stages, in a Phase II study of 150 ovarian cancers and 212 control samples. No data have been reported from prospective controlled clinical trials.
Approximately 1500 Australian women were diagnosed with ovarian carcinoma in 2014. The lifetime risk is around 1.5%. As the majority present with advanced disease (Stage 3-4), which has a 10-40% ďŹ ve-year survival rate, it is disproportionately represented in cancer deaths (900 p.a.). Early disease detection has proved difďŹ cult â€“ testing for ovarian cancer in asymptomatic women can lead to false reassurance (false negatives), unnecessary highly invasive procedures (false positives) and signiďŹ cant anxiety.
Other biomarkers are being developed, including gene microarray proďŹ ling technology either as a single marker, or in a panel of biomarkers, and often in combination with CA125. No results from prospective randomised trials in a healthy, asymptomatic population are available and there is no evidence for survival advantage using these markers for screening.
Screening trials not instructive The low incidence and prevalence results in high rates of false positives unless a test is extremely accurate. Data suggests that screening leads to a small increase in the number of cases detected but no impact on outcomes or survival.
The only proven preventive strategy for women with a genetic predisposition is risk reduction bilateral salpingo-oophorectomy (+/- hysterectomy), which removes 99% of the ovarian carcinoma risk and halves the risk of breast cancer in BRCA mutation carriers. The other strategy is the oral contraceptive pill, which halves the risk of ovarian carcinoma across all women taking it (not proven in mutation carriers). More recent discussion has revolved around removal of the fallopian tubes, which have been implicated as a potential source especially in BRCA gene mutation carriers. Whilst an attractive option without the risk of menopause there is no conclusive evidence that this is protective. Recommendations. The National Breast and Ovarian Cancer Centre 2009 national guidelines say screening is not indicated for asymptomatic women (see Figure 1). Screening in high-risk populations is controversial and lacks consensus.
The PLCO (Prostate Lung Colorectal Ovarian) trial showed no change in the stage of disease detected or survival with screening (US scan and CA 125 marker) and 15% of women who underwent surgery for a false positive ďŹ nding experienced a serious complication. WHO criteria for disease screening perfectly suit breast or cervical cancers, however ovarian carcinoma lacks a pre-invasive disease stage or latent period. Patients with early stage disease perform better but are difďŹ cult to identify with any screening test. The poor sensitivity and speciďŹ city of the tests is also a problem.
The harsh reality for surgeons is that the majority of women with ovarian cancer present with advanced disease (Stage 3-4)
Large-scale prospective clinical screening trials are in progress. Until ďŹ nal results are in, consensus is that women at average risk for ovarian cancer should not undergo screening. Available tests CA125, a low molecular weight glycoprotein, is neither sensitive nor speciďŹ c for early stage disease. It can be normal in 50% of women with early stage ovarian carcinoma or elevated by numerous benign conditions including benign cysts, endometriosis, ďŹ broids, PID and even normal menses. Whilst suggested to be a better predictor of disease in postmenopausal women, the PLCO trial data only showed a positive predictive value of 3.6%
Ultrasound, is effective in assessing ovarian masses, but not as a screening tool. Three large trials looked at Multimodal Screening; PLCO, UKCTOCS and a Japanese trial involving 68,557, 202,638 and 83,000 women. These showed some promise to a multimodal approach using CA125 and transvaginal ultrasound (TVUS). Repeat CA125 measurements over time increases the sensitivity and speciďŹ city of this approach. A Risk of Ovarian Cancer (ROC) algorithm incorporating serial measurements of CA125 is being further evaluated as part of the UK Collaborative Trial of Ovarian Cancer Screening trial. High risk women
Human Epididmys Protein 4 (HE4) has a similar sensitivity but higher speciďŹ city. It is more effective than Ca125 in classifying benign and ovarian masses. OvPlexâ„˘, a commercial blood test marketed for early detection of ovarian cancer, measures CA125 and four additional protein biomarkers. Unpublished company data reports over 90% sensitivity and speciďŹ city across all ovarian
National guidelines help in explaining to patients the lack of evidence for screening but unfortunately some still seek testing and discussing the pros and cons can take a lot more time than simply requesting a blood test and ultrasound. The signiďŹ cant downside and risks of screening asymptomatic women should be remembered. Highrisk women should be referred to appropriate genetics counselling and gynaecologic oncology services.
Women with a family history or genetic mutation predisposing them to ovarian carcinoma (BRCA one and two and HNPCC) present a challenge. No current data shows that screening is effective in this population either. Many doctors will screen with the proviso that screening has many pitfalls. Most women who develop cancers do so during screening intervals.
Risk Factors for Ovarian Carcinoma sĂĽ 'ENETICĂĽPREDISPOSITIONĂĽ ĂĽINĂĽTHEĂĽ absence of proven genetic mutation sĂĽ &AMILIALĂĽOVARIANĂĽCANCERĂĽSYNDROMEĂĽnĂĽ BRCA 1 & 2, HNPCC sĂĽ !GEĂĽnĂĽPOSTMENOPAUSAL sĂĽ 2EPRODUCTIVE%NDOCRINEĂĽDECREASEĂĽ risk â€“ pregnancy, OCP, breast feeding, tubal ligation/hysterectomy; increase risk â€“ infertility, endometriosis, ?HRT There is currently no evidence that any test, including pelvic examination, CA125 or other biomarkers, ultrasound (including transvaginal ultrasound), or combination of tests, results in reduced mortality from ovarian cancer. Author competing interests; no relevant disclosures. Questions? Contact author on 9388 3495.
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