Ovarian Cancer Screening Editorial

M. Wilkinson^1,2, D. Brennan^1,2

Mater Misericordiae Hospital, Eccles St., Dublin 7
The Conway Institute, University College Dublin, Belfield Dublin 4.

The development of an effective strategy for early detection of ovarian cancer remains a significant unmet medical need .In the late 1980’s the discovery of the serum biochemical marker cancer antigen 125 (CA 125) offered potential for the development of an ovarian cancer screening test. However, thirty years on, are we any closer to developing an accurate, cost effective ovarian cancer screening programme?

There are approximately 410 new cases of ovarian cancer diagnosed in Ireland each year. The lifetime risk of developing ovarian cancer is low and estimated to be approximately 1.6%. Unfortunately 75% of women present with advanced disease and peritoneal carcinomatosis. As a result the median 5-year survival in Ireland is only 35% which is one of the lowest in the world[1]. Internationally, 5 year survival rates increase to around 50% making ovarian cancer the fifth leading cause of cancer death in women [2, 3]. Over the last three decades extensive efforts have been made to develop effective screening strategies to detect ovarian cancer at an earlier stage, which should result in improved survival rates. Although significant progress has been made in understanding the tubal origin of many “ovarian cancers”, our basic understanding of carcinogenesis within the fallopian tube or ovary is still limited and we have been unable to identify a pre-malignant lesion. As a result serum biomarkers such as CA 125 and Human Epididymis Protein 4 (HE4) have been proposed as adjuncts to ultrasounds in an attempt to develop new screening strategies.

Two large populations based studies examined various combinations of serum biomarkers and ultrasound: the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) ovarian cancer screening trial in the United States and the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)[4, 5]. The PLCO study, published in 2011, enrolled almost 70,000 women, deemed to be at ‘average risk’ of developing ovarian cancer. Participants were randomized to receive usual care or to undergo annual screening with a CA 125 serum sample and transvaginal ultrasound. After a median follow up of twelve years there was no difference in ovarian cancer mortality between the two groups[4].

The UKCTOCS study, published in 2016, included more than 200,000 “average risk” women who were randomized to three different care pathways; Half received routine care, one quarter had an annual Trans-Vaginal Ultrasound (TVUSS) and one-quarter multimodal screening (MMS) which included an annual CA-125 blood test and a TVUS if indicated. The aim of the study was to establish if early detection by screening could reduce ovarian cancer mortality. The risk of ovarian cancer algorithm (ROCA) was used to interpret the CA125 results by examining the change and rate of change of CA125 over time[6], which was an advantage over the less dynamic PLCO study, which utilised a ‘one off’ single assessment of CA125. In the MMS group, TVUSS was used as a second line intervention in women with a rising CA125 using the ROCA algorithm. After a median follow-up of 11 years, there was no difference in the primary outcome (ovarian cancer mortality) in the 3 groups and 60% of women who developed ovarian cancer in the more intensive MMS arm still presented with high volume disseminated disease. A post hoc analysis suggested a 15% reduction in mortality in the MMS group after prevalent cases were excluded.

In fact, the UKCTOCS study demonstrated potential harm with significant numbers of false positive laparoscopies in both the MMS and TVUS only arms. For every diagnosis of ovarian or primary peritoneal cancer in the MMS group two unnecessary surgeries were performed while in the USS group, ten false positive surgeries were performed for every diagnosis of ovarian cancer. This has led to the US preventive Services Task Force (USPSTF) to release a clear statement recommending that screening for ovarian cancer in an average or low risk population is not advised. They make this statement without ambiguity on the basis of a persistent lack of data to demonstrate the benefit of screening. This reflects the current opinion worldwide in this group of women. The possibility of a delayed effect on mortality in the UKCTOCS is currently being investigated with the results due in late 2018.

But what is the role of screening in women deemed to be at increased risk of ovarian cancer due to a genetic predisposition? Results from the phase II of the United Kingdom Familial Ovarian Cancer Screening Study (UKFOCSS) looked to address this question [7]. They reported on screening in women whose lifetime risk of developing ovarian cancer exceeded 10%. Over four thousand women were subjected to CA125 based ROCA screening every four months and annual TVUSS if ROCA screening was normal and TVUSS within two months of an abnormal ROCA screen. A total of 37 patients developed ovarian cancer during the study period, 18 of which were within one year of a screening test. Promisingly, 12/18 were screen detected while 6/18 were occult cancers found at risk reducing surgery. Women who developed cancer less than one year after their last screen were more likely to have lower volume disease at primary surgery and more likely to have complete cytoreduction compared to those diagnosed with cancer greater than one year after their last screening test. The UKFOCSS study demonstrated that the positive predictive value of this screening regimen was only significantly increased in women with BRCA 1/2 mutations versus patients with unknown mutational status at 42.9% V 7.7%[7]. The PPV in the entire study was only 10.8% which was similar to an American study which found a PPV of 10% where ROCA criteria were used with three-monthly Ca125 measurement intervals, but the predictive value was not assessed specifically for BRCA mutation carriers [8]. Neither of these studies were adequately powered to make any conclusions about the effect of screening on overall survival and larger studies are required to determine the value and schedule for screening in this population.

In conclusion, there is still a lack of evidence to support any form of screening in women deemed to be at ‘average risk’ of developing ovarian cancer. There is a body of evidence growing in support of the benefits of screening in women with confirmed BRCA1/2 mutations. While it is agreed that shorter intervals between tests are required further larger population based studies are required to determine whether or not it screening improves overall survival. At present the best approach to reduce the risk of ovarian cancer in high risk populations is to consider risk reducing prophylactic surgery. Current guidelines suggest risk reducing surgery in BRCA1 mutation carriers at 35 years of age and BRCA2 carriers at 40 if their family is complete.

Correspondence:
Michael Wilkinson,
Mater Misericordiae Hospital,
Eccles St,
Dublin 7
E-mail: [email protected]

References

1. Registry, I.C. Ovarian cancer factsheet. 2018, May 1st; Available from: https://www.ncri.ie/sites/ncri/files/factsheets/Factsheet ovary.pdf.
2. Torre, L.A., et al., Global cancer statistics, 2012. CA Cancer J Clin, 2015. 65(2): p. 87-108.
3. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2018. CA Cancer J Clin, 2018. 68(1): p. 7-30.
4. Miller, E.A., et al., Secondary prostate cancer screening outcomes by race in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial. Prostate, 2018.
5. Pavlik, E.J., Ovarian cancer screening effectiveness: A realization from the UK Collaborative Trial of Ovarian Cancer Screening. Womens Health (Lond), 2016. 12(5): p. 475-479.
6. Salim, E., et al., Diagnostic Accuracy of Risk of Ovarian Malignancy Algorithm (ROMA) in Post-Menopausal Patients with Ovarian Mass. J Coll Physicians Surg Pak, 2018. 28(6): p. 440-444.
7. Rosenthal, A.N., et al., Evidence of Stage Shift in Women Diagnosed With Ovarian Cancer During Phase II of the United Kingdom Familial Ovarian Cancer Screening Study. J Clin Oncol, 2017. 35(13): p. 1411-1420.
8. Skates, S.J., et al., Early Detection of Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing in Women at Increased Familial Risk - Combined Results from Two Screening Trials. Clin Cancer Res, 2017. 23(14): p. 3628-3637.

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