Annual screening for ovarian cancer with CA-125 testing and transvaginal ultrasound does not reduce mortality in average-risk women but does increase invasive medical procedures and harms. Screening higher-risk women shows potential for earlier detection through the UKFOCSS trial, but results are pending. While tumor markers like HE4 show promise in detecting early cancers missed by CA-125, more research is needed to determine an effective screening strategy. Overall, there is currently no established role for population-wide ovarian cancer screening.

1. Is there a role for ovarian cancer
screening?
O&G Dept CME
29 Nov 2013
Dr Voon Hian Yan
Supervisor: Dr Sim Wee Wee

2. What do they have in common?

3. 7 Commandments on Screening
Adapted by WHO after Wilson and Jungner
Significant prevalance and severity
Fixed spectrum of symptoms
Tests which are simple and acceptable to the patient
Accurate screening test
Confirmatory test available
Treatable disease
Favourable cost/benefit ratio
Screening is done where direct diagnostic tests are costly/invasive /
requires specialised personnel or equipment / greater risk to patient

4. Burden of Ovarian cancer
2nd most common cancer of the female genital tract
5th most common cancer in females
7000 women in the UK are diagnosed with ovarian cancer/yr
8 in 10 are diagnosed in women >50yrs old
Incidence: 17 in 100,000
Lifetime risk: 1 in 71
No identifiable premalignant stages ex CIN
5yr survival 94% if detected in Stage I (15% )
Majority 60% are detected late with 5 yr survival 28%

5. Incessant ovulation
Inflammation

6. How and who to screen?
HOW
Tumor markers: Ca-125
-only 50% stage I and II epithelial ovarian cancers
-only 80% of epithelial ovarian cancers
-false +ve esp in younger women
Imaging
: TVS
(patient acceptability, skilled operator)
WHO
Post-menopausal women
General population vs high risk groups

7. Is there a role of Ca125 or Ultrasound screening?
Effect of Screening on Ovarian Cancer Mortality:
The Prostate, Lung, Colorectal and Ovarian (PLCO)
Cancer Screening Randomized Controlled Trial
JAMA. 2011;305(22):2295-2303. doi:10.1001/jama.2011.766

8. Target group
Postmenopausal women

9. PLCO: Ovarian cancer mortality
cancers
deaths

10. Mortality rates were similar
between both groups
Intervention group (screened) 118 deaths
3.1 er 10,000 person years
Usual care group 100 deaths
2.6 per 10,000 person years
(mortality RR, 1.18; 95% CI, 0.91-1.54 [unadjusted] )
(mortality RR, 1.18; 95% CI, 0.82-1.71 [sequentially adjusted])

11. Stage at detection, histology of
ovarian cancers detected and
treatment needed did not differ

12. Screening-related harms: Minor
Bruising or Fainting
58.3 in 10,000 Ca125
3.3 in 10,000 TVS

13. Screening-related harms
3285 false positive (5%),1080 (33%) of whom needed surgery
Major complication rate of 20/100 (some women had >1 complication)
Oophrectomy rates were 33% higher in intervention (85/10000) vs control (64/10,000)

14. Author's conclusion
"Annual screening for ovarian cancer as performed in the
PLCO trial with simultaneous CA-125 and transvaginal
ultrasound does not reduce disease-specific mortality in
women at average risk for ovarian cancer but does increase
invasive medical procedures and associated harms"

15. Other population cohorts
UKTOCS
200,000 (largest) ;50-74yrs old
70,000 (=PLCO); median 58yrs
Multimodal (annual Ca125 +/- TVS)
N
Shizuoka Cohort Study of ovarian
cancer screening
Annual TVS+CA125
Screening strategies Annual TVS
Control
Multimodal= 42 cancers
Annual TVS= 45 cancers
Preliminary results
*Overall 48% detected in stage I or II, no
difference in stage distribution in both groups
Control
Intervention= 35 cancers detected
after a mean period of 9yrs
Control= 32 cancers
*Results from controls not released yet
Significant withdrawal rate 5% in USS
and 1% in MMS group
?Acceptability of TVS as a screening modality
Mortality benefit
Pending (trial completes in 2014)
Pending (trial completed)

16. Screening in the high risk population

17. Before and after

18. BRCA-1/BRCA-2/HNPCC
BRCA1-/BRCA-2
Prophylactic BSO reduces lifetime risk of ovarian cancer from 40% to 1-2%
Reduces risk of breast cancer by 50%
Reduces risk of recurrent breast cancer if previously diagnosed
Risk of primary peritoneal cancer reduced 1% per year to 0.2% per year
(4% up to 20yrs after BSO)

19. Rarer famillial ovarian cancer
syndromes
Muir-Torre syndrome (MTS)
- sebaceous skin tumorss, colorectal, ovarian, endometrial
Turcot syndrome
-colorectal, CNS tumors, endometrial, ovarian

20. UKFOCSS
UK Familial Ovarian Cancer Screening Study
2002-2010
Overview
-Over 3500 women between 35-75 yrs old
-> 10% lifetime risk of developing ovarian cancer
-yearly Ca125 and TVS
Results
-14 of 37 women (38%) diagnosed with Stage I or II
-23 of 37 women (62%) diagnosed with Stage III or IV
Conclusion
Gap between screening may have impact on stage at diagnosis.
Interval > 1 year more likely to have advanced cancer at diagnosis

21. Phase II UKFOCSS
Will increased screening interval improve stage at detection?
4 monthly screening

22. So............... is there a role in
Ovarian Cancer Screening?
1) Low risk population
-Does not increase the detection of early stage ovarian cancer or
alter treatment rendered
- No statistically significant change in mortality
- Increased intervention (33% more oophrectomies) and complications
(1 in 5), especially in false positive cases
2) High risk population
-Awaiting outcome of Phase II UKFOCSS
-Genetic screening instead?

23. Is there a role for Ovarian
Cancer screening?
3) Type of tumor markers
Nested trials within the PLCO did not show any increase in sensitivity with
-HE4
-transthyretin
-CA15.3 / CA72.4
-apolipoprotein A1
-transferrin
-hepcidin
-beta-2 microglobulin
-connective tissue activating protein III
-inter-alpha-trypsin inhibitor heavy-chain
4) Serial rather than single Ca125 value?
"Ca125 trajectory"

24. HE-4
Raised in 50% of epithelial ovarian tumours that do not
express Ca125
Highly specific, allowing it to differentiate benign from
malignant tumors
Greater sensitivity than with Ca125 alone in detecting early
stage ovarian cancers

25. References
Sueblinvong T, Carney ME. Current of risk factors for ovarian cancer.
Current Treatment Options in Oncology 2009;10:67-81
Devlin LA and PJ Morrison PJ. Inherited gynaecological cancer syndromes.
TOG 10.1576/toag.10.1.009.27371 2008;10:9–15
Darnforth KN et al. Addendum to Screening for Ovarian Cancer: Evidence
Update for the U.S. Preventive Services Task Force Reaffirmation
Recommendation Statement. AHRQ Publication No. 12-05165-EF4
April 2012
Buys SS, Partridge E, Black A, et al. Effect of screening on ovarian cancer
mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer
Screening Randomized Controlled Trial. JAMA. 2011;305(22):2295-303

26. References
Menon U, Gentry-Maharaj A, Hallett R, et al. Sensitivity and specificity of
multimodal and ultrasound screening for ovarian cancer, and stage
distribution of detected cancers: results of the prevalence screen of the
UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet
Oncol. 2009;10(4):327-40.

27. THANK YOU

28. Limitations PLCO
The trial was powered for a 35% mortality reduction based on a predicted
number of mortality events (n = 226) that was essentially met. However, from a
public health point of view, smaller effect sizes are still potentially worthwhile
to detect.
The sequentially adjusted lower 95% CI for the mortality RR was 0.82,
indicating at most an 18% relative benefit within the limits of reasonable
probability. ( Ci was 0.82-1.71)
Additionally, the data collected on treatment were somewhat limited. The
PLCO trial neither abstracted the type of systemic therapy used, nor the type of
surgeon who performed the oophorectomy (eg, gynecologic oncologist or not);
both factors have been shown to be related to ovarian cancer survival.
However, we have no reason to suppose that these factors differed by study
group.