Is there a role for ovarian cancer screening?

O&G Dept CME29 Nov 2013

Dr Voon Hian YanSupervisor: Dr Sim Wee Wee

What do they have in common?

7 Commandments on ScreeningAdapted by WHO after Wilson and Jungner

Significant prevalance and severityFixed spectrum of symptomsTests which are simple and acceptable to the patientAccurate screening testConfirmatory test availableTreatable diseaseFavourable cost/benefit ratio

Screening is done where direct diagnostic tests are costly/invasive / requires specialised personnel or equipment / greater risk to patient

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/yr8 in 10 are diagnosed in women >50yrs old

Incidence: 17 in 100,000 Lifetime risk: 1 in 71

No identifiable premalignant stages ex CIN5yr survival 94% if detected in Stage I (15% )Majority 60% are detected late with 5 yr survival 28%

Incessant ovulationInflammation

How and who to screen?HOWTumor 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)

WHOPost-menopausal womenGeneral population vs high risk groups

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

Target groupPostmenopausal women

PLCO: Ovarian cancer mortality

cancers deaths

Mortality rates were similar between both groups

Intervention group (screened) 118 deaths3.1 er 10,000 person years

Usual care group 100 deaths2.6 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])

Stage at detection, histology of ovarian cancers detected and

treatment needed did not differ

Screening-related harms: Minor

Bruising or Fainting

58.3 in 10,000 Ca1253.3 in 10,000 TVS

Screening-related harms

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

Author's conclusion

"Annual screening for ovarian cancer as performed in the PLCO trial with simultaneous CA-125 and transvaginalultrasound does not reduce disease-specific mortality in women at average risk for ovarian cancer but does increase invasive medical procedures and associated harms"

Other population cohorts

UKTOCS Shizuoka Cohort Study of ovarian cancer screening

N 200,000 (largest) ;50-74yrs old 70,000 (=PLCO); median 58yrs

Screening strategies

Multimodal (annual Ca125 +/- TVS)

Annual TVS

Control

Annual TVS+CA125

Control

Preliminary results

Multimodal= 42 cancers

Annual TVS= 45 cancers *Overall 48% detected in stage I or II, no difference in stage distribution in both groups

*Results from controls not released yet

Significant withdrawal rate 5% in USS and 1% in MMS group?Acceptability of TVS as a screening modality

Intervention= 35 cancers detected after a mean period of 9yrs

Control= 32 cancers

Mortality benefit Pending (trial completes in 2014) Pending (trial completed)

Screening in the high risk population

Before and after

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 diagnosedRisk of primary peritoneal cancer reduced 1% per year to 0.2% per year(4% up to 20yrs after BSO)

Rarer famillial ovarian cancer syndromes

Muir-Torre syndrome (MTS)- sebaceous skin tumorss, colorectal, ovarian, endometrial

Turcot syndrome-colorectal, CNS tumors, endometrial, ovarian

UKFOCSSUK 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

ConclusionGap between screening may have impact on stage at diagnosis. Interval > 1 year more likely to have advanced cancer at diagnosis

Phase II UKFOCSS

Will increased screening interval improve stage at detection?

4 monthly screening

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?

Is there a role for OvarianCancer screening?

3) Type of tumor markersNested 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"

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

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-EF4April 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

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.

THANK YOU

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.