Screening for ovarian cancer may 15

SCREENING FOR OVARIAN CANCER.

HASSAN LATIFAH GYNECOLOGIC ONCOLOGIST KFSH&RC – JEDDAH May 2015

Ovarian cancer – the troublesome female genital cancer.

Background

Ovarian cancer has a poor survival rate because it is often diagnosed at an advanced stage.

About 75% are in FIGO stage 3 and 4 at the time of diagnosis.

5-year survival is over 90 percent for the minority of women with stage I disease, 25% for those with distant metastasis.

Survival rate is almost identical for all gynaecological cancers stage‐by‐stage.

In order to improve survival the malignancy should be detected and treated at an earlier stage.

RISKS AND BENEFITS OF SCREENING

The potential benefit of screening is its ability to identify ovarian cancer at a more localized and curable stage, leading to reduced mortality from the disease.

The risk is that a positive screening test for ovarian cancer most often is followed by surgery (either laparoscopy or laparotomy).

Screening tests

PPV : 10% ie no more than 9 healthy women with false positive screens would undergo unnecessary procedures for each case of ovarian cancer detected.

A screening program that targets all women over age 50 would require a test with a specificity of at least 99.6 % , a sensitivity of at least 80 % to achieve a PPV of 10%,

Screening tests:Tumor markers

CA-125 : - raised in 50% of women with early stage ovarian cancer

and over 80% of women with advanced disease.

Limited specificity :

- raised in 1 % of healthy women , fluctuates during menstrual cycle .

- Endometriosis – Fibroids-Cirrhosis-PID

- Cancers of the endometrium , breast ,lung

and Pancreas.

- Pleural or peritoneal fluid due to any cause.

Screening tests : CA-125

Annual CA 125 measurements alone lack sufficient specificity for use in an average-risk population of postmenopausal women.

Its use in premenopausal women carries a substantially higher likelihood of false-positive tests due to menstrual cycle variations and the prevalence of benign gynecologic conditions.

Screening tests: CA-125

Three large screening studies have shown that the specificity of a single CA 125 level for detection of ovarian neoplasms in postmenopausal women ranged from 98.6 to 99.4 percent, resulting in an unacceptably low positive predictive value of 3 percent.

.Elevated serum CA 125 levels prior to diagnosis of ovarian neoplasia: relevance for early detection of

ovarian cancer. Zurawski VR Jr et al Int J Cancer. 1988;42(5):677.

.Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonography. AUJacobs I et al BMJ. 1993;306(6884):1030. .

Screening tests: CA-125

In the ovarian component of PLCO, 78,237 healthy women between

55 and 74 years of age were randomly assigned to screening and control groups.

39,115 women were assigned to screening with annual CA 125 and annual transvaginal ultrasound.

Data from the baseline prevalence screen in 28,816 women found an abnormal CA 125 in 436 women (1.5 percent)

The positive predictive value for invasive cancer was 3.7 percent .

Pelvic ultrasonography

UKCTOCS the largest study to date, 48,230 women aged 50 to 74 years were randomly assigned to screening with annual TVUS as one arm of a randomized trial comparing multimodal screening (MMS), TVUS, and no screening.

The sensitivity, specificity, and positive predictive value were 75, 98.2, and 2.8 percent respectively for primary invasive cancer.

Pelvic ultrsonography

Specificity was lower for TVUS compared to multimodal screening, resulting in nine times as many surgeries performed for the TVUS compared to the MMS group to detect one cancer.

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).

Menon U et al Lancet Oncol. 2009;10(4):327

Multimodal screening

The combination of serum CA 125 and ultra -sonography, either performed sequentially (ultrasound only if the CA 125 is elevated) or concurrently.

In the UKCTOKS both MMS and USS strategies had encouraging sensitivity for primary EOC (89.5% and 75%, respectively).

PPV was significantly higher in the MMS group

(35.1% versus 2.8% in USS) resulting in lower rates of repeat testing and surgery .

The MMS has superior sensitivity (88.6% vs 65.8%) and PPV (21.7% vs 5.8%) compared to the USS arm for detection of primary EOC.

Ca-125 is interpreted ROCA is a Bayesian algorithm that compares the CA125 profile of cases to that of healthy women and incorporates age-specific incidence of OC in calculating the risk.

The closer the individual's profile is to the pattern of diseased women, the higher the estimated risk

The Kentucky study

Single arm prospective study 37,293 women received annual ultrasonographic screening between 1987-2011.

47 invasive EOC and 15 epithelial ovarian tumors of LMP were detected.

stage I, 22 (47%) stage II, 11 (23%) stage III, 14 (30%) and stage IV, 0 (0%). Follow-up varied from 2 months to 20.1 years (mean,

5.8 years)

The Kentucky study

SURVIVAL DATA.

The 5-year survival rate for invasive EOC detected by screening was:

- Stage I: 95%±4.8%

- Stage II: 77.1%±14.5%;

- Stage III: 76.2%±12.1%.

The Kentucky study

Survival data:

The 5-year survival rate for all women with EOC detected by screening as well as interval cancers was 74.8%±6.6% compared with 53.7%±2.3% for unscreened women with ovarian cancer from the same institution treated by the same surgical and chemotherapeutic protocols (P<.001).

Healthy volunteer effect . Long-Term Survival of Women With Epithelial Ovarian Cancer Detected by

Ultrasonographic Screening van Nagell et al .

Obstetrics & Gynecology :December 2011 - Volume 118 - Issue 6 - p 1212–1221

PLCO

Screening of 30,630 women found 1740 with either an abnormal CA 125 or ultrasound, and 34 had both .

RCT with 1 screening strategy : Ultrasound and CA-125 using a 35 kU/l cut-off

Lower sensitivity (69.5%) for primary OC/FT

cancer; (only 28% were Stage I/II)

Nearly one in three women who had a positive

screening test underwent surgery .

PLCO Among 570 women who had surgery, 29 tumors were found, of

which 20 were invasive (90 percent of these stage III or IV)

There was no difference in the stage of ovarian cancer, with advanced disease (stage III or IV) in 77 percent of the cancers in the intervention group and 78 percent in the usual care group.

No mortality benefit: 118 ovarian cancer deaths in the screened arm, 100 in the control arm.

The trial was stopped prior to scheduled completion because the monitoring board determined futility.

Japanese study

In a randomized controlled trial of 83,000 postmenopausal women in Japan, 42,000 women were invited to participate in annual screening with pelvic ultrasound and CA 125.

No significant difference in the detection of ovarian cancer, at an average follow-up of 9.2 years, between patients who received screening (27 cases) and control patients (32 cases).

There was a non-significant trend toward earlier-stage disease in the screened group. Thirty-three surgeries were performed to detect each case of ovarian cancer. Mortality data are not yet available.

UKCTOCS ( Promising trial)

The trial randomly assigned 202,638 postmenopausal women aged 50 to 74 years to no screening, annual TVUS, or multimodal screening (MMS) .

Two screening arms (ultrasound) and CA125 followed by ultrasound (multimodal, MMS) CA125 interpreted using the Risk of Ovarian Cancer (ROC) algorithm

Specificity was significantly greater for MMS compared to TVUS. Mortality data for this trial will be available in 2015.

The PPV for detection of primary invasive cancer was 35.1 %

Prospective study using the risk of ovarian cancer algorithm to screen for ovarian

cancer.AUMenon J Clin Oncol. 2005;23(31):7919.

Superior sensitivity (88.6% vs 65.8%) and PPV (21.7% vs 5.8%) of MMS compared to the USS arm for detection of primary invasive epithelial OC/FT cancers during incidence screening.

40.3% in the MMS and 51.5% in the USS arm detected at early stage.

Mortality data awaited in 2014/2015Mortality data to be reported in 2015

Discussion The largest ovarian cancer screening trial ever.

41,4 % ( 55 of 133 ) of women were detected with stage 1 or 2 disease.

Compared to single threshold rule , risk algorithm using serial biomarker measurement doubled the number of screen detected cancers .

ROCA detected 86,4 % .

35 : 41,3 %

30 : 48,4 %

22 : 66,5%

For each iEOC detected, four additional women underwent surgery.

High risk women

In a cohort of 888 women carriers of BRCA 1 or 2 mutations who underwent screening with annual transvaginal ultrasound and CA 125.

5 of 10 incident cancers were interval cases diagnosed in women who had had normal screening results 3 to 10 months previously .

Eight of the ten cancers were stage III at diagnosis.

Use of a stochastic simulation model to identify an efficient protocol for ovarian cancer screening.AUUrban N et al Control Clin Trials. 1997;18(3):251.

UK Familial Ovarian Cancer Screening Study (UKFOCSS)1

Annual screening with CA-125 using a cut-off and TVS does not detect early stage cancers.

(UKFOCSS) 3563 women underwent annual screening with serum CA125 and TVS.

Only 30.8% of screen-detected OC/FTCs were Stage I/II.

UKFOCSS 2

Phase II where annual CA125 screening was replaced by 4-monthly serum CA125 interpreted using the ROCA.

ASCO meeting in 2013 :

high sensitivity (67– 100%) for EOC with no interval cancers reported.

42% of incident screen-detected OC/FT cancers were Stage I/II.

92% of incident screen-detected cancers were completely cytoreduced compared to 62% on Phase I

Unsafe alternative to risk reducing surgery.

SYNTHESIS OF THE EVIDENCE

Women at average risk

- Screening for ovarian cancer with CA 125 or

ultrasound is NOT recommended for premenopausal and postmenopausal women without a family history of ovarian cancer.

- The predictive value of either test alone (less than 3

percent) yields an unacceptably high rate of false-positive results and attendant morbidity and costs.

SYNTHESIS OF THE EVIDENCE

High-risk family history - Women with a suspected hereditary ovarian cancer

syndrome should be referred to a genetic counselor for consideration of testing for BRCA1 and BRCA2 mutations.

- Women who have not elected risk-reducing surgery,

screening with TVUS plus CA 125 assays every 4 months starting at age 35 years or 5 to 10 years earlier than the earliest age of first diagnosis of ovarian cancer in the family.

Cancer specific biomarkers

TP53, BRAF and KRAS are frequently mutated in OC.

TP53 mutated in almost all Type II cancers whilst mutations in BRAF and KRAS are more common in borderline ovarian tumours and Type I cancers.

Li M, Diehl F, Dressman D, et al. BEAMing up for detection and quantification of

raresequence variants. Nat Methods 2006;3:95–7.

Liquid cytology cervical samples. A sequencing method to test for mutations in a

panel of 12 gene.

It identifies the expected tumor specific mutation. Increasing the number of potential gene targets and

improving collection methods could theoretically allow a more highly enriched sample of cells coming from the fallopian tube and ovary.

Kinde I, Bettegowda C, Wang Y, et al. Evaluation of DNA from the Papanicolaou testto detect ovarian and endometrial cancers. Sci Transl Med 2013;5:167ra164.

Summary

Screening average risk women for ovarian cancer is not recommended.

2 of 3 randomized trials of screening with annual CA 125 and TVUS in average-risk postmenopausal women has shown no decrease in mortality from ovarian cancer.

UKCTOCS mortality figures are still awaited.

UKCTOCS mortality figures are still awaited.

Preliminary data from the trial suggests that CA125 rise within normal range can be detected by the ROCA well before any abnormalities are detected on transvaginal imaging.

Whether this converts into a mortality impact will only be known in 2015.

Ca-125 is elevated in 50 to 90 percent of women with early ovarian cancer, but also can be elevated in numerous other conditions.

Screening with a single measurement of CA 125 alone, either in average- or high-risk women is not recommended.

TVUS when used as a sole screening intervention for higher-risk women, has not been effective in identifying early-stage cancer.

TVUS may be more effective when used as part of MMS, in conjunction with CA 125 interpreted using ROCA.

Periodically screening women with a familial ovarian cancer syndrome, who have not undergone prophylactic oophorectomy, with a combination of CA 125 and transvaginal ultrasound is recommeded.

Initiation at age 35 years or 5 to 10 years earlier than the earliest age of first diagnosis of ovarian cancer in the family.

Thank you