98ca screening

SCREENING FOR OVARIAN CANCER.

HASSAN LATIFAH GYNECOLOGIC ONCOLOGIST KFSH&RC -‐ JEDDAH

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.

SCREENING

§  Screening has the potential to pick up the disease at a much earlier stage, and therefore potentially could save thousands of lives world-‐wide.

§  But do we have screening methods that enable us to detect ovarian cancer at an earlier stage of the disease?

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).

PLCO study (Prostate,Lung,Colon and Ovary) §  A large RCT (PLCO) was conducted to determine

whether screening for ovarian cancer compared with no screening can achieve earlier diagnosis and decreased mortality.

§  The data showed no change in the stage of cancer detected by screening and no decrease in cancer-‐specific or overall mortality for women who underwent annual screening (four years of transvaginal ultrasound and six years of CA 125 serum levels).

Buys SS et al : Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA 2011

PLCO study

§  15 percent of women who underwent surgery for false positive findings experienced a serious complication related to surgery .

§  The problem of false-‐positive screening tests becomes critically important in diseases with low prevalence.

§  Unless the test or sequence of tests is extremely accurate, a large number of healthy women would be at risk for unnecessary surgery.

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

§  Pelvic exams : §  Early stage presymptomatic tumors are rarely detected .

§  The majority are at an advanced stage and associated with poor prognosis.

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 .

At four years of follow-‐up, the positivity rates of CA 125 remained essentially unchanged from baseline and the positive predictive value was 2.6 percent .

Other tumor markers: HE4 §  HE4 — Human Epididymis Protein 4

-‐ Similar sensitivity to CA 125 when comparing serum

from ovarian cancer cases to healthy controls, and a higher sensitivity when comparing ovarian cancer cases to benign gynecologic disease.

-‐In a study of 531 women with pelvic masses, an algorithm

using HE4 and CA 125 correctly classified 93.8 percent of cases of epithelial ovarian cancer as high risk.

-‐This model can be used to effectively to triage patients to

centers of excellence.

A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. AUMoore RG et al Gynecol Oncol. 2009;112(1):40.

CA-‐125+HE4+CEA+VCAM-‐1

§  A four-‐marker panel had the highest diagnostic power, with 86 percent sensitivity for early-‐stage ovarian cancer at 98 percent specificity.

§  Another study looked at tumor markers in stored

serum samples and compared between 70 case-‐matched controls and 34 women who developed ovarian cancer after the trial onset .

Development of a multimarker assay for early detection of ovarian cancer.

AUYurkovetsky Z et al J Clin Oncol. 2010;28(13):2159.

CA 125 + mesothelin and HE4

§  Three tumor markers (CA 125, mesothelin, and HE4) began to increase three years before the diagnosis of ovarian cancer.

§  CA 125 was most strongly predictive of ovarian cancer, with evidence for some incremental contribution of HE4 and mesothelin to risk prediction.

-‐ Development of a multimarker assay for early detection of ovarian cancer.

AUYurkovetsky Z et al J Clin Oncol. 2010;28(13):2159.

-‐ Assessing lead time of selected ovarian cancer biomarkers: a nested case-‐control study.AUAnderson GL et al J Natl Cancer Inst. 2010:;102(1):26.

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.

The Kentucky 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).

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

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

§  Three large randomized trials have evaluated combination screening with serum CA 125 and ultrasonography, either performed sequentially (ultrasound only if the CA 125 is elevated) or concurrently. One trial has reported final data and two are ongoing.

PLCO

§  Screening of 28,816 women found 1740 with either an abnormal CA 125 or ultrasound, and 34 had both .

§  Nearly one in three women who had a positive

screening test underwent surgery . §  Among 570 women who had surgery, 29 tumors

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

PLCO §  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.

§  Both the incidence of ovarian cancer and the mortality rate were non significantly greater for women allocated to the intervention (rate ratios 1.21, 95% CI 0.99-‐1.48 and 1.18, CI 0.91-‐1.54, respectively)

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

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) .

§  This study found 42 primary ovarian and tubal cancers in the

MMS group; 8 tumors were borderline and 16 of the 34 invasive cancers (47 percent) were stage I or II.

§  The PPV for detection of primary invasive cancer was 35.1 %

§  Specificity was significantly greater for MMS compared to TVUS.

Mortality data for this trial will be available in 2015. Prospective study using the risk of ovarian cancer algorithm to screen for ovarian cancer.AUMenon J Clin Oncol. 2005;23(31):7919.

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.

High risk women

§  In one surveillance program for women over 35 years of age with a family history of ovarian, breast, colon, or endometrial cancer, or a personal history of breast cancer.

§  1261 participants were screened with transvaginal sonography, color doppler imaging, and CA 125 every one to two years for a total of 6082 screens .

§  Three stage I ovarian carcinomas were detected by ultrasound, but an

additional seven peritoneal serous papillary carcinomas with metastasis occurred despite the screening intervention.

CA125 and transvaginal ultrasound monitoring in high-‐risk women cannot prevent the diagnosis of advanced ovarian cancer.AUOlivier RI et al Gynecol Oncol. 2006;100(1):20.

High risk women

§  Four years of screening with CA 125 and transvaginal ultrasound had a sensitivity of 40 percent and specificity of 99 percent in a series of 312 women 35 years or older who were carriers for BRCA 1 or 2 (screened semiannually) or members of a family with hereditary breast and/or ovarian cancer syndrome (screened annually).

§  Three out of the four-‐early stage tumors found at prophylactic bilateral salpingo-‐oophorectomy (n = 156) were in women who had normal Ca-‐125 and ultrasound.

AULacey et al Obstet Gynecol. 2006;108(5):1176.o had normal CA 125 and ultrasound findings.

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.

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.


§  Women at increased risk For women with a family history of ovarian

cancer, it is important to differentiate those with a possible rare familial ovarian cancer syndrome and those with the more common presentation of an isolated family member with ovarian cancer, without evidence of a hereditary pattern.

Risk assessment criteria for inherited breast-‐ovarian cancer syndome, combining several guidelines Non-‐Jewish families.

Any of the following:

§  One case of breast cancer ≤40 yo in a FDR or SDR

§  One FDR or SDR with breast and ovarian cancer, at any age

§  Two or more cases of breast cancer in FDRs or SDRs if one is diagnosed at ≤50 years old, or is bilateral

§  One FDR or SDR with breast cancer at ≤50 years old, or bilateral and one FDR or SDR with ovarian cancer

§  Three cases of breast and ovarian cancer (at least one case of ovarian cancer) in FDRs and SDRs

§  Two cases of ovarian cancer in FDRs and SDRs

§  One case of male breast cancer in an FDR or SDR if another FDR or SDR has (male or female) breast or ovarian cancer


§  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 six 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.

Summary

§  Screening average risk women for ovarian cancer is not recommended.

§  1 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.

§  Two other large trials are ongoing.

§  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. However, the PPV for MMS in high risk groups remains low.

§  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.

§  Women with a family history of ovarian cancer but do not have a confirmed ovarian cancer syndrome should be managed in a similar manner to women at average risk.

Thank you

98ca screening

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