Screening for Ovarian Cancer

1. Screening for Ovarian Cancer

2. Why screen for ovarian cancer? • For advanced disease 5-year survival rates are reported to be less than 30%, whereas for patients diagnosed with stage I disease, the 5-year survival is reported to be in excess of 90%

3. Why Not Screen for Ovarian Cancer • The incidence and prevalence of ovarian cancer in the general population is low -> low PPV and high false positives • False positives are followed up by invasive procedures with a small, but significant risk of complications • Up to 15% of women who undergo surgery for false positive findings develop serious complications resulting in morbidity and high cost of treatment • The predictive value of either CA125 or transvaginal ultrasonography (less than 3 percent) yields an unacceptably high rate of false-positive results and attendant morbidity and costs. • The combination of annual CA 125 testing with ultrasonography did not decrease mortality at 13 year follow-up in a large randomized trial and screening caused harm related to adverse effects from surgery for false positive findings

4. Screening For Ovarian Cancer Using CA 125 • CA 125 — Measurement of the serum concentration of the CA 125 glycoprotein antigen is the most widely studied biochemical method of screening for ovarian cancer. • Serum CA 125 values are elevated in approximately 50 percent of women with early stage disease and in over 80 percent of women with advanced ovarian cancer • a prospective study of asymptomatic postmenopausal women found that an elevated CA 125 concentration (≥30 U/mL) was a powerful predictor of subsequent ovarian cancer risk (RR 35.9 at one year and 14.3 at five years)

5. Problems With Screening for Ovarian Cancer using CA 125 • The specificity of CA 125 is limited. CA 125 levels are elevated in approximately 1 percent of healthy women and fluctuate during the menstrual cycle. CA 125 is also increased in a variety of benign and malignant conditions, including: • Endometriosis • Uterine leiomyoma • Cirrhosis with or without ascites • Pelvic inflammatory disease • Cancers of the endometrium, breast, lung, and pancreas • Pleural or peritoneal fluid due to any cause • Mean CA 125 levels further vary with ethnicity and smoking status (lower in non-White women and current smokers) and increase with age • Studies of CA 125 in screening for ovarian cancer have focused upon postmenopausal women, since menstrual cycle variations and the prevalence of benign gynaecologic conditions in premenopausal women would result in a substantially higher likelihood of false-positive tests. Accumulated evidence suggests that annual CA 125 measurements alone lack sufficient specificity for use in an average risk population of postmenopausal women

6. Hereditary Breast-Ovarian Cancer Syndrome • The absolute risk of developing ovarian cancer over a lifetime associated with the presence of a BRCA1 mutation is 35 to 45 percent, while it is less for those with BRCA2 mutations (15 to 25 percent) • For women with a BRCA mutation, The American College of Obstetricians and Gynecologistsrecommends periodic screening with CA 125 and transvaginal ultrasonography beginning between the ages of 30 and 35 years or 5-10 years earlier than the earliest age of first diagnosis of ovarian cancer in the family. • Risk-reducing salpingo-oophorectomy surgery—which removes both of the ovaries and fallopian tubes—can reduce the risk of ovarian and fallopian tube cancer by about 85% to 90% among BRCA carriers. Women who have BRCA1 or BRCA2 mutations should be offered risk-reducing salpingo-oophorectomy by age 40 or when childbearing is complete. The ideal time for this surgery depends on the type of gene mutation.

7. Lynch II Syndrome • Women with Lynch syndrome have a lifetime risk of ovarian cancer that is 3 to 14 percent (compared with 1.5 percent in the general population) and develop ovarian cancer at an earlier age than the general population • HNPCC is an autosomal dominant inherited predisposition to develop colorectal and other cancers, including ovarian resulting from failure of the DNA mismatch repair system (MMR). • Screening involves a detailed Hx, especially FHx of colorectal, ovarian and other cancers, followed up by PCR amplification of MMR genes (MLH1, MSH2 followed by others if first test is negative)

8. Ultrasonography • Transvaginal ultrasonography has been evaluated as a screening toolSensitivity (80 to 100%) and specificity (94-99%) are operator dependent • It has shown to be a poor screening tool for high risk women, detecting cancers at stage III at the earliest. • Studies have found the method more useful in screening lower risk women (with a family Hx of ovarian cancer as opposed to familial types) where early stage cancers are more likely to be detected.

9. Multimodal Screening • Combining CA 125 with transvaginal ultrasonography • One UK study found elevated CA 125 (adjusted using an algorithm to correct for stuff) followed by confirmatory ultrasound had an 89.5% sensitivity, with 45% of cancers detected at stages I & II. Specificity was 99.8% • A UK study of Risk of Malignancy Index combined ultrasound score, menopausal status and serum CA 125. Three criteria are combined in a risk of malignancy index (RMI) which is calculated using the product of the serum CA 125 level (U/ml), the ultrasound scan result (expressed as a score of 0, 1 or 3) and the menopausal status (1 if premenopausal and 3 if postmenopausal). Using an RMI cut-off level of 200, the sensitivity was 85% and the specificity was 97%. • Patients with an RMI score of greater than 200 had, on average, 42 times the background risk of cancer and those with a lower value 0.15 times the background risk.

10. Ovarian Cancer Symptom Index • The index is considered to be positive in women who report pelvic or abdominal pain, bloating, increased abdominal size, difficulty eating or early satiety occurring more than 12 times a month, with symptoms present for less than one year. • A study found the combination of the symptom index, CA 125 and HE4 serum markers as a first-line screen had a sensitivity of 83.8 percent and specificity of 98.5 percent when two of the three tests were positive. • If used for screening, a positive symptom index should lead to transvaginal ultrasonography before surgical referral.

11. When to Screen – 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. • The combination of annual CA 125 testing with ultrasonography did not decrease mortality at 13 year follow-up in a large randomized trial and screening caused harm related to adverse effects from surgery for false positive findings

12. When To Screen – Lower Risk Family Hx • Women with a family history but without evidence of a high-risk pattern. • There is no evidence to support screening in this group, and decisions regarding screening should be based on individualised considerations involving the patient and clinician.

13. When To Screen – High Risk • Women who are found to have BRCA1 and/or BRCA2 or MMR gene defects. • Even though evidence for screening effectiveness has not been demonstrated, the decision to screen this patient population is based on their very high lifetime risk of ovarian cancer. • The optimal screening protocol, or frequency for screening, has not been determined (Up To Date 2011).