APPENDIX VII: OVARIAN CANCER SCREENING

Carolyn D. Runowicz, M.D.

Since ovarian cancer is the fifth leading cause of all cancer deaths in women, the goal of effective ovarian cancer screening would be to detect early stage disease with a subsequent improvement in overall survival. A successful screening program aimed at the early detection of ovarian cancer would require that major abdominal surgery (laparoscopy and/or laparotomy) be performed, as this is the only means of a definitive diagnosis. Because of the low incidence of ovarian cancer and the necessity of major abdominal surgery, a screening program requires a very high accuracy. The lowest acceptable positive predictive value (PPV) for an ovarian cancer screening test for the general population should be 10%; that is, no more than 10 women subjected to laparoscopy/laparotomy to detect one case of ovarian cancer. With the low incidence of ovarian cancer and a requirement of a PPV = 10%, the sensitivity must be 100% and the specificity = 99.5%. This high specificity is essential to minimize morbidity associated with major abdominal surgery. The level of specificity could be increased by screening a population with a higher incidence of ovarian cancer, such as women with a hereditary ovarian cancer syndrome or a known genetic mutation (e.g. BRCA1). Women with a family history of a hereditary ovarian cancer syndrome or with a BRCA1 mutation in a cancer family kindred have a lifetime probability of ovarian cancer of up to 40 - 60%.

CA-125 is an antigenic determinant on a high-molecular-weight glycoprotein recognized by a monoclonal antibody (OC125). CA-125 levels are elevated in a variety of physiologic benign and non-gynecologic malignant conditions (Table 1). CA-125 levels are greater than 35 U/mL in only 50% of patients with Stage I ovarian cancer (PPV = 2.4). Serial determinations of CA-125 may improve the specificity and sensitivity of the assay.

Jacobs and associates screened 22,000 postmenopausal patients with CA-125 and rescreened 340 women with elevated levels (CA-125 > 30 U/mL) using transabdominal ultrasound. Surgical exploration was performed in 41/340 (12%). At two years follow-up, 19 ovarian cancer cases were detected. Eleven of these ovarian cancer cases were detected by the screening program, yielding a sensitivity of 78.6% with a PPV of 26.8%. However, these investigators felt that there was a need to improve the sensitivity. This group evaluated a panel of six tumor markers and found the most useful additional marker was OVX1. The OVX1 antibody was developed by immunization with three ovarian cancer cell lines in a sequential manner. The use of both tests in combination, with a cut-off of CA-125 > 25 U/mL or OVX1 > 12 U/mL achieved a sensitivity of 80% and a specificity of 91%. This group has now launched a randomized prospective study of 120,000 postmenopausal women > 50 years, with the intervention arm screened with CA-125, OVX1 annually, and a calculation of the risk of ovarian cancer (ROC). Based on this calculation, the patients are either followed by annual markers or undergo further work-up with sonography.

The National Institutes of Health has included ovarian cancer screening in the Prostate, Lung, Colon and Ovarian (PLCO) study. A total of 74,000 women > 60 years will be randomized to a control group or to screening with clinical examination, CA-125 and ultra-sound as first-time test. It will take 16 years to detect a 30% reduction in mortality with 80% power.

The European Multicentre Study is an ongoing trial of 120,000 postmenopausal women randomized to a control group or to two study groups to be screened by vaginal ultrasound either every 1.5 or 3 years. Women with abnormal ultrasound findings will have a color flow Doppler examination. The trial has a 78% power to detect a significant difference between the combined ultrasound groups and the control group after eight years, assuming a 33% reduction of mortality for both screened groups.

Recommendations of professional organizations:

1. US Preventive Services Task Force (1989): Screening of asymptomatic women for
   ovarian cancer is not recommended.

2. American College of Obstetricians and Gynecologists (1992, 1993):
   Routine screening for ovarian cancer using currently available techniques is not
   recommended.

3. American Cancer Society: Periodic (yearly) pelvic examinations.

4. National Institutes of Health Consensus Conference on Ovarian Cancer:

All women should have a comprehensive family history taken by a physician knowledgeable in the risks associated with ovarian cancer and should continue to undergo annual rectovaginal pelvic examination as part of routine medical care. For patients with a hereditary ovarian cancer syndrome (assuming autosomal dominant inheritance with 80% penetrance), the lifetime risk of ovarian cancer is approximately 40%. There are no data demonstrating that screening these high-risk women reduces their mortality from ovarian cancer. Nonetheless, at least annual rectovaginal pelvic examination, CA-125 determinations, and transvaginal sonography are recommended in these women. When childbearing is completed, or at least by age 35, prophylactic bilateral oophorectomy is recommended to reduce this significant risk. Prophylactic oophorectomy does not preclude a small risk of developing peritoneal carcinomatosis, which is clinically similar to advanced ovarian cancer.

Review of literature for "high-risk" patients:

Karlan BY, et al studied 597 asymptomatic women with a family history of at least one first-degree relative with breast, colon, ovarian or other gynecologic cancer or a first-degree relative with ovarian cancer. Patients were followed with blood and urine biomarkers. 1.4% had CA-125 values >35 U/mL. A more recent evaluation of these data suggests an elevation of CA-125 in 18% of patients (Karlan by personal communication). The majority of patients are premenopausal. Ultimately, 19 patients underwent laparotomy and one tumor of low malignant potential was identified.

Click here to view
"Table I: Elevations of CA-125 (>35 U/mL)"

References:

1. Galen RS, Gambino SR: Beyond normality: the predictive value and efficiency of medical diagnosis. New York, John Wiley & Sons, 1975.

2. Jacobs I, Davies AP, Bridges J et al: Prevalence screening for ovarian cancer in postmenopausal women by CA-125 measurements and ultrasonography. BMJ 306:1030, 1993.

3. Kramer BS, Gohagen J, Prorok PC, Smart CI. A National Cancer Institute sponsored screening trial for prostate, lung, colorectal and ovarian cancers. Cancer 71:589, 1993.

4. Easton DF, Ford D, Bishop T and the Breast Cancer Linkage Consortium. Breast and ovarian cancer incidence in BRCA1 mutation carriers. Am J Hum Genet 56:265-271, 1995.

5. Carlson KJ, Skates SJ, Singer DE. Screening for ovarian cancer. Ann Int Med 121:124, 1994.

6. Karlan BY, Raffel LJ, Crvenkovic G et al. A multidisciplinary approach to the early detection of ovarian carcinoma: Rationale, protocol design, and early results. Am J Obstet Gynecol 169:494, 1993.

7. Jacobs I et al: Combinations of markers and screening for ovarian cancer. Int J Gynecol Obstet 46:83, 1994.