Screening for Ovarian Cancer

Ovarian cancer is the fifth most common cancer in women and is the most common cause of gynecologic cancer mortality. Approximately 1 in 70 women will develop ovarian cancer in their lifetime. Many risk factors have been identified in the carci-nogenesis of ovarian cancer, and patients with varying levels of risk can be further stratified into different groups. Recommendations for ovarian cancer screening vary according to the patient's level of risk. Advancing age, infertility, endometriosis, and postmenopausal hormone replacement therapy typically lead to a mildly increased risk of ovarian cancer in individuals compared with that of the general female population (relative risk [RR] < 3),2-5 whereas inherited mutations in the cancer susceptibility genes such as BRCA1, BRCA2, and mismatch repair genes associated with hereditary nonpolyposis colon cancer (HNPCC) syndrome lead to much higher RRs of approximately 30 to 45, 6 to 20, and 6 to 9, respectively, compared with RRs of the general population.6-13 In the absence of genetic testing information, a family history of ovarian cancer or early-onset breast cancer has been associated with intermediately increased risk of ovarian cancer with a RR of approximately 3 to 5 compared with the general population,14-16 but it is not clear how much of this increased risk is accounted for by mutations in the known ovarian cancer susceptibility genes.

A number of tests have been evaluated as potential methods of screening for ovarian cancer. Screening tests with the greatest evidence base include serum CA-125 and transvaginal ultrasound. Although a number of imaging modalities have been evaluated for possible use in ovarian cancer screening, transvaginal ultrasound has consistently been the most promising imaging modality for routine screening for ovarian cancer. In the largest study to date evaluating ultrasound as a screening method for ovarian cancer, 14,469 women predominantly with an average risk of ovarian cancer were followed up with annual transvaginal ultrasounds.17 In this study, ultrasound was found to have 81% sensitivity and 98.9% specificity, resulting in a positive predictive value of 9.4%. The authors also suggested that transvaginal ultrasound was associated with an early detection of ovarian cancer, with 11 of 17 screen-detected ovarian cancers being diagnosed at stage I. Critics, however, have pointed out that only 2 of the 11 stage I screen-detected cancers were high grade, compared with all six of the screen-detected advanced-stage ovarian cancers.

Several studies have evaluated the simultaneous use of transvaginal ultrasound and testing for CA-125. These studies have suggested that the combination of these tests results in a higher sensitivity for ovarian cancer detection, but at the cost of an increased rate of false-positive results. In the ongoing Prostate, Lung, Colorectal and

Ovarian Cancer (PLCO) Screening Trial, 28,816 women were randomized to receive annual transvaginal ultrasound and CA-125. At baseline, 1338 (4.7%) ultrasounds and 402 (1.4%) CA-125 tests were abnormal. Workup of these abnormalities led to the diagnoses of 20 invasive ovarian cancers. The positive predictive values of abnormal tests were 1.0% for transvaginal ultrasound and 3.7% for CA-125. When both tests were abnormal, however, their combined positive predictive value was 23.5%.18 Final results comparing this screened cohort to a control group of 39,000 women randomized to usual care are expected in 2015.

Several national organizations, including the American Cancer Society, the American College of Obstetricians and Gynecologists/Society of Gynecologic Oncologists, the United States Preventive Services Task Force, and the National Cancer Institute, have stated that there is inadequate evidence to determine whether routine screening for ovarian cancer will result in decreased mortality rates and that therefore transvaginal ultrasound and CA-125 blood tests are generally not recommended for ovarian cancer screening of women without known strong risk factors, although genetic counseling may be helpful for women with intermediately increased risk (RR 3-5) to clarify the risk of ovarian and related cancers. For women with inherited risk (i.e., documented mutations in BRCA1 or BRCA2), the Cancer Genetics Studies Consortium recommended screening with CA-125 and transvaginal ultrasound one to two times per year, starting between ages 25 and 35 years. The National Comprehensive Cancer Network recommends risk-reducing salpingo-oophorectomy in these high-risk individuals ideally between the ages of 35 and 40 years. For patients who do not choose to undergo risk-reducing salpingo-oophorectomy, ovarian cancer screening is recommended with transvaginal ultrasound and CA-125 twice a year starting at age 35 or 5 to 10 years earlier than the earliest ovarian cancer diagnosis in the family.

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