Ovarian cancer remains the leading cause of death from gynecologic malignancy in the United States. The poor survival rate associated with ovarian cancer is largely because of the advanced stage of the cancer at the time of diagnosis in the majority of patients. As with other cancers, survival is significantly increased when ovarian cancer is detected at an early stage. For example, for women with stage I cancer, the 5-year survival rate is 89%; 66% for stage II; 34% for stage III, and 18% for stage IV. Consequently, there has been a significant amount of research aimed at early detection and the development of screening strategies. Screening methods evaluated include serum tumor markers and ultrasonography. An ovarian cancer symptom index has been developed which has been used in combination with tumor markers. Nevertheless, the current evidence strongly argues against routine screening in average-risk women with CA-125 and/or ultrasonography (JAMA 2011;305:2295-303). We will briefly discuss the current evidence as well as the current guidelines for screening inpatients with and without a strong family history.
Dr. Daniel L. Clarke-Pearson
Tumor markers, most specifically CA-125, have received significant attention as they are noninvasive, easy to repeat, and relatively inexpensive. While serum CA-125 is elevated in 50% of women with early stage ovarian cancer, it is nonspecific and can be elevated in up to 1% of healthy women as well as in women with other benign and malignant conditions. Therefore, trials looking at annual screening CA-125 levels have failed to show sufficient specificity for the test to be used in an average risk population. In addition, the lifetime risk of developing ovarian cancer in the United States is 1.4%. As a consequence of this low prevalence, CA-125 has shown unacceptably low positive predictive values as a stand-alone test, ranging from 2.6%-3.7% (Am. J. Obstet. Gynecol. 2005; 193:163-9; Obstet. Gynecol. 2009;113:775-82).
A second tumor marker, with similar sensitivity to CA-125, is HE4, human epididymis protein 4. In a validated algorithm, using both tests appears to be more sensitive than either test alone, correctly classifying 93.8% of masses as high risk of being an epithelial ovarian cancer (Gynecol. Oncol. 2009;112:40-6).
Nevertheless, the HE4 assay has not been studied for the purpose of screening. The improved sensitivity seen with this combination suggests that such a strategy may provide improved detection rates as the first step in screening protocols. However, in order for any of these tumor markers to serve as screening tests, they should be able to predict disease before the clinical diagnosis has been established, and this has not been the case.
Both of these tumor markers have been evaluated in combination with the ovarian cancer symptom index. The index screens women for symptoms related to ovarian cancer such as bloating, increased abdominal girth or early food satiety occurring more than 12 times per month for less than a year. The symptom index, when used in combination with CA-125, improves the sensitivity over CA-125 alone. Furthermore, if HE4 is included, the sensitivity is 84% when two of the three tests are positive. However, because of the lack of specificity of the symptoms included in the index, the test should only be used in a stepwise fashion, and women who test positive need follow-up with transvaginal ultrasound.
Dr. Dario R. Roque
Unfortunately, the sensitivity of transvaginal ultrasonography (TVUS) is user dependent, and the test has not been shown to be much better than CA-125 when used alone or in combination with the tumor marker. In the UKCTOCS (U.K. Collaborative Trial of Ovarian Cancer Screening) trial, TVUS detected 25 invasive carcinomas but only 12 of those were early-stage disease. The UKCTOCS trial also enrolled patients into a multimodal screening arm. In that arm, the Risk of Ovarian Cancer Algorithm (ROCA) was utilized as the first screening step and patients that were deemed high risk based on the algorithm had a TVUS. The ROCA is a computer algorithm that essentially compares changes that happen in a woman’s baseline CA-125 levels over time with the baseline changes seen in women who developed ovarian cancer. Patients are then deemed low risk, intermediate or high risk based on their ROCA score. For those who are low risk, a CA-125 is repeated in a year; patients at intermediate risk have a CA-125 repeated within 3 months. Each time the CA-125 is checked, the patient undergoes a new risk stratification using ROCA and her risk may be upgraded or downgraded, based on the new score. Lastly, if a patient is deemed to be at high risk, she undergoes a TVUS for further evaluation. Using this algorithm, the UKCTOCS demonstrated that multimodal screening with TVUS and CA-125 had better sensitivity, specificity, and positive predictive for detection of invasive primary cancer than TVUS alone (Lancet Oncol. 2009;10:327-40).