There is no well-established strategy for early detection of ovarian cancer. Discovery of a pelvic mass on routine physical examination can lead to surgery prior to the dissemination of a malignancy, but conventional diagnosis detects only 20% of patients in Stage I. Given the prevalence of ovarian cancer in the postmenopausal population, any screening strategy must be highly specific (> 99.6%) as well as highly sensitive for early stage disease (> 75%) to achieve a positive predictive value of 10% (ie, 10 laparotomies for each case of ovarian cancer detected). Two approaches have been evaluated for early detection of ovarian cancer: ultrasonography and serum tests such as CA 125.

Ultrasound
Transvaginal sonography (TVS) has proven superior to transabdominal sonography (TAU) for the detection of a pelvic mass. In three large studies that screened 66,620 women, 565 operations were performed to detect 45 ovarian cancers, 34 of which were invasive. Overall, the sensitivity for early stage disease was 78%, but the specificity fell just short of that required for a positive predictive value of 10% with 12 operations per case of ovarian cancer detected. The most promising single study achieved a positive predictive value of 9.9%. Confirmatory tests with Doppler ultrasound have not proven consistent, but additional studies with 3-D power Doppler are underway to improve specificity in distinguishing malignant from benign ovarian abnormalities.

CA 125 CA 125 is elevated in 50% - 60% of patients with stage I and in 90% with stage II ovarian cancer. CA 125 levels can rise 10 to 60 months prior to diagnosis with an average estimated lead time of 1.9 years prior to diagnosis of disease in all stages. Specificity for a single determination of CA 125 is not adequate to screen a population at average risk, but specificity can be improved with a two-stage strategy that utilizes CA 125 followed by ultrasound in a subset of women with elevated CA 125. Use of CA 125 to trigger ultrasound has been evaluated in trials in Sweden and in the United Kingdom. The latter randomized 22,000 women to conventional surveillance or to annual CA 125 with TAU if the value were elevated. When TAU was abnormal, surgery was undertaken. Among 10,985 women screened, 29 operations were performed to detect 6 cancers, providing a positive predictive value of 21%. During 7 years follow-up, 10 more cancers were diagnosed in the screened group. Over the same intervals, 21 ovarian cancers were diagnosed in the control group. Median survival in the screened group (72.9 months) was significantly greater (p = .0112) than that in the control group (41.8 months).

Risk of Ovarian Cancer (ROC) Algorithm
Analyzing serum samples stored from screening studies in Stockholm and in the United Kingdom with an improved CA 125II assay, it has been possible to improve the specificity of CA 125 as a screening tool by following the values of an individual over time. Elevated CA 125 levels in women without ovarian cancer remain static or decrease with time, whereas levels associated with ovarian malignancy tend to rise. This finding has been incorporated into an algorithm that uses age, rate of change of CA 125 and absolute levels of CA 125 to calculate an individual’s “risk of ovarian cancer” (ROC). Patients at sufficient risk undergo TVS. Some 10,000 volunteers greater than 50 years of age have been randomized in the United Kingdom to a screening group (5,046) or to a control group (4,954). Using the ROC algorithm, 101 patients were found to be at sufficiently high risk to undergo TVS. Seventeen patients had abnormal findings prompting operations that detected 4 cases of ovarian cancer, yielding a positive predictive value of 20%.

Currently, a trial has begun in the United Kingdom that will include 200,000 post menopausal women who will be randomized to a control group (100,000) who will be followed with conventional pelvic examinations; a second group (50,000) who will have annual TVS; and a third group (50,000) who will have CA125 determined at least annually. Based on the ROC algorithm, patients in the third group will be referred for TVS and/or surgery. Women will be screened for 3 years and followed for 7 years. This trial may demonstrate more definitively the feasibility of screening for ovarian cancer as well as the impact of early detection on survival.

Complementary Markers
Whatever the outcome of the current trial in the United Kingdom or of the Prostate, Lung, Colon and Ovary (PLCO) screening trial with CA 125 and TVS in the United States, strategies based on CA 125 alone are not likely to exceed a sensitivity of 80%, as CA 125 is not expressed by 20% of epithelial ovarian cancers. Greater sensitivity might be attained through the use of multiple serum markers in combination, provided that specificity were not compromised. From a recent review, some 27 serum markers have been evaluated for their ability to complement CA 125 and to improve sensitivity for detection of ovarian cancer. Use of markers 2 to 3 at a time increased sensitivity 5% to 15%, generally at the expense of a substantial decrease in specificity. For example, use of CA 125 in combination with OVX1, a Lewis X determinant on mucin, and M-CSF, a cytokine, increased sensitivity for Stage I disease from 69% with CA 125 alone to 84% with the combination, but specificity declined from 99% to 84%.

A number of novel markers for ovarian cancer have been identified in recent years including mesothelin, a 110 kD fragment of EGFR, lysophosphatidic acid, HE4, prostasin, osteopontin, and human kallikreins 6 and 10. Use of surface laser desorption and ionization (SELDI) with subsequent resolution by mass spectroscopy has demonstrated a pattern of low molecular weight moieties that has been reported to distinguish sera from ovarian cancer patients from those of healthy individuals with 100% sensitivity and 95% specificity. Prospective replication of these results and determination of sensitivity for stage I disease should be available in the near future. SELDI may also identify a limited number of protein peaks that could be assayed by more conventional techniques. Mathematical techniques to combine markers, enhancing their sensitivity without sacrificing specificity, have also been developed. Both artificial neural networks and mixtures of multivariate normal distributions have been used to combine values for four serum markers (CA125 II, CA72-4, CA15-3 and M-CSF) from patients with stage I ovarian cancer and from healthy individuals. Using either technique, sensitivity could be increased from 48% using CA 125II alone to 72% to 75% using the combination, while maintaining specificity at 98%. In a two-stage strategy, an initial stage with 98% specificity would require ultrasounds to be performed in only 2% of women screened.

Current Recommendations for Women at Average Risk
The application of screening techniques other than pelvic examination for ovarian cancer in the entire female population is unwarranted at this time. The sensitivity and specificity of ultrasound and CA125 are low in premenopausal women, making it unlikely that this approach will be useful in this group. However, with refinements of the transvaginal and flow techniques, as well as the addition of other serum markers, screening could become a reality in the future. There is a need for critical studies to define the potential of different screening startegies and to determine whether their application can decrease mortality from the disease.

Current Recommendations for Screening Women at High-Risk
In women with strong evidence of a hereditary predisposition for ovarian cancer, screening has been frequently advocated, although the efficacy of such surveillance to reduce risk is unknown. Screening can be problematic because this high-risk population often includes premenopausal women who have a higher incidence of false positive CA 125 elevations and ultrasound abnormalities. In these high-risk populations, initial screening trials using ultrasound alone or in combination with color-flow Doppler and were associated with high false-positive rates (2.5% to 4.9%). The current trend is to combine ultrasound with CA 125.

There are now 5 prospective studies where combined screening has been undertaken in high-risk populations. In three screening programs involving a total of 1,228 women with a family history of ovarian cancer, no invasive ovarian cancer was detected and false-positive rates have ranged from 0.4% to 3.9%. In one of the remaining two studies, one case of ovarian cancer was detected on screening 137 high risk women with a false positive rate of 0.7%; in the other study 9 ovarian cancers were detected in screening 180 women with a false positive rate of 3.9%.

Women in the high-risk population who request screening should be counseled about the current lack of evidence for the efficacy for either CA 125 or for sonography as well as the associated false-positive rates. Many will still opt for screening despite the risks and limitations of the available strategies. Screening is best carried out in clinical trials such as those conducted by the Cancer Genetics Network or by several university centers. Screening with TVS every 6 to 12 months and with CA 125 every 3 to 6 months is currently being evaluated.