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Dr. Mutch reports receiving research support from the National Institutes of Health and the Gynecologic Oncology Group but no financial relationships relevant to this article. Dr. Novetsky reports no financial relationships relevant to this article.
To improve outcomes in women who have ovarian cancer—the deadliest gynecologic malignancy in the United States—we need to pursue a number of investigative approaches:
- We need to determine how to diagnose the disease in its early stages. At present, fewer than 20% of ovarian cancer cases are identified while disease is localized to the adnexae. Although a symptom index has been suggested as a useful tool to highlight women at risk for ovarian cancer, its appropriate implementation and effectiveness have yet to be determined.1 Moreover, the symptoms of ovarian cancer are vague and may not become apparent until after the disease has metastasized. Might screening trials detect ovarian cancer in its earlier stages? Are there harms involved in screening women with transvaginal ultrasonography (TVUS) and cancer antigen (CA) 125?
- We need new first-line agents to treat ovarian cancer. Traditional therapy is surgical cytoreduction followed by platinum-based chemotherapy. More recently, the addition of intraperitoneal chemotherapy has prolonged survival by approximately 16 months in women who have advanced disease.2 Despite this advance, the relapse rate remains high. What new therapies can we offer in addition to traditional platinum-based chemotherapy?
- Ovarian cancer recurs in most women, and the response to subsequent therapy is short-lived.3,4 Novel biologic agents may offer new hope as a means of treating recurrent disease with greater specificity and lower toxicity. Do any biologic agents increase survival and reduce the toxicity of treatment?
In this article, we highlight notable studies published in the past year that address these questions.
Screening for ovarian cancer is not useful in average-risk women
Buys SS, Partridge E, Black A, et al; PLCO Project Team. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Randomized Screening Trial. JAMA. 2011;305(22):2295–2303.
Gilbert L, Basso O, Sampalis J, et al; DOvE Study Group. Assessment of symptomatic women for early diagnosis of ovarian cancer: results from the prospective DOvE pilot project. Lancet Oncol. 2012;13(3):285–291.
The Prostate, Lung, Colorectal and Ovarian (PLCO) trial addresses the utility of screening for ovarian cancer using two readily available tests—TVUS and CA 125.
Effective screening for any disease requires the following:
- The disease must have a presymptomatic stage during which diagnosis leads to better outcomes (compared with waiting until the onset of symptoms)
- The screening test must be acceptable to the population in which it is used
- The test must lead to a reduction in morbidity and mortality that outweighs the harms of false-positive tests
- The benefits of the test must be achieved at an acceptable level of risk.5
The PLCO trial was designed to determine the effect of specific ovarian cancer screening tests on cause-specific mortality. Women aged 55 to 74 years were randomly assigned to annual screening with TVUS and CA 125 or to standard gynecologic care. A CA-125 level of 35 or higher was classified as abnormal, as were TVUS findings of enlarged ovaries or solid or papillary components. The trial had 88% power to detect a 35% reduction in ovarian cancer mortality using a one-side a of 0.05.
Early results demonstrated that a large number of surgeries would be required to detect one case of ovarian cancer. Mortality data from the study only recently matured.6
Details of the PLCO trial
Approximately 39,000 women were allocated to each arm of the PLCO trial and followed for 6 years. Ovarian cancer was diagnosed in 212 and 176 women in the screening and usual-care groups, respectively (relative risk, 1.21; 95% confidence interval [CI], 0.99–1.48). Equal percentages of women in each group were given a diagnosis of Stage III/IV cancer.
No survival benefit was seen in the screening group. Overall, 3,285 women had a false-positive screening test, with 33% undergoing surgery (21% surgical complication rate).
Barriers to effective screening
One of the major obstacles to the development of an accurate screening test for ovarian cancer has been the low prevalence of the disease. The relationship between sensitivity, specificity, prevalence, and positive predictive value (PPV) is demonstrated in the TABLE. With sensitivity of 100% and specificity of 95%, the PPV for ovarian cancer screening with TVUS and CA 125 is only 1%. Ovarian cancer has an annual prevalence of approximately 1 case in every 2,500 women.