Cancer Screening: How Good Is Good Enough?

Ovarian cancer is diagnosed in approximately 25,000 women and accounts for more than 14,000 deaths in the United States each year. Stage for stage, the prognosis for women with ovarian cancer does not differ greatly from that of women with breast cancer. However, the higher mortality associated with ovarian cancer is related to the fact that approximately three fourths of women have stage III or IV disease at diagnosis. Like early-stage breast cancer, earlystage ovarian cancer is potentially curable, with survival rates in excess of 80% for patients with stage I and II disease. Thus, there is intense interest in the development of a screening test capable of diagnosing ovarian cancer in its presymptomatic, early stages. The challenges to this effort are several. The prevalence of ovarian cancer is an order of magnitude lower than that of breast cancer. When the sensitivity and specificity of any single screening procedure or assay are relatively low, the application of such tests in a low-prevalence disease results in very low positive predictive value. Finally, in ovarian cancer, positive test results require an invasive procedure— laparoscopy or laparotomy—to rule out malignancy. It has been suggested that an ovarian cancer screening test should have a positive predictive value of at least 10%; therefore, 10 women would undergo surgery to diagnose one cancer. Given the low prevalence of ovarian cancer in the general population, to achieve this positive predictive value, the screening test would require a sensitivity of greater than 75% and a specificity of at least 99.6%. These high test performance thresholds were nearly achieved in a pilot randomized trial of 22,000 postmenopausal women using CA-125 screening compared with no screening, and sonography for screened women with elevated CA-125 values. The specificity of CA-125 was 98% (thus 2% of all women were referred for sonography) and the sensitivity of the two-step screening strategy was 71% for all ovarian cancers. However, the sensitivity for early-stage cancers was only 40%. Overall survival did not differ between the screened and nonscreened groups, although the study was neither designed nor powered to detect such a difference. In addition, although 31% of the cancers in the screened group were stage I or II, compared with 10% of the cancers in the nonscreened group, there is no clear evidence that this shift was attributable to screening. Historically, even among nonscreened populations, 25% to 30% of women present with early-stage cancers, and it is unlikely that presymptomatic detection of stage III and IV cancers would significantly reduce ovarian cancer mortality. In this issue of the Journal of Clinical Oncology, Skates et al report the results from a study that aimed to improve the first-step sensitivity of serum screening for early-stage ovarian cancers, while fixing specificity at 98%. Their approach was to combine the information contributed by four serum markers using logistic regression, classification trees, and mixture discriminate analysis, and then determine which combination yielded the highest sensitivity for early-stage cancers. Using sera collected before surgery, the authors created a training set of 63 ovarian cancer patient cases (27 of which were from women with early stage cancers) and 126 controls, and a validation set of 60 patient cases and 98 controls. The authors determined that the greatest sensitivity for early-stage ovarian cancer was obtained with the combination of CA-125, CA 72-4, and macrophage colonystimulating factor. In the mixture discriminant analysis model, this combination had a sensitivity of 70% for earlystage cancer when specificity was fixed at 98%. The authors postulate that a first-step specificity of 98%, when combined with a second-step sonography, would yield a combined two-step screening approach specificity of 99.6%. Given this substantial improvement in sensitivity over firststep screening with CA-125 alone, with preserved specificity, why is this three-marker approach not yet ready for general application? The answers relate to some of the greatest challenges in ovarian cancer screening, including our currently limited knowledge of the pathophysiology of tumor progression and the difficulty of screening for a lowprevalence disease. A strength of this study is the use of an independent validation data set from patients at institutions other than JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 20 OCTOBER 15 2004