The multivariate index assay was substituted for CA 125 in the College guidelines and the results are summarized in Tables 4, 5, and 6. Using McNemar's test, the sensitivity of the College guidelines with the multivariate index assay was significantly higher than the College guidelines (χ2 of 21.5 [df=1], P<.001). Compared with the College guidelines, the calculated negative predictive value for the College guidelines with the multivariate index assay also increased, whereas the specificity and positive predictive value decreased (Table 4). The improvement in sensitivity and negative predictive value was most notable for premenopausal women. When a subanalysis for primary ovarian malignancy was performed, the College guidelines with the multivariate index assay were more sensitive but less specific for early-stage disease than the original College criteria for premenopausal (Table 5) and postmenopausal (Table 6) women. When all 161 malignancies are evaluated, the College guidelines with the multivariate index assay identified 79% (15/19) of missed malignancies in premenopausal, and 67% (12/18) of malignancies missed in postmenopausal women compared with the College criteria. Furthermore, for primary ovarian malignancies (epithelial and nonepithelial ovarian malignancies), the College guidelines with the multivariate index assay correctly identified 78% (7/9) of missed early-stage premenopausal malignancies, and all five missed malignancies in postmenopausal women. The College guidelines with the multivariate index assay detected 93% (25/27) of premenopausal and all (76/76) postmenopausal primary ovarian malignancies.
There is agreement on the importance of early involvement of a gynecologic oncologist in the care of women with ovarian cancer.2–10 The challenge is how best to identify tumors at risk for malignancy, particularly in premenopausal women who account for up to 20% of all ovarian cancers.18,19 Examination alone is often unreliable.20,21 Although several algorithms have been proposed,5,6,22–28 they either are used infrequently or are ineffective given that only 30–40% of women with ovarian cancer initially are treated by a gynecologic oncologist.9,10 Sensible referral guidelines are important to help concentrate ovarian cancer care at centers where surgical expertise improves outcomes.29
In this multicenter trial, the College guidelines were evaluated in a diverse group of primary care and specialty centers. The sensitivity of the College referral criteria was lower than previously published.11,12 The predictive values were also lower in this study, which may be a consequence of lower overall cancer prevalence (31% compared with 37%). Considering the Dearking modifications, eliminating family history and lowering the CA 125 threshold for premenopausal women further emphasized the significance of the CA 125 result. In our trial, most patients did not show signs of advanced disease on imaging (8% ascites; 1% metastatic implants). So for all remaining premenopausal women, CA 125 was the only criterion left to determine the risk of malignancy.
The multivariate index assay is approved for use in women scheduled for surgery for an ovarian tumor. This assay combines CA 125 with four additional biomarkers, enhancing its ability to detect malignancy, particularly early-stage cancers. When the multivariate index assay replaces CA 125 in the College guidelines, the new guidelines detect almost 80% of all missed malignancies and more than 90% of missed epithelial ovarian cancers. The high sensitivity in premenopausal women and early-stage cancers is where CA 125 and the College guidelines have underperformed. Identifying these patients for referral is valuable because many are not receiving appropriate surgical staging and treatment.13,14 The College guidelines with the multivariate index assay are also effective at detecting advanced disease, where aggressive cytoreductive surgery and chemotherapy improve overall survival.7–10,29 In addition, the College guidelines with the multivariate index assay permit a simplified algorithm for evaluating a pelvic mass. Because menopausal status is incorporated into the multivariate index assay result and family history appears to be of marginal significance, the referral criteria can be simplified (Box 1). The clinical performance of this simplified algorithm is similar to Table 4, with sensitivity 93%, specificity 40%, positive predictive value 41%, and negative predictive value 93%.
Beyond identifying more malignancies, it is not known precisely how the multivariate index assay will affect the referral of patients. Adding the multivariate index assay to the College criteria resulted in a decrease in specificity, which implies that women with nonmalignant tumors may be referred to gynecologic oncologists. In actual practice, lower specificity does not necessarily translate into more benign tumor referrals. The decision to refer a patient is an individualized integration of medical and nonmedical variables. Historically, 12% to 40% of women referred to a gynecologic oncologist have an ovarian malignancy11,12,23; thus, current practice demonstrates that more than 60–80% of referrals are for benign disease. In this trial, the calculated specificity of the College criteria was 68%, yet the number of nonmalignant tumors referred to the gynecologic oncologist was very high. Of the 355 benign ovarian tumors in the study, 72% were referred to a gynecologic oncologist for surgery, including 45% of patients referred despite the belief by the enrolling physician that the tumor was benign. It is possible that the higher negative predictive value of the College guidelines with the multivariate index assay may add enough reassurance to deter referral in situations where the clinician is uncertain.
One of the strengths of this study is the multicenter design, enrolling a diverse patient population from numerous geographic sites. All study information was collected prospectively and recorded before surgery, including blood, imaging studies, physical examination, and family history. Also, internal biomarker validation was performed at two independent laboratories. A potential limitation of this study is the use of the newer CA 125-II assay rather than the original assay. Today, there are numerous CA 125 and CA 125-II assays which are available and used interchangeably for preoperative evaluations with very similar diagnostic accuracy.30 The cancer prevalence in this study is similar to previous reports.11,12 In a population with lower cancer prevalence, the test performance will have a lower positive predictive value and higher negative predictive value, although sensitivity and specificity will be unaffected.
In conclusion, replacing CA 125 with the multivariate index assay improves the sensitivity and negative predictive value of the College referral guidelines while decreasing specificity and positive predictive value. Using the multivariate index assay in the College guidelines will identify more malignancies before surgery, but further study is needed to determine the effect on patient referral.
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