Screening for Ovarian Cancer
abstract & commentary
Synopsis: Screening for ovarian cancer remains of unproved value. In this randomized, controlled trial, Jacobs and colleagues from the United Kingdom examined the feasibility of a strategy that used serum CA-125 determination followed by pelvic ultrasonography for those with elevated marker levels. More than 10,000 women were randomized to this screening strategy that was used annually for three straight years. An equal number of women were followed without screening. Mortality from ovarian cancer was lower in the screened population.
Source: Jacobs IJ, et al. Lancet 1999;353:1207-1210.
The value of screening for ovarian cancer remains to be established. In this report, a novel screening strategy was used which involved both serum determination of the tumor marker CA-125 and, in patients with high marker levels, pelvic ultrasonography and gynecology consultation.
Postmenopausal women, aged 45 years or older, were randomly assigned to a control group (n = 10,977) or screened group (n = 10,958). No other risk factors (e.g. nulliparity) were evaluated to select subjects for screening. Those in the screened group were offered three annual evaluations that included measurement of serum CA-125 and pelvic ultrasound, if the CA-125 value was 30 units/mL or more. Individuals were referred to a gynecologist if the ovarian volume was 8.8 mL or more on the ultrasound evaluation. All of the enrolled women were followed up to determine if they developed invasive epithelial cancers of the ovary or fallopian tube.
In the screened group, 468 women (4.3%) with elevated CA-125 values were identified. Twenty-nine of these women (6.2% of those with high CA-125 levels and 0.26% of all screened women) were referred for gynecologic opinion based upon their ovarian volume by ultrasound. In this group, the screening detected an indexed cancer in six patients, whereas 23 had false-positive results. Thus, the positive predictive value (i.e., the fraction of persons with a positive test who actually had the disease) was 20.7%.
During the follow-up period (7 years), 10 additional women with indexed cancers were identified in this screened group, and 20 ovarian cancers were found in the control group. The median survival for women with indexed cancers in the screened group was 72.9 months vs. 41.8 months in the control group. (P = 0.0112). The number of deaths from an indexed cancer did not differ significantly between the control and screened groups (18 in the control group vs 9 in the screened group for a relative risk of 2.0, but with 95% confidence interval 0.78-5.13). The results were interpreted as indicative of the potential value for this screening strategy for ovarian cancer. However, because there was a relatively small number of ovarian cancers in this population, it was impossible to determine absolute survival advantage. Jacobs and colleagues suggested that a larger, randomized trial would be of value to determine if the screening strategy affects mortality.
COMMENTARY
This trial from the United Kingdom provides a hopeful suggestion that screening for ovarian cancer may be of clinical value. The numbers of women screened were large, but the actual rates of ovarian cancer were too small to demonstrate a survival advantage from early detection. Nevertheless, for the women who were found to have cancer in the screened group, the median survival was significantly longer than that for the control group. Interpretation of this result must be made with great caution because of the lead time bias artifact which may have been operational. Thus, women who were found to have ovarian cancer at an earlier stage may have demonstrated longer survival, not because the screening influenced the success of therapy, but because it allowed recognition of the cancer for a longer period of time. The findings were of sufficient interest to warrant the conclusion made by Jacobs et al that the larger trial is warranted.
A positive feature of this is that the strategy used was fairly simple and logical. There seemed to be excellent compliance in the approach as the number of women who were screened for each of the three successive years fell only by a small percent. In fact, the first screen was completed by 86% of the women, the second screen was completed by 79.7%, and the third by 77.2%.
Furthermore, the positive-predictive value of this screening strategy was moderately high; 21% which was apparently quite similar to the positive-predictive value of this approach in a previous study from this group.1 Furthermore, this approach seems to have a higher positive predictive value than other approaches such as pelvic ultrasonography alone2 or pelvic ultrasonography with color-flow Doppler.3
In conclusion, this trial has provided useful information about the feasibility of a randomized investigation of ovarian cancer screening by the introduction of sequential CA-125 determination, ultrasonography, and gynecologic consultation. Although its cost-effectiveness has not been rigorously defined, it is not an expensive undertaking and may be a reasonable approach for primary care providers who are oriented toward early detection and possible disease prevention. However, it may take a larger study in which economic factors are evaluated before insurance companies get behind this strategy. Rather than screen an unselected population, it is possible that this approach would be proven to be effective in a population at greater than normal risk, such as nulliparous women, or those with a positive family history.
References
1. Jacobs I, et al. BMJ 1993;306:1030-1034.
2. Campbell S, et al. BMJ 1989;299:1363-1367.
3. Kurjak A, et al. J Ultrasound Med 1994;13:295-301.
With regard to a practical approach for screening for ovarian cancer, which of the following sequences of screening tools is most logical:
a. Serum CA-125, gynecology consultation, pelvic ultrasonograpy
b. Gynecology consultation, pelvic ultrasonograpy, serum CA-125
c. Pelvic ultrasonograpy, gynecology consultation, serum CA-125
d. Serum CA-125, pelvic ultrasonograpy, gynecology consultation
e. Pelivic ultrasonography, serum CA-125, gynecology consultation
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