It is well known that when ovarian cancer is detected in early stages cure rates are 70-90% compared to 10-30% for patients who present with advanced stage disease.1 Even with advanced stage disease there is significant improvement in overall survival (OS) in those patients in whom the surgeon is able to resect all the tumor and leave the patient with no visible residual disease. Recent studies have shown median OS is at least 110 months for those women optimally cytoreduced compared to 36-40 months for those with bulky disease left behind.2 The factor most predictive of a complete cytoreduction is extent of disease at presentation.1 Therefore, early detection of ovarian cancer either in Stage I/II or Stage III with minimal tumor bulk has the potential to significantly improve the cure rates for this disease.
Screening for Ovarian Cancer: Challenges and Recent Research
Over the past 20 years there have been significant research efforts directed toward identification of a screening test for ovarian cancer, but unfortunately there continue to be significant challenges that must be overcome before there will be a cost-effective screening test.3 One of the major barriers to screening is identifying a precursor or in situ lesion. Only recently have researchers identified a potential pre-cancerous lesion for ovarian cancer. Studies of prophylactic salpingo-oophorectomies from BRCA1 and BRCA2 mutation carriers has identified the fallopian tube as the likely site for precursor lesions for most of these patients and possibly most women with high grade serous lesions.4 One reason “ovarian” cancer screening may not have been successful is that investigators have targeted the wrong organ.
Another major challenge in developing a cost effective test is the low incidence of the disease.5 In women over 50, the incidence is 40 per 100,000. That means that even with a perfect screening test only 1/2,500 women screened will have ovarian cancer. If the screening test has even a 1% false positive rate then there would be 25 women referred for surgery for each case of cancer detected and would result in a positive predictive value (PPV) of only 4%. In general, the lowest acceptable PPV is 10% or 10 surgeries for each case of cancer detected. In order to have a PPV of 10% a screening test must have a specificity of 99.6% or only a 0.4% false positive rate. In addition, because at least 2,500 women need to be screened to detect a single case of ovarian cancer, the cost must be reasonable, the screening process must be acceptable to women and feasible for providers. Screening tests must successfully detect ovarian cancer in its most curable stages. Finally, we may need different screening strategies for these with family history compared to average-risk women.
Several large clinical trials have been conducted to evaluate the efficacy of ovarian cancer screening. In 2011 the final results of the ovarian portion of The Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial were reported.6,7 In this study, post-menopausal women were randomized to usual care versus annual CA125 and transvaginal ultrasound for four screens. There were approximately 39,000 women randomized to each arm and they were followed for 13 years. Overall, the PPV of screening tests was under 2%. There was no difference in ovarian cancer mortality between the screened and usual care patients indicating that this screening strategy was ineffective. In addition, of those women who had a false positive screen and underwent surgery, 15% had a significant complication indicating that this screening strategy resulted in harm to women.
The other major trial to evaluate screening, the UK Collaborative Trial Ovarian Cancer Screening (UKCTOCS)8 Trial, enrolled over 200,000 post-menopausal women and randomized them to 3 groups: control or usual care, annual TVS or annual CA125 using risk of ovarian cancer followed by TVS (multimodality screening [MMS]). The final results are still not yet reported, but the preliminary results from the prevalence screen were encouraging. In the approximately 50,000 women screened with TVS, 845 (1.8%) underwent surgery; 24 had primary ovarian or fallopian tube cancer, 20 had borderline tumors, and 733 (87%) had benign tumors. Half of the primary ovarian and fallopian tube cancers were diagnosed in early stage. However, because TVS as a primary screen led to many false positives, the PPV of TVS screening was only 5.4%. In the approximately 50,000 women screened with MMS there were only 97 (0.2%) that underwent surgery. Ovarian and fallopian tube cancer was found in 34 women and 47% of those were diagnosed in early stage. Because initial screening with CA125 followed by TVS as a secondary screen led to much fewer false positives, the PPV for MMS was 43.3%. The overall comparison of mortality data from screened women versus controls is still pending and should be reported within the next one-two years. While the PPV for initial screening with CA125 followed by secondary TVS screen (MMS) is encouraging, the screening protocol is quite complex with several to multiple repeat screens required. Feasibility and acceptability outside of a clinical trial must be determined as well as the cost effectiveness of such a program.