Ultrasonography
CA 125 Levels
Other Markers

Potential screening tests for ovarian cancer include vaginal ultrasound and the serum cancer antigen (CA) 125 assay. Several biomarkers with potential application to ovarian cancer screening are under development but have not yet been validated or evaluated for efficacy in early detection and mortality reduction.

Bimanual pelvic examination is a part of the routine pelvic examination. The sensitivity and specificity of the pelvic examination are not characterized, but examination generally detects advanced disease.[1,2]

The Pap test may occasionally detect malignant ovarian cells, but it is not sensitive (reported sensitivity of 10%–30%) and has not been evaluated for the early detection of ovarian cancer.[1] Another method of detection, cytologic examination of peritoneal lavage obtained by culdocentesis, is technically difficult, is uncomfortable for the patient, has low sensitivity for detecting early-stage disease, and has not been evaluated for screening.[1,3]

Transvaginal ultrasonography (TVU) has been proposed as a screening method for ovarian cancer because of its ability to reliably measure ovarian size and detect small masses.[4] The benefit of ultrasonography for the early detection of ovarian cancer and reduction in mortality has not been evaluated in controlled studies. The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) is an ongoing randomized clinical trial evaluating the efficacy of annual TVU in combination with CA 125 tests to reduce ovarian cancer mortality. The results of screening on ovarian cancer mortality are not yet available.

An estimate of the false-positive rate associated with screening women aged 55 to 74 years is available from the baseline (prevalent) screening examination of women who participated in the PLCO and who were randomly assigned to be screened with TVU and serum CA 125 concentrations.[5] Among the 39,115 women randomized to the screening arm, 83.4% (28,519) had an initial TVU. Of these, 1,338 (4.7%) had an abnormal TVU examination; 1.9% of examinations were considered inadequate. The following TVU results were classified as abnormal (positive): “ovarian volume greater than 10 cm³; cyst volume greater than 10 cm³; any solid area or papillary projection extending into the cavity of a cystic ovarian tumor of any size; or any mixed (solid/cystic) component within a cystic ovarian tumor.”[5] Among women having both the TVU and CA 125 tests (28,506), 1,703 had an abnormal result on at least one test; only 34 were abnormal on both screening tests. About 15% of women with at least one abnormal test did not undergo further evaluation. Of the 29 malignant neoplasms detected by follow-up procedures, 22 had an abnormal TVU. Nine of the neoplasms were of low malignant potential. Of the 21 invasive malignancies diagnosed, only two were stage I. Among women with an abnormal ultrasound, the number of surgeries performed per invasive cancer diagnoses was 41.2. The positive predictive value (PPV) for an abnormal TVU was 1%. This study provides a good assessment of the expected PPV for general population screening compared with programs selectively screening high-risk groups in which the PPV will be higher owing to a higher prevalence of ovarian cancer.

Accurate estimates of sensitivity and specificity are difficult to obtain because few studies have conducted adequate follow-up to identify all cases. Among 1,048 women who were at increased risk due to a family history or known mutation in a cancer susceptibility gene and who underwent annual screens, TVU was abnormal in only 6 of 13 women who were diagnosed with ovarian cancer, for a sensitivity lower than 50%.[6]

CA 125 is a tumor-associated antigen that is used clinically to monitor patients with epithelial ovarian carcinomas.[7,8] The measurement of CA 125 levels, in combination with TVU,[9] is the ovarian screening intervention being evaluated in the PLCO.[5,10] The most commonly reported CA 125 reference value that designates a positive screening test is 35 U/mL, and this was the reference value used in the PLCO to define an abnormal test result. Elevated CA 125 levels are not specific to ovarian cancer and have been observed in patients with nongynecological cancers [8] and in the presence of other conditions such as the first trimester of pregnancy [11,12] or endometriosis.[13] The sensitivity of the CA 125 test for the detection of ovarian cancer was estimated in two nested case-control studies using serum banks.[14,15] The sensitivity for CA 125 levels of at least 35 U/mL ranged from 20% to 57% for cases occurring within the first 3 years of follow-up; the specificity was 95%. The baseline (prevalent) screening from the PLCO [5] obtained CA 125 levels from 28,803 women (84.2%) randomly assigned to the screened arm. Of these women, 402 (1.4%) had abnormal CA 125 levels (>35 U/mL); 34 of these also had abnormal TVUs. Sixteen (55%) of the 29 women with diagnosed ovarian cancer had abnormal CA 125 levels. One of two women with invasive stage I disease had an elevated CA 125 level. Among women who had only an abnormal CA 125 level, 4.2 surgeries were performed per invasive cancer diagnosed. Among women with either an abnormal TVU or an abnormal CA 125 level, 28.5 surgeries were performed per invasive cancer diagnosed.

A CA 125 screening program of 22,000 postmenopausal women with subsequent transabdominal ultrasound for those with elevated CA 125 levels (reference value of 30 U/mL) detected 11 of 19 cases of ovarian cancer occurring in the cohort, for an apparent sensitivity of 58%.[16] The specificity for this screening study was 99.9%. Three of the 11 cases detected through screening were stage I disease. In one prospective screening study, the specificity of CA 125 levels of 35 U/mL was 97.6%.[17] Ten-year follow-up of this cohort of 5,550 women screened from 1987 to 1989 in the Stockholm region of Sweden revealed 29 ovarian cancers versus 24 expected cases. Compared with the cancers diagnosed after the screening period, those detected by CA 125 tests had a higher proportion of early-stage disease and better survival measured from diagnosis. Both end points, however, are subject to bias, and the survival of all ovarian cancers combined did not differ from the age-adjusted ovarian cancer survival in the Stockholm population.[18]

A pilot randomized trial in the United Kingdom randomly assigned 10,977 women to a control group and 10,958 women to a screened group in 1989.[19] The primary screen was the CA 125 test, followed by ultrasonography when CA 125 levels were elevated. Women were offered three annual screening rounds, and both groups were followed for 7 years. Compliance was 70.7% for all three screenings and 85.5% for at least one screening. There were 20 ovarian cancers in the control group and 16 in the screened group, only six of which were detected by screening. There was a higher proportion of stage I/II cancers in the screened group (31.3% vs. 10.0%). There were 18 ovarian cancer deaths in the control group and nine in the screened group (relative risk = 2.0; 95% confidence interval, 0.78–5.13). The outcome for women with ovarian cancer in the control group, however, was unexpectedly poor.

Women with mutations in genes associated with breast and ovarian cancer family syndromes or hereditary nonpolyposis colorectal cancer are at an increased risk for the development of ovarian cancer. No controlled studies have evaluated the efficacy of ovarian cancer screening in this population. A Dutch study of BRCA1- or BRCA2-mutation carriers involved surveillance via annual TVUs and serum CA 125 measurements beginning in women aged 30 to 35 years. Six cases of ovarian cancer were detected, all advanced-stage disease.[20,21]

Proteomics has been used to identify patterns or specific serum markers that may be used in place of, or in conjunction with, CA 125 measurements for the early detection of cancer.[22,23] These studies have been small case-control studies that are limited by sample size and by the number of early-stage cancer cases included. Further evaluation is needed to determine whether any additional markers have clinical utility for the early detection of ovarian cancer.

References

1. Smith LH, Oi RH: Detection of malignant ovarian neoplasms: a review of the literature. I. Detection of the patient at risk; clinical, radiological and cytological detection. Obstet Gynecol Surv 39 (6): 313-28, 1984.  [PUBMED Abstract]
   
   
2. Hall DJ, Hurt WG: The adnexal mass. J Fam Pract 14 (1): 135-40, 1982.  [PUBMED Abstract]
   
   
3. Keettel WC, Pixley EE, Buchsbaum HJ: Experience with peritoneal cytology in the management of gynecologic malignancies. Am J Obstet Gynecol 120 (2): 174-82, 1974.  [PUBMED Abstract]
   
   
4. Higgins RV, van Nagell JR Jr, Woods CH, et al.: Interobserver variation in ovarian measurements using transvaginal sonography. Gynecol Oncol 39 (1): 69-71, 1990.  [PUBMED Abstract]
   
   
5. Buys SS, Partridge E, Greene MH, et al.: Ovarian cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial: findings from the initial screen of a randomized trial. Am J Obstet Gynecol 193 (5): 1630-9, 2005.  [PUBMED Abstract]
   
   
6. Stirling D, Evans DG, Pichert G, et al.: Screening for familial ovarian cancer: failure of current protocols to detect ovarian cancer at an early stage according to the international Federation of gynecology and obstetrics system. J Clin Oncol 23 (24): 5588-96, 2005.  [PUBMED Abstract]
   
   
7. Bast RC Jr, Feeney M, Lazarus H, et al.: Reactivity of a monoclonal antibody with human ovarian carcinoma. J Clin Invest 68 (5): 1331-7, 1981.  [PUBMED Abstract]
   
   
8. Bast RC Jr, Klug TL, St John E, et al.: A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 309 (15): 883-7, 1983.  [PUBMED Abstract]
   
   
9. Jacobs I, Stabile I, Bridges J, et al.: Multimodal approach to screening for ovarian cancer. Lancet 1 (8580): 268-71, 1988.  [PUBMED Abstract]
   
   
10. Gohagan JK, Levin DL, Prorok JC, et al., eds.: The Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial. Control Clin Trials 21(6 suppl): 249S-406S, 2000. 
    
    
11. Niloff JM, Knapp RC, Schaetzl E, et al.: CA125 antigen levels in obstetric and gynecologic patients. Obstet Gynecol 64 (5): 703-7, 1984.  [PUBMED Abstract]
    
    
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14. Zurawski VR Jr, Orjaseter H, Andersen A, et al.: Elevated serum CA 125 levels prior to diagnosis of ovarian neoplasia: relevance for early detection of ovarian cancer. Int J Cancer 42 (5): 677-80, 1988.  [PUBMED Abstract]
    
    
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16. Jacobs I, Davies AP, Bridges J, et al.: Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonography. BMJ 306 (6884): 1030-4, 1993.  [PUBMED Abstract]
    
    
17. Einhorn N, Sjövall K, Knapp RC, et al.: Prospective evaluation of serum CA 125 levels for early detection of ovarian cancer. Obstet Gynecol 80 (1): 14-8, 1992.  [PUBMED Abstract]
    
    
18. Einhorn N, Bast R, Knapp R, et al.: Long-term follow-up of the Stockholm screening study on ovarian cancer. Gynecol Oncol 79 (3): 466-70, 2000.  [PUBMED Abstract]
    
    
19. Jacobs IJ, Skates SJ, MacDonald N, et al.: Screening for ovarian cancer: a pilot randomised controlled trial. Lancet 353 (9160): 1207-10, 1999.  [PUBMED Abstract]
    
    
20. Vasen HF, Tesfay E, Boonstra H, et al.: Early detection of breast and ovarian cancer in families with BRCA mutations. Eur J Cancer 41 (4): 549-54, 2005.  [PUBMED Abstract]
    
    
21. Olivier RI, Lubsen-Brandsma MA, Verhoef S, et al.: CA125 and transvaginal ultrasound monitoring in high-risk women cannot prevent the diagnosis of advanced ovarian cancer. Gynecol Oncol 100 (1): 20-6, 2006.  [PUBMED Abstract]
    
    
22. Zhang Z, Bast RC Jr, Yu Y, et al.: Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer. Cancer Res 64 (16): 5882-90, 2004.  [PUBMED Abstract]
    
    
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