Ultrasonography
CA 125 Levels
Combined Screening with CA 125 and TVU
Other Markers

Potential screening tests for ovarian cancer include transvaginal 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 initial four rounds of screening of women who participated in the PLCO and who were randomly assigned to be screened with TVU and serum CA 125 concentrations.[5,6] Among the 39,115 women randomly assigned to the screening arm, 34,261 were eligible for screens because they had not had a prior oophorectomy. Among these women, 89% had at least one screen during the four rounds of screening. 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.”[5,6] The screen positivity rates decreased slightly from 4.6% at the prevalent (baseline screen) to 2.9% at the fourth round of screening. The positive predictive value (PPV) of TVU was relatively constant over the screening rounds ranging from 0.7% to 1.1%.

Accurate estimates of sensitivity and specificity are difficult to obtain because few studies have conducted adequate follow-up to identify all cases. The U.K. Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) published results from their prevalent screen. The ultrasound screening arm had several levels of screening and possible referral strategies: an abnormal scan resulted in a repeat scan in 6 to 8 weeks, and if still abnormal, referral was made for a clinical assessment. Of 53 total cancers (screen-detected and interval cancers in the following year), 45 were screened positive by ultrasound (two abnormal scans) for a sensitivity of 84.9%. For invasive cancer, the sensitivity was 75%. Specificity of the ultrasound screening arm was calculated at 98.2%.[7]

CA 125 is a tumor-associated antigen that is used clinically to monitor patients with epithelial ovarian carcinomas.[8,9] The measurement of CA 125 levels, in combination with TVU,[10] is the ovarian screening intervention being evaluated in the PLCO.[5,11] 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 [9] and in the presence of other conditions such as the first trimester of pregnancy [12,13] or endometriosis.[14] The sensitivity of the CA 125 test for the detection of ovarian cancer was estimated in two nested case-control studies using serum banks.[15,16] 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 positive rates across the first four rounds of screening in the PLCO trial were fairly constant, ranging from 1.4% to 1.7% and were lower than the rates for TVU. The PPV was higher for CA 125 than for TVU, ranging from 2.1% to 3.2% in the four rounds of screening.

Another study, the Shizuoka Cohort Study of Ovarian Cancer Screening randomly assigned women to a screening group (41,668) or a control group (40,799) between 1985 and 1999 at 212 hospitals in the Shizuoka prefecture of Japan. The screening protocol comprised ultrasound and CA 125 tests annually. Women with abnormal findings were referred to a gynecological oncologist. Ovarian cancer diagnoses were determined by record linkage to the Shizuoka Cancer Registry in 2002. The annual death certificate file in Shizuoka was checked to ascertain vital status. The mean follow-up time was 9.2 years, and the mean number of screens per woman was 5.4. There were 35 ovarian cancers detected in the screening group and 32 in the control group with a nonsignificant difference in the stage distribution. Nine percent of regular screening attendees had at least one false-positive result.[17]

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%.[18] 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%.[19] 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.[20]

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.[21] 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 of which were in the advanced stage of disease.[22,23]

The PLCO trial is evaluating the combination of TVU and CA 125 for screening with positive on either test interpreted as a positive screen. Across the four screening rounds, 11.1% of women had at least one positive test; 8.1% of women had at least one positive TVU, and 3.4% of women had at least one positive CA 125 test.[6] The yields of both tests were similar. The overall ratio of surgeries to screen-detected cancers was 19.5 to 1, and 72% of screen-detected cases were late stage (III/IV). The effect of screening on mortality is not yet known.

In the UKCTOCS trial,[7] multimodality screening included a two-stage screening arm with CA 125 measured and used to estimate an ovarian cancer risk score. That risk score determined follow-up. Elevated risk was followed with a transvaginal ultrasound. Intermediate risk scores were followed up with a repeat CA 125 measure and recalculation of the risk score, if risk remained intermediate or higher than an ultrasound. The reported sensitivity and specificity scores from the prevalent screen for the multimodality screening arm were 89.4% and 99.8% overall; 89.5% and 99.8% for invasive cancers.

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.[24,25] 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

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