Evidence of Lack of Mortality Benefit Associated With Different Screening Modalities
Ovarian cancer often presents with persistent but vague symptoms, usually occurring after the cancer has metastasized. Some investigators have proposed the use of symptom indices as a method of screening for ovarian cancer.[1,2] Because this is not, by definition, asymptomatic screening, it is not considered further in this summary.
Gynecologic examination usually includes a manual pelvic examination, but this procedure is commonly viewed as lacking sensitivity for detection of early-stage disease.[3,4] There is no evidence of the benefit of this test for the early detection of and decreased mortality from ovarian cancer, so it is not further considered.
Other screening tests include transvaginal ultrasound (TVU) and the serum cancer antigen 125 (CA-125) assay. These tests are often performed in combination. 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.
A U.S. Food and Drug Administration Safety Communication issued in September 2016 recommends against using currently offered screening tests to screen for ovarian cancer in any population of women. Asymptomatic high-risk women who have a false-negative screening test may delay effective preventive treatments.
The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)
TVU (or transvaginal sonogram [TVS]) has been proposed as a screening method for ovarian cancer because of its ability to reliably measure ovarian size and detect small masses.
In the UKCTOCS, outcomes among 50,623 postmenopausal women aged 50 to 74 years who were randomly assigned to 7 to 11 rounds of annual screening with TVU alone and 50,625 who underwent multimodal screening with CA-125 testing and TVU (see below) were compared with results from a comparison group of 101,299 women who were not screened. Women were recruited in 13 trial centers across the United Kingdom from 2001 to 2005. After trial initiation, but before analysis, the protocol was amended twice: 1) the study was extended to achieve greater power and 2) criteria for referral in the multimodal arm were liberalized to increase the percentage of positive screens. Because the number of events were less than anticipated on the planned censorship date, the authors extended the follow-up period. No formal adjustments were made to account for the previously analyzed data in 2015, rather the authors acknowledged the P values were not adjusted for multiplicity. Additionally, the authors changed the statistical analysis plan for the extended follow-up analysis from a Cox version of the log-rank test to the versatile test in efforts to be sensitive to delayed mortality effects in screening trials.
TVUs were scored as normal, resulting in continued annual screening; intermediate, leading to repeat CA-125 and TVU at 3 months; or abnormal, requiring repeat testing within 6 weeks. In the TVU arm, 445 cancers were diagnosed and 291 ovarian cancer–related deaths occurred compared with the nonscreened arm, in which 905 cancers were diagnosed and 619 ovarian cancer–related deaths occurred. TVU screening resulted in 50 surgeries per 10,000 women for a false-positive screen. Complications occurred in less than 1% of screening examinations and 3.4% of surgeries. Over a median of 16.3 years, ovarian cancer deaths occurred among 0.6% of screened women and 0.6% of unscreened women.[6,7,8]
CA-125 Serum Testing for Ovarian Cancer Screening
CA-125 is a tumor-associated antigen that is used clinically to monitor patients with epithelial ovarian carcinomas.[9,10] Measurement of CA-125 concentrations has been proposed as a potential marker for the early detection of ovarian cancer, either as a single test with a threshold cutpoint or in algorithms examining the change in levels over time. The two randomized trials have included CA-125 either in parallel or sequentially with TVU for multimodality screening. The most commonly reported CA-125 reference value that designates a positive screening test is 35 U/mL; this was the reference value used in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial (NCT01696994) to define an abnormal test result. The measurement of CA-125 levels, in parallel combination with TVU, is the ovarian screening intervention evaluated in the PLCO trial.[12,13] Elevated CA-125 levels are not specific to ovarian cancer and have been observed in patients with nongynecological cancers, endometriosis, liver disease, congestive heart failure, pleural or peritoneal fluid accumulation, and in the first trimester of pregnancy.[15,16] The sensitivity of the CA-125 test for the detection of ovarian cancer was estimated in two nested case-control studies using serum banks.[17,18] 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%.
A phase II/III biomarker study was conducted to evaluate the sensitivity of several markers of ovarian cancer, including CA-125 concentrations, using specimens collected from ovarian cancer patients at four sites. The estimated sensitivity for early-stage disease (stage I and II ovarian cancer) was 56% (95% CI, 49%–72%) for a cutpoint set to obtain a fixed specificity of 95%. The threshold for the cutpoint for CA-125 at 95% specificity was 24 U/mL. For all cases (56% of cases had stage III or IV disease at diagnosis), the sensitivity was 73% (95% CI, 64%–84%). When the clinical cutpoint of 35 U/mL was used, the sensitivity decreased.
The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial: Single-Threshold CA-125 Levels and TVU
The PLCO trial evaluated the effect of screening on ovarian cancer mortality among women aged 55 to 74 years on the basis of six annual screens with serum CA-125 testing at a threshold for positive of 35 U/mL and four annual screens with TVU. Women were randomly assigned to screening (n = 39,105) or usual care (n = 39,111) at ten screening centers across the United States between November 1993 and July 2001. Participants and their health care practitioners received the screening test results and managed evaluation of abnormal results. The usual-care group was not offered screening with CA-125 or TVU but received their usual medical care. Participants were initially monitored for a maximum of 13 years (median, 12.4 years; range, 10.9–13.0 years) for cancer diagnoses and death until February 28, 2010. Mortality from ovarian cancer, including primary peritoneal and fallopian tube cancers, was the main outcome measure. Secondary outcomes included ovarian cancer incidence and complications associated with screening examinations and diagnostic procedures. After transition of PLCO trial participants to a centralized follow-up process, follow-up for mortality was extended until the end of 2012, for a maximum of 19.2 years and a median of 14.7 years.
Compliance with screening ranged from 85% at the initial round to 73% at the sixth round, while contamination in the usual-care group ranged from about 3.0% for CA-125 to 4.6% for TVU. Across the first four screening rounds, 11.1% of women had at least one positive test, 8.1% had at least one positive TVU, and 3.4% had at least one positive CA-125 test. The yields of both tests were similar. Ovarian cancer was diagnosed in 212 women (5.7 per 10,000 person-years) in the intervention group and 176 women (4.7 per 10,000 person-years) in the usual-care group (rate ratio, 1.21; 95% CI, 0.99–1.48). The stage distributions were similar by study group, with stage III and IV cancers comprising most cases in both the intervention group (163 cases, 77%) and the usual-care group (137 cases, 78%). The cancer case treatment distributions were very similar between groups within each stage. Through the original period of follow-up (maximum, 13 years), ovarian cancer caused 118 deaths (3.1 per 10,000 person-years) in the intervention group and 100 deaths (2.6 per 10,000 person-years) in the usual-care group (mortality rate ratio, 1.18; 95% CI, 0.82–1.71). Long-term follow-up of a median of 17 years for women with at least one ovary demonstrated an ovarian cancer mortality rate of 4.4 deaths per 10,000 person-years (246 ovarian cancer deaths) in the intervention arm and 3.8 deaths per 10,000 person-years (209 ovarian cancer deaths) in the usual-care arm (rate ratio, 1.18; 95% CI, 0.98–1.4).
Of the 3,285 women with false-positive results, 1,080 underwent surgical follow-up. Of the 1,080 women who underwent surgical follow-up, 163 women experienced at least one serious complication (15%). A total of 1,771 women in the intervention group (7.7%) and 1,304 in the usual-care group (5.8%) reported oophorectomy. There were 2,924 deaths resulting from other causes (excluding ovarian, colorectal, and lung cancer) (76.6 per 10,000 person-years) in the intervention group and 2,914 such deaths (76.2 per 10,000 person-years) in the usual-care group (rate ratio, 1.01; 95% CI, 0.96–1.06).[20,23]
In the PLCO trial, women with visualized ovaries were at slightly higher risk of ovarian cancer (hazard ratio, 1.42; 95% CI, 1.00–2.01) than were women who had nonvisualized ovaries. A nested analysis found that ovarian volume increases were detectable 1 to 2 years before diagnosis, but the magnitude of change did not appear translatable to clinical management. Thus, among women in the general U.S. population, simultaneous screening with CA-125 and TVU did not reduce ovarian cancer mortality when compared with usual care.
The Shizuoka Cohort Study of Ovarian Cancer Screening randomly assigned women to either a screening group (n = 41,668) or a control group (n = 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 nonstatistically significant difference in the stage distribution. Nine percent of regular screening attendees had at least one false-positive result. Mortality results from this trial are not available.
Ovarian Cancer Screening Using CA-125 Analyzed According to the Risk of Ovarian Cancer Algorithm (ROCA) for a Positive Test Result in Combination With TVU
The UKCTOCS trial evaluated longitudinal CA-125 measurements using the ROCA, which defines a positive test as a statistically significant increase in a woman's serial measurements based on the algorithm, irrespective of the absolute level. The goal of this approach is to detect cancers earlier by identifying subtle within-person changes. The UKCTOCS multimodal screen incorporated a two-stage approach with ROCA as the primary screen and TVS as a secondary screen (based on results of the ROCA) for its impact on ovarian cancer mortality compared with observation without screening. Of 50,078 women in the multimodality screening arm, 452 women were diagnosed with ovarian cancer and 296 died of the disease. In this arm, less than 1% of screens led to complications, and 3.1% of women developed surgical complications. Using multimodal screening, 14 per 10,000 screens led to surgery for a false-positive result.
There was a 39.2% (95% CI, 16.1–66.9) higher incidence of stage I or II disease and a 10.2% (95% CI, -21.3 to 2.4) lower incidence of stage III and IV disease in the multimodality screening arm compared with the no screening arm. However, despite the stage shift, at a median follow-up of 16.3 years, there was no significant difference in mortality, with 0.6% deaths in the multimodality screening arm compared with 0.6% in the observation arm.
A post hoc nested study was conducted within the PLCO trial to determine if the use of ROCA could potentially improve the identification of early-stage (stage I and stage II) ovarian cancer. The study evaluated the potential impact under two scenarios: best case and stage shift. Best-case scenario assumed that all cancers that would have been detected earlier with ROCA than with single-threshold CA-125 concentrations would have avoided mortality. The stage-shift scenario applied the observed PLCO early-stage survival rates to cases detected at an earlier stage with ROCA. The risk of death from ovarian cancer with ROCA was lower, but estimates were not statistically significant (relative risk [RR] of 0.90 for best-case scenario [95% CI, 0.69–1.17] and RR of 0.95 for stage-shift scenario [95% CI, 0.74–1.23]).
Another retrospective study using annual CA-125 concentrations from the PLCO trial examined the potential impact of parametric empirical Bayes (PEB) longitudinal algorithm for the earlier detection of 44 incident ovarian cancers identified in the PLCO trial. Setting the specificity at 99%, PEB signaled "abnormal" CA-125 concentrations, on average, 10 months earlier than with the single-threshold cutpoint. An analysis of serial CA-125 concentrations from the UKCTOCS trial demonstrated superior performance characteristics for ovarian cancer screening using longitudinal algorithms, compared with a single CA-125 threshold. Whether either of these approaches translates into a mortality benefit could not be determined.
CA-125 velocity has also been examined using a multiple logistic regression model within the PLCO trial as a predictor for the development of ovarian cancer. Both CA-125 velocity and time intervals between screening tests were associated with the development of ovarian cancer. The risk of ovarian cancer increased as velocity (measured as U/mL per month) increased, and the risk of ovarian cancer decreased when the time intervals between screening tests increased.
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