Description of the Evidence
Incidence and mortality
Types of Ovarian Cancer
Evidence of Benefit or Lack of Benefit Associated With Different Screening Modalities
Transvaginal ultrasonography (or transvaginal sonography)
Combined CA-125 and TVU
Incorporating data from multiple measures of CA-125 concentrations
Other Potential Markers
Harms From Screening
Incidence and mortality
Ovarian cancer is the fifth leading cause of cancer death among women in the United States and has the highest mortality rate of all gynecologic cancers. It is estimated that 21,980 new cases of ovarian cancer will be diagnosed in the United States in 2014, and 14,270 women will die of this disease. The median age at diagnosis is 63 years. The prognosis for survival from ovarian cancer largely depends on the extent of disease at diagnosis, which is usually advanced, with only about 15% of women presenting with localized disease at diagnosis.[1,2]
From 2006 to 2010, incidence rates decreased by 0.9% per year, and mortality rates decreased by 2.8% per year in women younger than 65 years and by 1.7% per year in women aged 65 years and older.
Ovarian cancer is rare; the lifetime risk of being diagnosed with ovarian cancer is 1.38%.Types of Ovarian Cancer
The term “ovarian cancer” encompasses a heterogeneous group of malignant tumors of ovarian origin that may arise from germ cells, stromal tissue, or epithelial tissue within the ovary. Epithelial cancers are the most common type of ovarian cancer and are further classified into five main types: high-grade serous, endometrioid, clear cell, mucinous, and low-grade serous carcinomas. What has been thought to be primary ovarian cancer often originates in the fallopian tube or endometrium; in particular, the serous, mucinous, and endometrioid forms of ovarian cancer.[3,4] Detection of epithelial carcinomas, the most common and lethal forms of ovarian cancer, has been the focus of screening programs.
Malignant germ cell tumors and stromal tumors such as granulosa cell tumors are rare and account for 10% or less of malignant ovarian tumors.Risk Factors
For a complete description of factors associated with an increased or decreased risk of ovarian cancer, refer to the Factors With Adequate Evidence of an Increased Risk of Ovarian Cancer section in the PDQ summary on Ovarian Cancer Prevention for more information. Several cancer family syndromes, such as BRCA1 and BRCA2 hereditary breast-ovarian syndrome and Lynch syndrome are associated with a marked increased risk of ovarian cancer.[4,5] (Refer to the Autosomal Dominant Inheritance of Breast/Ovarian Cancer Predisposition section in the PDQ summary on Genetics of Breast and Ovarian Cancer for more information about these syndromes and risk of ovarian cancer, which also includes a summary of other known risk factors for ovarian cancer.)Evidence of Benefit or Lack of 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 for screening for ovarian cancer.[6,7] Because this is not, by definition, asymptomatic screening, it is not considered further in this summary.
Manual 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.[8,9] There is no evidence for the benefit of this test for the early detection of and decreased mortality from ovarian cancer and it is not further considered.
Other screening tests include transvaginal ultrasound (TVU) and the serum cancer antigen 125 (CA-125) assay. These 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.Transvaginal ultrasonography (or transvaginal sonography)
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.
TVU as an independent screening modality is being evaluated in one arm of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) (NCT00058032). The UKTOCS is an ongoing randomized, controlled trial of 202,638 postmenopausal women recruited in 13 trial centers across the United Kingdom. Women were randomly assigned to receive multimodality screening with CA-125 as a primary test and TVS as a secondary screen (multimodal group); an ultrasound only (ultrasound group); or no routine screening (control group). Of the 50,639 women randomly assigned to receive ultrasound screening, 48,230 attended the first-year screening, with 48,053 women with data to evaluate ovarian morphology. Of these, 9.1% (4,367) had an abnormal adnexal scan. Among women with an abnormal scan, the absolute risk of epithelial ovarian cancer in the next 3 years was 1.08%. Thus, most of these abnormal scans represented a false-positive test result. In the ultrasound group, 11,982 women had both ovaries visualized and normal scans at all UKCTOCS annual visits during the 3-year study period. Among this group, eight women were diagnosed with epithelial ovarian cancer within 3 years of the first scan.
The UKCTOCS published sensitivity and specificity 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, a referral was made for clinical assessment. Of 53 total cancers (screen-detected and interval cancers in the following year), 45 were screen 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 to be 98.2%.CA-125 concentrations
CA-125 is a tumor-associated antigen that is used clinically to monitor patients with epithelial ovarian carcinomas.[13,14] 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, and this was the reference value used in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial (NCT00002540) 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.[16,17] Elevated CA-125 levels are not specific to ovarian cancer and have been observed in patients with nongynecological cancers, pleural or peritoneal fluid accumulation, the first trimester of pregnancy,[18,19] or endometriosis. The sensitivity of the CA-125 test for the detection of ovarian cancer was estimated in two nested case-control studies using serum banks.[21,22] 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% confidence interval [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.
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%. 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%.
Evaluation of longitudinal measurements, incorporating the information into an algorithm termed “risk of ovarian cancer algorithm” or ROCA, is being evaluated in the UKCTOCS. The UKCTOCS is evaluating two-stage screening 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 TVS alone or no screening. Estimated sensitivity data for multimodality two-stage screening with ROCA followed by TVS has been published from the prevalent screen. Of the 50,078 women who underwent the prevalent screen in the multimodality screening arm, 409 were determined to have an intermediate or elevated risk of ovarian cancer based on the ROCA and were referred for TVS. Of the 409 women,167 women were referred for clinical evaluation, 97 underwent surgery, and 42 were diagnosed with either malignant ovarian or fallopian tube cancers. Among the women who had negative screens, five were diagnosed with ovarian or fallopian tube cancer within 1 year of screening. The estimated sensitivity was 89.4% (95% CI, 76.9–96.5%).Combined CA-125 and TVU
The objective of the ovarian component of the PLCO trial was to evaluate the effect of screening on ovarian cancer mortality. The trial included 78,216 women aged 55 to 74 years who were randomly assigned to undergo either annual screening (n = 39,105) or usual care (n = 39,111) at ten screening centers across the United States between November 1993 and July 2001. The intervention group was offered annual screening with CA-125 for 6 years and TVU for 4 years. 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 followed 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.
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 the majority of 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. There were 118 deaths caused by ovarian cancer (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). 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).[26,27]
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.CA-125 levels
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.
A randomized pilot trial in the United Kingdom randomly assigned 10,977 women to a control group and 10,958 women to a screened group in 1989. 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, six of which were detected by screening. There was a higher proportion of stage I/II cancers in the screened group than in the control group (31.3% vs. 10.0%). There were 18 ovarian cancer deaths in the control group and nine in the screened group (relative risk [RR], 2.0; 95% CI, 0.78–5.13).Incorporating data from multiple measures of CA-125 concentrations
Longitudinal measurement of CA-125 concentrations has been proposed as means to increase the performance of single-threshold measurements of CA-125 concentrations. As noted previously, the ROCA method is being evaluated in the UKCTOCS in conjunction with TVS as a two-stage screening process, and results from that trial are pending. Other methods to include multiple longitudinal CA-125 concentrations in order to examine change of CA-125 levels over time have been proposed but none have been independently evaluated for the impact on ovarian cancer mortality. A 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/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 compared 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 (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 trials examined the potential impact of parametric empirical Bayes (PEB) longitudinal algorithm for the earlier detection of 44 incident ovarian cancers identified in PLCO. Setting the specificity at 99%, PEB signaled “abnormal” CA-125 concentrations on average 10 months earlier than with the single-threshold cutpoint. Whether or not this translated 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.Other Potential Markers
Research continues to find other biomarkers that either alone or in combination with CA-125 concentrations may lead to the early detection of ovarian cancer. A panel of biomarkers that included CA-125, HE4, transthyretin, CA15.3, and CA72.4 was evaluated using specimens assembled from multiple cohort and randomized trials, including the PLCO trial. The phase II and III biomarker studies concluded that CA-125 remained the “single-best biomarker” for ovarian cancer. Another retrospective study, nested within the PLCO trial and included 118 ovarian cancer cases and 8 controls per case, evaluated 7 proteomic biomarkers (apolipoprotein A1, truncated transthyretin, transferrin, hepcidin, beta-2 microglobulin, connective tissue activating protein III, and inter-alpha-trypsin inhibitor heavy-chain) in addition to CA-125. The addition of the seven protein biomarkers to CA-125 did not improve the sensitivity beyond the use of CA-125 levels alone. This contrasted with this same group’s preliminary evaluation of these markers using postdiagnostic rather than prediagnostic blood samples.Harms From Screening
The PLCO trial provides the most reliable data to date on screening-related harms. The rate of minor complications associated with CA-125 and TVU, such as bruising or fainting, occurred at a rate of 58.3 cases per 10,000 women screened with CA-125 and 3.3 cases per 10,000 women screened with TVU. Major complications associated with the diagnostic procedures among women diagnosed with ovarian cancer included infections, blood loss, bowel injury, and cardiovascular events. At least one major complication was reported among 52% of women diagnosed in the usual-care group and 45% among women diagnosed with ovarian cancer in the screened group.
False-positive tests occurred among 3,285 women, translating to a rate of about 5% at each screening round. The majority of false-positive tests (60%) result from TVU. Of the 3,285 women with false-positive results, 33% underwent surgery. Of the 1,080 women who underwent surgery, 15% had 222 major complications, for a rate of 20.6 complications per 100 surgical procedures.
Women in the intervention group were more likely to have had an oophorectomy than those in the control group. Rates of oophorectomy were 85.7 per 10,000 person-years in the screened group compared with 64.2 per 10,000 person-years in the usual-care group (rate ratio, 1.33; 95% CI, 1.24–1.43).References
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