Screening for ovarian cancer

Author:
Karen J Carlson, MD
Section Editors:
Barbara Goff, MD
Joann G Elmore, MD, MPH
Deputy Editor:
Judith A Melin, MA, MD, FACP

INTRODUCTION — Ovarian cancer is the leading cause of death from gynecologic malignancy in the
United States. In the United States each year, there are approximately 22,000 new cases of ovarian cancer
and 14,000 cancer-related deaths [1,2]. Worldwide, the number of new cases of ovarian cancer each year
is approaching 250,000 [3]. It is the seventh most common cancer in women, and incidence rates are
highest in developed countries. The incidence of ovarian cancer increases with age. (See "Epithelial
carcinoma of the ovary, fallopian tube, and peritoneum: Epidemiology and risk factors".)
Interest in early detection as a method of reducing mortality developed with the discovery of serum tumor
markers associated with ovarian malignancies (particularly CA 125) and with the improved diagnostic
accuracy of pelvic ultrasonography. This topic will review the risks and benefits of screening for ovarian
cancer in asymptomatic women. The issue of testing for ovarian cancer in women with nonspecific
symptoms that may be associated with ovarian cancer is discussed separately. (See "Early detection of
epithelial ovarian cancer: Role of symptom recognition".)

Additionally, screening in women at high risk of ovarian cancer, the clinical manifestations of epithelial
ovarian cancer, epidemiology and risk factors for ovarian cancer, and surveillance for patients who have
been treated for ovarian cancer are discussed separately. (See "Cancer risks and management of BRCA
carriers without cancer" and "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical
features and diagnosis" and "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum:
Histopathology" and "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Epidemiology and
risk factors".)

BIOLOGICAL BASIS FOR SCREENING — Survival from ovarian cancer is related to the stage at
diagnosis; five-year survival is over 90 percent for the minority of women with stage I disease [4]. This
number drops to about 75 to 80 percent for regional disease and 25 percent for those with distant
metastases.

Despite the good prognosis associated with early-stage disease, overall five-year survival in women with
ovarian cancer is less than 45 percent. This poor survival rate in large part is due to the spread of cancer
beyond the ovary at the time of clinical detection in 75 percent of patients. Mortality from ovarian cancer
has decreased only slightly in the past 30 years [4].

Little is known about the mechanism or timing of progression from localized to disseminated ovarian
cancer. The model of unifocal disease progressing to diffuse disease is plausible. However, ovarian cancer
also may develop from multiple foci within the abdomen, since carcinomatosis can develop even after the
removal of normal ovaries [5]. Additionally, it has been proposed that a substantial number of ovarian
cancers may be multifocal and extra-ovarian at their earliest recognizable state so that early detection
efforts focused only on the ovary may miss many tumors [6].

Ovarian cancer is traditionally referred to as a single entity, but it consists of a heterogeneous group of
neoplasms with multiple histologic subtypes [7]. This heterogeneity may affect the outcomes of screening
interventions. The majority of ovarian malignancies are epithelial tumors (including serous, mucinous,
endometrioid, and clear-cell tumors); the remainder arise from germ cell and other tissues. A subgroup of
epithelial tumors, known as "borderline tumors" or "cystadenomas of low malignant potential," have a more
favorable prognosis. Benign cystadenomas, another subgroup of epithelial tumors, have a low rate of
malignant transformation. The benefit of identifying asymptomatic benign cystadenomas is unknown.
(See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Epidemiology and risk factors",
section on 'Epidemiology'.)

FACTORS THAT AFFECT RISK — Identification of women at high risk for ovarian cancer may help to
identify a group that would most benefit from screening strategies. Known risk factors for ovarian cancer
include age, genetic, endocrine and reproductive factors; certain environmental factors also seem to affect
risk. These risk factors are discussed in detail separately (table 1). (See "Epithelial carcinoma of the ovary,
fallopian tube, and peritoneum: Epidemiology and risk factors".)

The strongest known risk factor for ovarian cancer is a family history [8]. The risk is increased when the
family history indicates a sporadic case and is substantially greater when there is a hereditary cancer
syndrome (eg, breast-ovarian cancer syndrome usually associated with a BRCA1/BRCA2 mutation (table
2 and table 3), Lynch syndrome, or other syndromes). In these hereditary cancer syndromes, ovarian
cancer typically occurred in a first- or second-degree relative at age under 50 years, or relatives in two or
more generations had ovarian or related cancers. However, small family size may mask the presence of a
hereditable disorder [9].

Several reproductive factors appear to increase the risk of ovarian cancer, including a history of infertility,
endometriosis, hormone replacement therapy, early menarche, late menopause, nulliparity and other
obstetric factors, polycystic ovarian syndrome, endometriosis and intrauterine devices. However, studies
have found that fertility treatment does not independently increase ovarian cancer risk.

Factors strongly associated with a reduced risk of ovarian cancer include pregnancy, use of oral
contraceptive pills, breastfeeding, tubal ligation, hysterectomy, and salpingo-oophorectomy.

RISKS AND BENEFITS OF SCREENING — The potential benefit of screening is its ability to identify
ovarian cancer at a more localized and curable stage, leading to reduced mortality from the disease.

The potential risks associated with screening for ovarian cancer must also be considered. A positive
screening result suggestive of ovarian cancer most often is followed by surgery (either laparoscopy or
laparotomy). Invasive procedures are associated with physical and psychological morbidity, a small risk for
serious complications, and substantial financial costs.

Although ovarian cancer is an important cause of cancer death, its incidence and prevalence in the general
population are relatively low. The problem of false-positive screening tests becomes critically important in
diseases with low prevalence. Unless the test or sequence of tests is extremely accurate, a large number
of healthy women would be at risk for unnecessary surgery. (See "Evidence-based approach to
prevention".)

SCREENING TESTS — Most experts feel that a screening protocol for ovarian cancer should have a
positive predictive value of at least 10 percent (that is, no more than nine healthy women with false-positive
screens would undergo unnecessary procedures for each case of ovarian cancer detected) [10-12]. A
screening program that targets all women over age 50 would require a test with a specificity of at least 99.6
percent (assuming a sensitivity of 80 percent) to achieve a positive predictive value of 10 percent.
(See "Evidence-based approach to prevention", section on 'Performance of screening tests'.)

Tests that have been evaluated for screening in certain circumstances include measurement of the CA 125
tumor marker or other serologic markers, ultrasonography, and combinations of these modalities
(multimodal screening [MMS]). Image-based screening by computed tomography (CT) scanning is unlikely
to be effective in diagnosing presymptomatic early disease [13].

Screening in women at high risk of ovarian cancer is discussed separately. (See "Cancer risks and
management of BRCA carriers without cancer".)

Tumor markers — Tumor markers have received considerable interest as possible screening tests
because they are noninvasive, easily repeated over time, and relatively inexpensive compared with
imaging studies.

CA 125 — Measurement of the serum concentration of the CA 125 glycoprotein antigen is the most widely
studied biochemical method of screening for ovarian cancer. Serum CA 125 values are elevated in
approximately 50 percent of women with early-stage disease and in over 80 percent of women with
advanced ovarian cancer [14].

However, the specificity of CA 125 is limited. CA 125 levels are elevated in approximately 1 percent of
healthy women and fluctuate during the menstrual cycle [15]. CA 125 is also increased in a variety of
benign and malignant conditions, including:

●Endometriosis [16]
●Uterine leiomyoma
●Cirrhosis with or without ascites [17,18]
●Pelvic inflammatory disease
●Cancers of the endometrium, breast, lung, and pancreas [19]
●Pleural or peritoneal fluid due to any cause [20]
Mean CA 125 levels further vary with ethnicity and smoking status (lower in non-white women and current
smokers) and increase with age [21].

Nonetheless, a prospective study of asymptomatic postmenopausal women found that an elevated CA 125
concentration (≥30 Units/mL) was a powerful predictor of subsequent ovarian cancer risk (relative risk [RR]
35.9 at one year and 14.3 at five years) [22].

Studies of CA 125 in screening for ovarian cancer have focused upon postmenopausal women, since
menstrual cycle variations and the prevalence of benign gynecologic conditions in premenopausal women
would result in a substantially higher likelihood of false-positive tests. Accumulated evidence suggests that
annual CA 125 measurements alone lack sufficient specificity for use in an average-risk population of
postmenopausal women:

●Three large screening studies in Sweden and England showed that the specificity of a single CA 125 level
for detection of ovarian neoplasms in postmenopausal women ranged from 98.6 to 99.4 percent, resulting
in an unacceptably low positive predictive value of 3 percent [23-25].
●A more definitive assessment of annual screening with CA 125 and its impact on cancer mortality in a
randomized controlled trial was conducted as a component of the Prostate, Lung, Colorectal, and Ovarian
(PLCO) Cancer Screening Trial [26]. In the ovarian component of PLCO, 78,237 healthy women between
55 and 74 years of age were randomly assigned to screening and control groups; 39,115 women were
assigned to screening with annual CA 125 and annual transvaginal ultrasound (TVUS). Data from the
baseline prevalence screen in 28,816 women found an abnormal CA 125 in 436 women (1.5 percent); the
positive predictive value for invasive cancer was 3.7 percent [27]. At four years of follow-up, the positivity
rates of CA 125 remained essentially unchanged from baseline and the positive predictive value was 2.6
percent [28].

The change in CA 125 levels over time is a more promising screening method. A large prospective study in
9233 postmenopausal women, with measurements of CA 125 at two or more times, used a modeling
method to estimate risk of ovarian cancer [29]. The model incorporates age-specific incidence of cancer,
absolute CA 125 level, and rate of change over time. Compared with a specific cutoff value of CA 125, the
model improved sensitivity for detection of ovarian cancer from 62 to 86 percent when specificity was fixed
at 98 percent. An algorithm incorporating change in CA 125 measurements over time was used in the UK
Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) [30]. (See 'Multimodal screening' below.)

Other tumor markers — A variety of other biomarkers have been investigated for early detection of
ovarian cancer. Studies are ongoing to evaluate combinations of bio-markers complementary to CA 125
that could offer greater sensitivity and specificity than CA 125 alone. Examples of these studies include:

●Human Epididymis Protein 4 (HE4) appears to have similar sensitivity to CA 125 when comparing serum
from ovarian cancer cases with healthy controls, and a higher sensitivity when comparing ovarian cancer
cases with benign gynecologic disease [31,32]. In a study of 531 women with pelvic masses, an algorithm
using HE4 and CA 125 correctly classified 93.8 percent of cases of epithelial ovarian cancer as high risk
[33]. A commercial assay for serum HE4 is available (the Architect HE4 Test, Abbott Laboratories).
However, at least in the United States, this assay is approved for monitoring women with ovarian cancer for
disease recurrence or progression but not for screening. (See "First-line chemotherapy for advanced (stage
III or IV) epithelial ovarian, fallopian tubal, and peritoneal cancer", section on 'Post-treatment surveillance'.)

●In a study evaluating a multi-analyte blood test that assays for genetic alterations and tumor-specific
circulation protein biomarkers in a healthy population and among patients who had one of eight common
solid tumors, including 54 patients with ovarian cancer, the blood test had a high sensitivity (98 percent)
and specificity (>99 percent) for detection of ovarian cancer at an early stage [34]. This test is not
commercially available. Additional studies are needed to determine if this blood test may improve detection
of ovarian cancer at an early stage.

●An earlier study evaluated serum biomarkers using multiplex immunoassays in 2031 healthy women and
1067 women with early- and late-stage ovarian cancers, benign pelvic tumors, or breast, colorectal, or lung
cancer [35]. A four-marker panel (CA 125, HE4, CEA, and VCAM-1) had the highest diagnostic power, with
86 percent sensitivity for early-stage ovarian cancer at 98 percent specificity. These results, while requiring
validation, suggest that combinations of biomarkers may provide improved detection as the first step in an
MMS protocol.

To determine the potential benefit of biomarkers for screening, however, it is important that they be able to
detect disease before it is clinically diagnosed. Two studies have evaluated newer biomarker panels in
serum collected pre-diagnostically from women who participated in longitudinal cohorts and subsequently
developed ovarian cancer [36,37]. In a case-control study nested within a randomized lung cancer
prevention trial in smokers, tumor markers in stored serum samples were compared between 70 case-
matched controls and 34 women who developed ovarian cancer after the trial onset [36]. Three tumor
markers (CA 125, mesothelin, and HE4) began to increase three years before the diagnosis of ovarian
cancer. CA 125 was most strongly predictive of ovarian cancer, with evidence for some incremental
contribution of HE4 and mesothelin to risk prediction. A second study used samples of serum collected
from women participating in the PLCO trial [37]. Pre-diagnostic sera from 118 women who subsequently
were diagnosed with ovarian cancer were compared with sera from 951 age-matched controls (one-fourth
at increased risk due to family history). CA 125 levels were elevated in 61.5 percent of women who were
diagnosed with ovarian cancer within the subsequent 12 months; testing with a panel of seven additional
biomarkers did not improve the sensitivity of CA 125 alone for preclinical diagnosis.

Tumors markers may be helpful to identify women at higher risk for ovarian cancer. One study found that
using a risk predictor that combined CA125 and HE4 with epidemiologic risk factors (for example, family
history of breast or ovarian cancer) identified women who were at higher risk for ovarian cancer [38].

Ovarian cancer symptom index — An ovarian symptom index has been developed and proposed for
screening purposes [39]. The index is considered to be positive in women who report pelvic or abdominal
pain, bloating, increased abdominal size, difficulty eating, or early satiety occurring more than 12 times a
month, with symptoms present for less than one year. Follow-up for a positive symptom index is discussed
separately. (See "Early detection of epithelial ovarian cancer: Role of symptom recognition", section on
'Symptom index'.)

In a study of 254 healthy women at high risk for ovarian cancer, and 75 women with ovarian cancer, the
combination of symptom index and CA 125 identified more women with cancer than CA 125 alone [39].
However, the symptom index was positive in 12 percent of high-risk women who did not have ovarian
cancer, and thus specificity was low. A case-control study, comparing retrospective reports of symptoms in
women with ovarian cancer and women in the general population, found a very low positive predictive
value for the symptom index (<0.5 percent for early-stage disease and <1.1 percent overall), reflecting the
low prevalence of ovarian cancer [40].

Another study in 211 high-risk women found that the combination of the symptom index, CA 125, and HE4
serum markers as a first-line screen had a sensitivity of 83.8 percent and specificity of 98.5 percent when
two of the three tests were positive [41].

Pelvic ultrasonography — Transabdominal and TVUS have been evaluated as potential first-line

screening methods for ovarian cancer. TVUS allows better visualization of the ovaries (independent of body
habitus) and shorter examination times.

The upper limit of ovarian volume is considered to be 20 cc in premenopausal women and 10 cc in

postmenopausal women [42]. In addition to size, morphologic characteristics (presence of septae or cyst
wall irregularity) are considered in the interpretation of an ultrasound study (See "Ultrasound differentiation
of benign versus malignant adnexal masses".)

The sensitivity of ultrasonography is in part observer-dependent and has ranged from 80 to 100 percent in
studies of women with clinically detected ovarian cancer and in several prospective screening studies [14].
The test's specificity has ranged from 94 to 99 percent in screening studies, including two studies of
women with a family history of ovarian cancer [43,44].
Ultrasonography has been evaluated for screening in both lower- and high-risk women:

●Lower-risk women – Compared with studies in women at high risk of ovarian cancer, studies of
screening with ultrasonography in women at lower risk have shown somewhat more favorable results. It is
possible that ultrasonography may be more effective in identifying early-stage disease in lower-risk women
than in women with hereditary cancer syndromes. Findings to date include the following:

•A large prospective study from the University of Kentucky evaluated annual TVUS in 37,293 asymptomatic
women aged 50 and older or aged 25 and older with a documented family history of ovarian cancer [45].
Mean follow-up was 5.8 years. The protocol evolved such that what was defined as a normal ovarian cyst
changed over time. The specificity and positive predictive value for primary invasive epithelial ovarian
cancer were 98.5 and 8.9 percent respectively. The five-year survival rate for women with screen-detected
invasive ovarian cancer was 84.6 percent compared with 53.7 percent for ovarian cancers in unscreened
women; whether this difference reflects a true mortality difference or biases related to nonrandomized
studies cannot be determined. Additionally, these results reflect findings from a center with high expertise in
ultrasound that may not be reproducible in the general community.

•The large UKCTOCS study randomly assigned 202,638 postmenopausal women aged 50 to 74 to no
screening, annual TVUS, or MMS (CA 125 followed by TVUS if CA 125 abnormal). The TVUS arm followed
50,639 women receiving annual TVUS for a median of 11.1 years [46,47]. Prevalence (initial) screening
from this study found 45 primary ovarian and tubal cancers in the TVUS group; 20 tumors were borderline,
and 12 of the 25 invasive cancers were stage I or II. The sensitivity, specificity, and positive predictive value
were 84.9, 98.2, and 5.3 percent respectively for all primary ovarian and tubal cancers and 75, 98.2, and
2.8 percent for primary invasive cancer [46]. After 11 years of follow-up, ovarian cancer was diagnosed in
314 (0.6 percent) of women in the TVUS arm, and there was no mortality reduction compared with no
screening [47]. Ten women had surgery for what proved to be benign findings for every one woman found
to have ovarian cancer.

●High-risk women – In screening studies in women at high risk of ovarian cancer, ultrasonography has
performed poorly in detecting early-stage epithelial ovarian cancer. In the National Ovarian Cancer Early
Detection Program, 4526 women at high risk for ovarian cancer (based on a personal or family history of
ovarian or breast cancer, other cancer syndromes, or the presence of a BRCA mutation) were screened
with ultrasonography scans starting in 1990 [48]. After 12,709 scans were performed, all ovarian,
peritoneal, and fallopian tubal cancers detected by ultrasonography during the screening period were stage
III; no early-stage disease was identified.

Pelvic exam — We do not recommend routine pelvic examination for ovarian cancer screening [49].
Ovarian tumors are occasionally detected during bimanual pelvic examination, although early-stage tumors
are rarely found due to the deep anatomic location of the ovary. Thus, tumors detected by bimanual pelvic
examination are usually at an advanced stage and associated with a poor prognosis [50]. The Pap smear
may occasionally reveal malignant ovarian cells, but its sensitivity for the detection of ovarian cancer is only
10 to 30 percent. A review of 52 studies found no data to support the use of the pelvic examination in
asymptomatic, average-risk women [51]. Indications for pelvic examination are discussed in detail
elsewhere. (See "The gynecologic history and pelvic examination", section on 'Indications and frequency
for examination'.)
Multimodal screening — Randomized trials have evaluated combination screening with serum CA 125
and ultrasonography, either performed sequentially (ultrasound only if the CA 125 is elevated) or
concurrently.

●Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial – One component of the randomized
PLCO trial in the United States evaluated cancer mortality as the primary outcome in 68,557
postmenopausal women (aged 55 to 74 years) who had been randomly assigned to receive screening with
both CA 125 and TVUS or usual care from their health care practitioner [27,52]. Women in the intervention
group received annual screening with CA 125 for six years and TVUS for four years. Management of
abnormal test results was at the discretion of their usual clinician. Screening did not reduce mortality, and
there was evidence that false-positive findings led to some harm.

At baseline, the prevalence (initial) screening of 28,816 women found 1740 with either an abnormal CA 125
or ultrasound, and 34 had both [27]. Nearly one in three women who had a positive screening test
underwent surgery. Among 570 women who had surgery, 29 tumors were found, of which 20 were invasive
(90 percent of these stage III or IV).

Ovarian cancer was detected in 212 women (5.7 per 10,000 person-years) in the screening group and 176
women (4.7 per 10,000 person-years) in the usual care group. There was no difference in the stage of
ovarian cancer, with advanced disease (stage III or IV) in 77 percent of the cancers in the intervention
group and 78 percent in the usual care group. Both the incidence of ovarian cancer and the mortality rate
were not significantly different for women allocated to the intervention (rate ratios 1.21, 95% CI 0.99-1.48
and 1.18, CI 0.91-1.54, respectively). Excluding deaths from ovarian, colorectal, and lung cancer, all-cause
mortality was similar in both groups (2924 intervention deaths and 2914 control deaths).

Compliance with screening in the intervention group was 84 to 85 percent at baseline and declined
modestly (78 to 79 percent at the fourth screening round, and 73 percent at the last round, which included
only CA 125). Positive screening rates for CA 125 ranged from 1.4 to 1.8 percent during the six rounds and
from 2.9 to 4.6 percent during the four ultrasound rounds. Subjects were followed for up to 13 years
(median 12.4 years) and the trial was stopped prior to scheduled completion because the monitoring board
determined futility.

False-positive results were found in 3285 women, and 1080 underwent surgical follow-up. Fifteen percent
of women who had surgery for a false-positive finding (166) experienced at least one serious complication.
In addition, more cancers were diagnosed in the intervention group (212) than the usual care group (176),
raising the possibility of over-diagnosis.

●The UK Collaborative Trial of Ovarian Cancer Screening – The UKCTOCS is the largest randomized
trial evaluating the use of CA 125 and TVUS for ovarian cancer screening. It was based on the results of
earlier studies that led to the development of algorithmic guidelines to determine interpretation of CA 125
results and indications for TVUS [25,29,30,46,53]. The trial randomly assigned 202,638 postmenopausal
women aged 50 to 74 years to no screening, annual TVUS, or MMS [46]. The 50,640 patients in the MMS
arm received annual screening with CA 125, followed by TVUS if the CA 125 was abnormal, using an
algorithmic guideline [30].

Prevalence (initial) screening from this study found 42 primary ovarian and tubal cancers in the MMS
group; 8 tumors were borderline and 16 of the 34 invasive cancers (47 percent) were stage I or II [46]. The
sensitivity, specificity, and positive predictive value were 89.4, 99.8, and 43.3 percent respectively for all
primary ovarian and tubal cancers and 89.5, 99.8, and 35.1 percent for primary invasive cancer.

After a median follow-up of 11 years, there were 338 cancers (0.7 percent) diagnosed in the MMS group,
314 (0.6 percent) in the TVUS group, and 630 (0.6 percent) in the no-screening group [47]. Compared with
no screening, MMS detected cancer at an earlier stage (I, II, and IIIa) (26 percent versus 39 percent).
During the trial, 148 (0.29 percent) women in the MMS group, 154 (0.30 percent) in the TVUS group, and
347 (0.34 percent) of the unscreened women died of ovarian cancer. The primary analysis showed a
nonsignificant trend toward a 15 percent (95% CI -3 to 30) reduction in mortality from ovarian cancer.
However, in a prespecified analysis that excluded prevalent cases, the hazard ratio showed a significant
reduction in mortality, although the average absolute reduction in mortality showed only a trend toward
reduction (20 percent, 95% CI -2 to 40). The authors suggest that there was no reduction in mortality in the
initial years of screening, with the survival curves separating later in the trial. Follow-up to confirm the
magnitude of this effect is underway. It is estimated that 641 women would need to be screened annually
for 14 years to prevent one death from ovarian cancer.

●The Shizuoka Cohort Study of Ovarian Cancer Screening – In a randomized controlled trial of 83,000
postmenopausal women in Japan, 42,000 women were invited to participate in annual screening with pelvic
ultrasound and CA 125 [54]. The control group in the same prefecture received usual care. There was no
significant difference in the detection of ovarian cancer, at an average follow-up of 9.2 years, between
patients who received screening (27 cases) and control patients (32 cases). There was a non-significant
trend toward earlier-stage disease in the screened group. Thirty-three surgeries were performed to detect
each case of ovarian cancer. Mortality data are not yet available.

The UKCTOCS’s more favorable results may reflect differences in trial design. The UKCTOCS defined an
abnormal CA 125 according to a sophisticated algorithm to estimate ovarian cancer risk. In addition, the
UKCTOCS utilized a centrally monitored protocol for clinical evaluation of abnormal results, whereas in the
PLCO evaluation of abnormal screening results was at the discretion of the community clinician. The chief
limitation of the UKCTOCS was its failure to anticipate a late effect of screening on mortality, which has
been noted in other large cancer screening trials. Although initial results of MMS in the UKCTOCS appear
promising, definitive assessment awaits additional follow-up, and cost-effectiveness needs to be
determined.

High-risk women — Randomized trials of screening for women with a familial ovarian cancer syndrome
are not likely to be performed, since women at high risk for ovarian cancer and their clinicians would not
accept assignment to a no-screening arm. Therefore, prospective cohort studies provide the available data
regarding the impact of screening for this population. Reports from surveillance programs using MMS in
women at high risk due to a genetic predisposition or family history have been largely disappointing and
include the following:

●In the largest cohort study, the United Kingdom Familial Ovarian Cancer Screen Study (UK FOCSS),
3563 women with a familial ovarian cancer syndrome (estimated minimum lifetime risk of 10 percent) who
had declined or deferred risk-reducing salpingo-oophorectomy (RRSO), participants were screened
annually for a mean of 3.2 years with a combination of TVUS and CA-125 [55]. The reported sensitivity for
the detection of incident ovarian cancer/fallopian tube cancer was 81.0 to 87.5 percent, depending on
whether occult cancers detected at the time of RRSO (in women who underwent the procedure prior to the
end of the study period) were classified as false negative or true positive. The positive predictive value of
incident screening was 25.5 percent, which exceeds the threshold of 10 percent considered necessary for
ovarian cancer screening. Four women underwent surgery for each case of detected cancer.
(See 'Screening tests' above.)

Among incident screen-detected cancers, 30.8 percent (4 of 13) were stage I or II. Women who had not
been screened in the year before cancer diagnosis were more likely to have stage IIIc or higher cancer
than women who had been screened in the preceding year (85.7 versus 26.1 percent), suggesting the
importance of adherence to the screening schedule. The study was not designed to determine whether
screening improves mortality. However, the detection of lower-stage disease in women who adhered to
screening has led to a decision to decrease the screening interval to four months for the next phase of this
study. Additionally, the Risk of Ovarian Cancer algorithm used in the UKCTOCS will be incorporated into
the next phase of this study for determining and following up on abnormal results.

Although RRSO remains the only reliable method of decreasing mortality from ovarian cancer in this high-
risk population, this study suggests that screening may have the potential to somewhat reduce risk for
women who wish to maintain their childbearing potential until they are ready to undergo surgery.

Other studies of screening in women at high risk have shown less favorable results, with most cases at late
stage at the time of screen detection:

●In a cohort of 888 women carriers of BRCA1 or BRCA2 mutations who underwent screening with annual
TVUS and CA 125, 5 of 10 incident cancers were interval cases diagnosed in women who had had normal
screening results 3 to 10 months previously [56]. Eight of the 10 cancers were stage III at diagnosis.

●Data from the PLCO trial through the first four screening examinations (baseline plus three annual
screens with CA 125 and ultrasound) include results for high-risk women [57]. Women who underwent
screening (n = 28,460) were stratified for risk by personal and family history: average risk (no history breast
or ovarian cancer), moderate risk (one first-degree relative with breast cancer), or high risk (family history
of ovarian cancer, ≥2 relatives with breast cancer, or personal history of breast cancer). After three post-
baseline screening exams, the positive predictive value for abnormal screening results was 2.8 percent in
the highest-risk group.

Lack of clear benefit from intensive surveillance programs in women at high risk due to genetic
predisposition has led some experts to advocate other interventions to reduce risk in this population,
including use of the oral contraceptive pill and prophylactic salpingo-oophorectomy. (See "Cancer risks and
management of BRCA carriers without cancer".)

Cost-effectiveness — The cost-effectiveness of an MMS protocol using annual CA 125 as a first-line test

was less than USD $100,000 per year of life saved in one study based on computer modeling in a
hypothetical cohort of women aged 50 at the start of screening [58]. Another analysis showed that annual
screening could be cost-effective (costing less than $100,000 per year of life saved) when the cost of the
initial screen was $100 or less [59]. More reliable data on cost-effectiveness await the completion of the
ongoing randomized trial in the United Kingdom.

SYNTHESIS OF THE EVIDENCE AND APPROACH TO SCREENING

A practical clinical approach to the issue of screening is based upon assessment of an individual woman's
risk of ovarian cancer.
Women at average risk — Screening for ovarian cancer with CA 125 or ultrasound is not recommended
for premenopausal and postmenopausal women without a family history of ovarian cancer [60,61].
Randomized trials evaluating screening with the combination of CA 125 testing and transvaginal
ultrasonography (TVUS) are not consistent. One trial did not find decreased mortality after 13 years of
follow-up, but another trial found a mortality reduction after 11 years of follow-up [47,52]. Based on the
available data, it is not clear that the benefits of screening for ovarian cancer outweigh the harms related to
the adverse effects related to false-positive findings. (See 'Multimodal screening' above.)

Women at increased risk — For women with a family history of ovarian or breast cancer, the possibility of
a hereditary cancer syndrome should be considered. It is important to differentiate those with the more
common lower-risk family history presentation (eg, an isolated family member with ovarian cancer, without
evidence of a hereditary pattern) and those with a high-risk family history (eg, possible hereditary cancer
syndrome) (table 4).

Lower-risk family history — Women with a family history but without evidence of a high-risk pattern
should be counseled about their individual risk (considering age, parity, and history of oral contraceptive pill
use), the limited evidence for effectiveness of screening, and potential adverse effects of screening. There
is no evidence to support screening in this group.

High-risk family history — Women with a suspected hereditary ovarian cancer syndrome should be
referred to a genetic counselor for consideration of testing for BRCA1 and BRCA2 mutations and Lynch
mutations; consideration should also be given to referring Ashkenazi Jewish women, especially those with
a family member with breast cancer before age 50 or with ovarian cancer. (See "Genetic counseling and
testing for those at risk of hereditary breast and ovarian cancer" and "Genetic testing".)

Screening and preventive measures (eg, risk-reducing surgery) for women who are carriers for
hereditary and/or familial breast and ovarian cancer syndromes and Lynch syndrome are discussed
elsewhere. (See "Cancer risks and management of BRCA carriers without cancer" and "Endometrial and
ovarian cancer screening and prevention in women with Lynch syndrome (hereditary nonpolyposis
colorectal cancer)".)

RECOMMENDATIONS OF EXPERT GROUPS — No North-American expert groups recommend routine

screening for ovarian cancer. The US Preventive Services Task Force (USPSTF) 2018 recommendation
statement continues to recommend against screening for ovarian cancer for asymptomatic women who are
not known to have a high-risk hereditary cancer syndrome [2,62]. USPSTF notes that women with a family
history of ovarian or breast cancer should discuss that with their clinician, and that women with symptoms
should talk with their clinician [2]. The recommendation incorporates results from the Prostate, Lung,
Colorectal, and Ovarian (PLCO) Cancer Screening Trial and the United Kingdom Collaborative Trial of
Ovarian Cancer Screening (UKCTOS).

The Society of Gynecologic Oncology (SGO) recommends against screening low-risk women with CA 125
or ultrasound and had endorsed the 2012 recommendations of the USPSTF, which noted that the
recommendation not to screen did not apply to known carriers of genetic mutations that increase ovarian
cancer risk (eg, BRCA1 or BRCA2 gene mutations) [62,63]. The American College of Obstetricians and
Gynecologists (ACOG) [64] and the Canadian Task Force on Preventive Health Care [65] also endorse
recommendations against routine screening for ovarian cancer in asymptomatic low-risk women.
Professional societies in Australia and New Zealand endorsed a 2009 position statement that there is no
evidence to support population screening for ovarian cancer in asymptomatic women [66].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics"
and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 th to
6th grade reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Ovarian cancer screening (The Basics)" and "Patient education:
Genetic testing for breast and ovarian cancer (The Basics)")

●Beyond the Basics topics (see "Patient education: Ovarian cancer screening (Beyond the
Basics)" and "Patient education: Genetic testing for breast and ovarian cancer (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Survival for ovarian cancer is much improved for earlier-stage disease. However, most ovarian cancers
have spread beyond the ovary at the time of diagnosis. (See 'Biological basis for screening' above.)

●Identification of women at high risk for ovarian cancer may help to identify a group that would most benefit
from screening strategies. The strongest known risk factor for ovarian cancer is a family history. Risk
factors for ovarian cancer are discussed in detail separately. (See "Epithelial carcinoma of the ovary,
fallopian tube, and peritoneum: Epidemiology and risk factors" and 'Factors that affect risk' above.)

●CA 125, the most widely studied tumor marker for ovarian cancer screening, is elevated in 50 to 90
percent of women with early ovarian cancer but also can be elevated in numerous other conditions. We
recommend NOT screening with measurement of CA 125 in average-risk women (Grade 1B). (See 'CA
125' above.)

●Serial measurements of CA 125, using an algorithm that incorporates age and rate of change, may
improve the positive predictive value of screening but not sufficiently to incorporate into clinical practice at
this time. (See 'Screening tests' above.)

●Transvaginal ultrasonography (TVUS), when used as a sole screening intervention, has not been
effective in identifying early-stage cancer. (See 'Pelvic ultrasonography'above.)

●We suggest not screening average-risk women for ovarian cancer (Grade 2B). (See 'Synthesis of the
evidence and approach to screening' above.)

●For women with a family history of ovarian cancer who do not have a confirmed ovarian cancer
syndrome, we suggest management as for women at average risk (Grade 2C). (See 'Synthesis of the
evidence and approach to screening' above.)

●Screening and preventive measures (eg, risk-reducing surgery) for women who are carriers for
hereditary and/or familial breast and ovarian cancer syndromes and Lynch syndrome are discussed
elsewhere. (See "Cancer risks and management of BRCA carriers without cancer" and "Endometrial and
ovarian cancer screening and prevention in women with Lynch syndrome (hereditary nonpolyposis
colorectal cancer)".)