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

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Jul 2018. | This topic last updated: Jun 29,
2018.
What's New
Updated USPSTF guidelines on ovarian cancer screening (April 2018)
Despite the incidence of ovarian cancer, routine screening for ovarian cancer has not generally
shown a mortality benefit for asymptomatic women not at high risk. The US Preventive Services
Task Force (USPSTF) 2018 statement continues to recommend against screening for ovarian
cancer for asymptomatic women who are not known to have a high-risk hereditary cancer
syndrome [1]. The USPSTF notes that a woman with a family history of ovarian or breast cancer
or symptoms should talk with her clinician. These recommendations are consistent with our
approach. (See "Screening for ovarian cancer", section on 'Recommendations of expert
groups'.)
Read more

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 "Management of patients at high risk for breast and ovarian
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 2and 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 "Management of patients at high risk for breast and ovarian 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/fallopiantube 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 "Management of patients at high risk for breast and
ovarian 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 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 "Management of patients at high risk for
breast and ovarian 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 5th 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 "Management of patients at
high risk for breast and ovarian cancer" and "Endometrial and ovarian cancer
screening and prevention in women with Lynch syndrome (hereditary
nonpolyposis colorectal cancer)".)