Download Screening for Ovarian Cancer

Routine screening for ovarian cancer is not
currently recommended, but forthcoming
studies and evolving technologies may lead
to effective screening in the future.
J. L. Munro. Salt Water Farm. Mixed media on canvas, 16⬙ × 20⬙.
Screening for Ovarian Cancer
Janiel Marie Cragun, MD
Background: Ovarian cancer remains the most deadly of the gynecologic cancers. It is difficult to diagnose
until in advanced stages. An effective screening test may help to decrease mortality from ovarian cancer. Due to
the low incidence of ovarian cancer in the general population, a good screening test must have high sensitivity
and specificity to allow accurate detection without excessive false-positive results. Thus, effective screening for
ovarian cancer has remained elusive.
Methods: Studies evaluating screening methods for ovarian cancer are reviewed. Screening methods investigated
include ultrasound, CA-125, and serum proteins.
Results: The use of CA-125 or ultrasound alone does not result in adequate sensitivity or specificity for routine
screening. A combination of the two modalities improves sensitivity, specificity, and positive predictive value.
Using a combination of serum proteins may also improve sensitivity, specificity, and positive predictive value,
but such studies have yet to be validated.
Conclusions: No effective screening methods for ovarian cancer that have been adequately validated are available.
Routine screening for ovarian cancer in the general population is not currently recommended.
Introduction
In the United States in 2010, an estimated 21,880 women
were diagnosed with ovarian cancer and 13,850 died
of the disease.1 It is the most deadly of gynecologic
cancers and responsible for the fifth highest mortality
of all cancers in women.1
Due to the nonspecific presenting symptoms,
ovarian cancer is usually diagnosed in advanced stages.
The primary treatment of ovarian cancer is tumor debulking and chemotherapy. For women with advancedFrom the Department of Obstetrics and Gynecology at the University
of Arizona, Tucson, Arizona.
Submitted January 25, 2010; accepted August 25, 2010.
Address correspondence to Janiel Marie Cragun, MD, Department
of OB/GYN, University of Arizona, 1515 N. Campbell Avenue, PO
Box 245024, Tucson, AZ 85724. E-mail: [email protected]
No significant relationship exists between the author and the companies/organizations whose products or services may be referenced in this article.
16 Cancer Control
stage disease, the 5-year survival rate is 28% to 45%.2
Conversely, those diagnosed with early-stage ovarian
cancer may achieve cure with adjuvant treatment. The
5-year survival rates for women diagnosed with earlystage disease range from 57% to 94%.2
Controversy exists regarding the biology of early vs
advanced disease: is it a continuum or does it represent
two different biologic processes on a molecular level?
Some believe that only indolent ovarian cancers are diagnosed in early stages. An understanding of the natural
progression and origin of ovarian cancer is essential in
discovering the most appropriate screening test but is
beyond the scope of this article. For the purposes of
this article, early ovarian cancer is assumed to progress
to advanced ovarian cancer in a step-wise fashion.
Screening Tests
Preferably, a screening test would detect premalignant
lesions before they became cancerous. The best screening
January 2011, Vol 18, No.1
test would detect premalignant conditions of the ovary,
much as premalignant conditions of the cervix or colon
are detected. Unlike cervical and colon cancer, the identity of a precursor lesion and how it develops into ovarian
cancer is unknown.3 Without targeting precursor lesions,
it is unlikely that a screening test would have a significant
impact on cure. However, if able to detect early disease,
screening may be able to improve interval survival. The
value of using a screening test to merely extend survival
rather than affect overall mortality is beyond the scope
of this paper. For the purposes of this paper, a screening
test would at minimum need to identify ovarian cancer in
its early stages in order to have an impact in patient care.
To date, an effective screening tool for ovarian cancer
has not been identified. A good screening test must satisfactorily address validity, reliability, yield, cost, acceptance,
and follow-up services.4 Validity is determined by both
sensitivity and specificity. A screening test needs to be
positive for those with the disease (ie, sensitivity) and
negative for those without the disease (ie, specificity).
A screening test with poor sensitivity and specificity
yields false-positive and false-negative results. In ovarian
cancer, this translates to unnecessary surgery or inaccurate diagnosis.
In terms of ovarian cancer, an effective screening test
must have a sensitivity greater than 75% and a specificity
greater than 99.6% to attain a positive predictive value
of 10%.5-8 A positive predictive value of 10% would limit
unnecessary surgeries to 10 patients to identify 1 patient
with cancer.7 The positive predictive value can be affected by prevalence of disease. The incidence of ovarian
cancer in the general population is 17 per 100,000.9
Therefore, most women in the general population do not
have ovarian cancer, and a positive result would likely be
a false-positive outcome.9 With low incidence of disease,
improving the accuracy of screening tests to provide an
acceptable positive predictive value and even a negative
predictive value is challenging.
Most studies aimed at finding a screening test focus
on sensitivity, specificity, and positive predictive value.
However, even valid tests must be reliable between observations and must yield the results necessary to change
overall outcome. Although a test may identify ovarian
cancer at an earlier stage, it may not be reproducible
between institutions and may not alter overall survival.
In addition, many of the proposed screening methods
require new technology, which is expensive and not
always readily available to the general public. Institutions
may not have the personnel trained to administer or
interpret the test. Therefore, the cost to the population,
both monetarily and in the form of trained professionals,
may delay an effective population screening program.
Subjective Symptoms
Symptoms preceding a diagnosis of ovarian cancer are
neither specific nor sensitive. In 2006, Goff et al10 reported
January 2011, Vol 18, No.1
a case-control study including 149 women with ovarian
cancer and 488 control patients. Through a questionnaire,
they identified urinary urgency/frequency, pelvic/abdominal pain, increased abdominal size/bloating, and difficulty
eating/feeling full as symptoms associated with cancer.
They developed a symptom index that showed a sensitivity
of 56.7% for early disease and 79.5% for advanced disease.
Specificity was 90% for women older than 50 years of age
and 86.7% for women younger than age 50.10
In 2007, the Gynecologic Cancer Foundation, the
American Cancer Society, and the Society of Gynecologic
Oncologists followed with a consensus statement that
“women experiencing bloating, pelvic or abdominal pain,
difficulty eating or feeling full quickly, or urinary symptoms almost daily for more than a few weeks should see
their doctor.”11 Although the symptom index allows for
greater awareness, the index does not provide enough
sensitivity and specificity for screening. Neither has the
index been tested in a prospective manner. Studies since
that time have combined the symptom index with other
targets (eg, CA-125, HE4) in an attempt to improve positive predictive value, but the sensitivity and specificity
remain too low for an adequate screening test.12,13
Pelvic Examination
Pelvic examination is unlikely to discriminate an early or
premalignant lesion from a normal ovary. The sensitivity in detecting a pelvic mass on pelvic examination is
45% and the specificity is 90%.14 In screening studies, a
pelvic examination could distinguish a benign mass from
a malignant mass with a pooled sensitivity of 58% and a
sensitivity of 98%.14
Tumor Markers
CA-125 is an epithelial marker derived from coelomic
epithelium.8 It is elevated in 90% of advanced ovarian
cancers and in 50% of early ovarian cancers.6,7,15 Any
process that disrupts the epithelial lining of the peritoneum has the potential to raise the CA-125 level. Therefore, CA-125 can be elevated in many benign conditions
including pregnancy, leiomyomata, ovarian cysts, endometriosis, appendicitis, and diverticulitis.6,16 CA-125 can
also be elevated in other cancers such as uterine, colon,
lung, or pancreas.6,16 It is neither sensitive nor specific
enough to screen for early disease in ovarian cancer.6
Although one nested case-control study that included
37 women showed a sensitivity of 57% and specificity of
100% over 3 years,17 based on other data, the sensitivity
of CA-125 for screening purposes is closer to 80%.16,18,19
Therefore, CA-125 may help raise an index of suspicion
when evaluating a pelvic mass,19 but it is not sufficiently
sensitive or specific for effective screening.
Skates et al20 retrospectively evaluated CA-125 levels
in a Swedish cohort. They applied linear regression to
longitudinal CA-125 levels and hypothesized that changes
in CA-125 over time may predict ovarian cancer. Their
Cancer Control 17
algorithm for risk of ovarian cancer reached a specificity of 99.7% and a positive predictive value of 16%.
The study was limited by sample size and retrospective
design. However, it led to the development of the risk
of ovarian cancer calculation later used in prospective
trials discussed below.
Imaging
The most effective and least expensive imaging for
ovaries is transvaginal ultrasound.3 Ultrasonography attempts to discriminate between benign and malignant
adnexal masses by utilizing information on the morphology of wall structure, septations, echogenicity, and volume.
Ultrasound has a pooled sensitivity of 82% to 91% and
specificity of 68% to 81% at distinguishing benign from
malignant masses.14 Doppler imaging utilized to discriminate between benign and malignant adnexal masses
has a pooled sensitivity and specificity of 72% to 88%
and 73% to 90%, respectively. Individually, sensitivities
and specificities are as follows: resistive index, 72% and
90%; pulsatility index, 80% and 73%; maximum systolic
velocity, 74% and 81%; and presence of vessels, 88% and
78%.14 Using morphology and Doppler imaging together
resulted in a pooled sensitivity of 86% and a specificity of
91%.14 Although characteristics noted by ultrasound have
been used to formulate a likely diagnosis of malignant
vs benign masses, no characteristic has the sensitivity or
the specificity necessary for ultrasound to be a reliable
screening test. Like CA-125, these characteristics may
raise an index of suspicion with an associated pelvic
mass but are not sufficient for screening.
The Kentucky Ovarian Cancer Screening Project
screened 14,469 asymptomatic women annually with
ultrasound. An abnormal finding (abnormal volume for
menopausal status or projections into a cystic tumor)
resulted in repeat ultrasound and, if persistent, a subsequent CA-125. Using this paradigm, in 2000 they reported a sensitivity of 81%, a specificity of 98.9%, and a
positive predictive value of 9.4%.21 Negative predictive
value was 99.97%.21 In 2007 an update to this study
was published that extended the screening to 25,327
women.22 Sensitivity reached 85%, specificity 98.7%, and
positive predictive value 14.01%. Negative predictive
value 99.9%.
A trial by the United Kingdom Collaborative Trial of
Ovarian Cancer Screening (UKCTOCS) published in 2009
involving 202,638 patients showed that the use of ultrasound alone resulted in a sensitivity of 75% for invasive
cancer and a specificity of 98.2% with a positive predictive
value of 2.8%.5,23 However, UKCTOCS researchers found
that when screening with CA-125 and using ultrasound
as a second-line test for an abnormal CA-125 (determined
according to a “patented risk associated algorithm”5), sensitivity, specificity, and positive predictive value improved
to 89.4%, 99.8%, and 43.3% overall, respectively, and 89.5%,
99.8%, and 35.1% for invasive cancers.5,23
18 Cancer Control
Menon et al5,24 also employed screening with CA-125
followed by the use of a risk of ovarian cancer algorithm.
The algorithm determines an individual’s risk of ovarian
cancer and was also used in the UKCTOCS trial. The
algorithm is complex, and a discussion of its elements
and calculations can be accessed through publications
by Skates et al.25,26 If CA-125 results were abnormal
with intermediate risk determined by the algorithm, the
patient had repeat testing and subsequent ultrasound if
indicated. If CA-125 results were abnormal with elevated
risk determined by the algorithm, the patient underwent
ultrasound. Among the 13,582 women screened, specificity was 99.8% and positive predictive value was 19%.24
A comparable study — the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) — is in
progress in the United States and has not yet reported
long-term data.23 Preliminary results of 39,115 women
randomized to receive screening for ovarian cancer
showed a positive predictive value with CA-125 at 3.7%,
with ultrasound at 1.0%, and with both tests together a
positive predictive value of 23.5%.27 Although the positive predictive value increased, if both ultrasound and
CA-125 were required to be abnormal for screening in
this trial, 20 of the 29 neoplasms (70%) and 12 of 20
invasive cancers (60%) would have been missed.
As technology improves, imaging may lead to earlier
detection but is unlikely to have the specificity or sensitivity to identify early or premalignant lesions; if used
alone, it is unlikely to be a good screening tool. Although
recent studies are encouraging, they have yet to be validated. In addition, the use of ultrasound as a screening test is unlikely to be successful because ultrasound
technique is highly dependent on the skill and training
of both the ultrasonographer and the interpreting physician. As such, the use of ultrasound is unlikely to be
consistently reproducible, accessible, or affordable for
the general public and across institutions.
Advancing Technologies
Proteomic approaches include a test developed by OvaCheck (Correlogic Systems, Germantown, MD), which
published its first results in 2002.28 Initial studies were
enticingly optimistic, quoting a sensitivity of 100% and
a specificity of 95% in distinguishing cancerous from
normal ovarian tissue in 116 samples.28 However, the
results were difficult to reproduce in independent evaluations of the data.29 In February 2004, the Society of
Gynecologic Oncologists issued a statement that “more
research is needed to validate the test’s effectiveness
before offering it to the public.”30 OvaCheck has yet to
be validated and is not commercially available.31
The OvaSure Yale Ovarian Cancer Test (Laboratory
Corporation of America, Burlington, NC) was recently
introduced as a commercially available blood test. Data
were initially presented in 2008.32 The initial study
combined six biomarkers (leptin, prolactin, osteoponJanuary 2011, Vol 18, No.1
tin, insulin-like growth factor II, macrophage inhibitory
factor, and CA-125) into a model that classified samples
as cancer vs normal. In 518 samples (362 healthy, 156
ovarian cancer), the final model was able to distinguish
normal from cancerous tissue with 95.3% sensitivity,
99.4% specificity, and a positive predictive value of 99.3%.
However, the OvaSure release to the market was considered premature, and it is currently unavailable. The
US Food and Drug Administration was not satisfied with
the validation of the testing and has asked for further
evaluation.33 In July 2008, the Society of Gynecologic
Oncologists stated that “it is our opinion that additional
research is needed to validate the test’s effectiveness
before offering it to women outside of the context of a
research study.”34 One criticism of the study is that the
positive predictive value was based on a prevalence of
ovarian cancer of 50%.3 When calculating the positive
predictive value using the prevalence of disease in the
population, it decreases to 6.5%.3
The US Food and Drug Administration recently
cleared the test OVA1 (Vermillion Inc, Fremont, CA) for
ovarian cancer. The test measures five serum proteins
and is to be used once a pelvic mass has been identified
and the patient is planned for surgery. The test is not
intended as a screening tool.35
Genomic investigation has traditionally targeted individual genes such as BRCA1 and BRCA2. Recent research
has evolved to include genomic microarrays, testing the
expression of multiple genes at one time. Most studies to
date involve small sample numbers making it difficult to
make definitive conclusions. Larger sample volumes will
be needed to generate the power necessary to validate
these methods.19
Emerging proteomic and genomic studies are hindered by similar limitations. Both are moving to high
throughput microarray assays resulting in vast numbers
of data points. Bioinformatic analysis of such multiple
point data sets is limited by statistical methods available
to adequately evaluate the data with reproducibility and
validity.19,36 However, with emerging technology and
capabilities, this is likely a future direction for screening
and individualizing diagnosis and treatment.
Additional serum markers are being researched.
Perhaps in proper combination, markers may provide
the needed specificity, sensitivity, and positive predictive value for effective screening, but this has not yet
been determined.6-8 Although combining markers may
increase the sensitivity, it may also decrease specificity.8
Markers that have been implicated include CA-72-4,
macrophage colony-stimulating factor, monoclonal antibody OVX1, lysophosphatidic acid, prostasin, osteopontin, inhibin, kallikrein, claudin 3, monoclonal antibody
DF3, vascular endothelial growth factor, MUC1, CA-19-9,
mesothelin, human epididymis protein 4, and interleukins.3,6-8 Additional targets continue to be identified as
research enters high throughput modalities.7
January 2011, Vol 18, No.1
High-Risk Populations
Hereditary syndromes account for 10% of ovarian
cancers.37,38 The risk of developing ovarian cancer is
39% to 46% for patients with BRCA1 mutations, 10% to
20% for those with BRCA2 mutations, and 9% to 12%
for those with Lynch syndrome.37,39-41 Despite a higher
prevalence of ovarian cancer among patients with these
syndromes, no effective screening method is available.
There is no evidence that biomarkers such as CA-125,
HE4, or mesothelin are more specific in high-risk populations.42,43 Although there may be utility in combining
multiple markers in the future,43 no current combination
of markers has been validated for screening purposes.
Annual screening with ultrasound and CA-125 has
been unsuccessful in detecting early ovarian cancers in
high-risk populations.41,44 In a retrospective audit of patients undergoing yearly surveillance with ultrasound and
CA-125,Woodward et al41 found the sensitivity, specificity,
and positve predictive value of screening in the high-risk
cohort (N = 179) to be 50.0%, 82.9%, and 1.3%, respectively.41 Only one of four ovarian cancers in the cohort
(N = 341) was discovered during routine surveillance.
Furthermore, three of the four cancers were advanced.
The authors concluded that annual screening is ineffective in high-risk populations.41
A high-risk screening program in the Netherlands followed BRCA1 and BRCA2 patients biannually and other
high-risk populations annually. Investigators noted a
sensitivity of 40%, a specificity of 99%, and a positve
predictive value of 40% combining CA-125 with transvaginal ultrasound.45 However, 80% of the patients diagnosed with cancer at the time of prophylactic salpingooophorectomy had negative screening prior to surgery.45
In addition, three of the four ovarian cancers detected
during screening were identified in advanced stages, an
endpoint unlikely to affect overall mortality.45
Although there are no validated screening methods
for patients at high risk of ovarian cancer, the National
Comprehensive Cancer Network has offered expert
opinion. Their guidelines suggest practioners consider
surveillance for high-risk patients with a pelvic examination, transvaginal ultrasound, and CA-125 every 6 months.
Surveillance should begin at age 35 years or 5 to 10 years
prior to the earliest age of diagnosis in the family.37,46
However, the guidelines stipulate that the effectiveness
of this strategy is undetermined.37,46 The ability of ultrasound and CA-125 to decrease mortality associated
with ovarian cancer in high-risk populations has yet to
be proven.37
Conclusions
At present, no validated testing modality is available with
enough sensitivity, specificity, and positive predictive
value to be used as a screening test for ovarian cancer.
Currently, no organizations recommend screening in the
general population.3 Despite developing technologies
Cancer Control 19
and some promising studies, it is unlikely that a screening
test will be available in the near future. Even if one could
achieve the necessary statistical criteria, developing an
effective screening test for ovarian cancer will need to
address many unresolved issues.
To date, we do not fully understand the progression
of ovarian cancer from early to advanced disease. We do
know that as the cancer presents on the surface of the
ovary, peritoneal fluid circulates over the ovary, transporting cancer cells and depositing them throughout the
abdominal cavity. This occurs on a microscopic level
that is unlikely to be detected by imaging or laboratory
values until the disease has significantly disseminated and
progressed to advanced cancer. Until nanotechnology
advances, screening tests employing current imaging
techniques are unlikely to be sensitive enough to determine such microscopic changes.
Further, we have yet to identify a precursor lesion
in ovarian cancer. Screening for precursor lesions offers
the best opportunity to impact mortality from ovarian
cancer. If screening is limited to early diagnosis, it must
at minimum improve interval survival to be effective.7
However, given the natural history of ovarian cancer, it is
unlikely that identifying ovarian cancer in its early stages
will have a significant impact on mortality.8
Finally, an effective screening program must be accessible to the general public, and trained personnel must
be available to act on the results of the testing. Such a
program will require training and costly investment that
are essential to provide the necessary technology and
personnel qualified to deliver reliable outcomes. Once
a screening test has been validated sufficiently, it will still
require a cost-benefit analysis.
To date, there is no effective screening method for
ovarian cancer. Aside from a clinical trial, routine screening for ovarian cancer in the general public is not currently recommended.3,9,37 For patients at risk for ovarian
cancer, biannual surveillance with ultrasound and CA-125
can be considered.37,46
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