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INTRODUCTION:
Ovarian cancer is a major killer and every year more and
more cases are being diagnosed with ovarian cancer. The
lifetime risk of dying from ovarian cancer is 1.1%.1,2 The
overall 5-year survival rate is at least 75% if the cancer
is confined to the ovaries and decreases to 17% in women
diagnosed with distant metastases. Symptoms usually do not
become apparent until the tumor compresses or invades
adjacent structures, ascites develops, or metastases become
clinically evident. As a result, in India, approximately 80%
of the patients are diagnosed in advanced stages of disease
and hence the morbidity and mortality is very high.
We know that carcinoma of the ovary is most common in women
over age 60. 3 Other important risk factors are low parity
and a family history of ovarian cancer. Less than 0.1% of
women are affected by hereditary ovarian cancer syndrome,
but these women may face a 40% lifetime risk of developing
ovarian cancer.11 Ovarian cancers are often observed within
hereditary breast cancer families.
Like in all malignancies survival from ovarian cancer is
related to stage at diagnosis. The 5-year survival rate is
89% for localized disease, 36% for women with regional
metastases, and 17% for women with distant metastases.
Studies have shown that the most important prognostic factor
in patients with advanced ovarian cancer is the size of
residual tumor after treatment.2 Surgical debulking and
chemotherapy for ovarian cancer appear to be more effective
in reducing the size of residual tumor when ovarian cancer
is detected early. Thus, screening for ovarian cancer is of
paramount importance.
Screening tests
Potential screening tests for ovarian cancer include the
bimanual pelvic examination, the Papanicolaou (Pap) smear,
tumor markers, and ultrasound imaging.
ANNUAL PELVIC EXAMINATION
The pelvic examination, which can detect a variety of
gynecologic disorders, is of unknown sensitivity in
detecting ovarian cancer. Although pelvic examinations can
occasionally detect ovarian cancer, small, early-stage
ovarian tumors are often not detected by palpation, due to
the deep anatomic location of the ovary. Thus, ovarian
cancers detected by pelvic examination are generally
advanced and associated with poor survival. The pelvic
examination may also produce false positives when benign
adnexal masses (e.g., functional cysts) are found.2 Palpable
ovary in a postmenopausal women should definitely raise
suspicion of ovarian cancer.
A large clinical trial has recently been launched by the
National Cancer Institute 4 to determine if annual pelvic
examination can have a role in screening. Under the most
optimistic assumptions (100% sensitivity, 30% reduction in
5-year mortality with screening, no lead-time bias), annual
pelvic examinations of 40-year-old women could reduce 5-year
mortality from ovarian cancer in the population by less than
0.0001%.
PAP SMEAR
Pap smear is extensively used in screening for cervical
disease in most countries. The Pap smear may occasionally
reveal malignant ovarian cells, but it is not considered a
valid screening test for ovarian carcinoma.2,3 Studies
indicate that the Pap smear has a sensitivity for ovarian
cancer of only 10-30%.
SERUM TUMOR MARKERS
Serum tumor markers are often elevated in women with
ovarian cancer. Examples of these markers include
carcinoembryonic antigen, ovarian cystadenocarcinoma
antigen, lipid-associated sialic acid, NB/70K, TAG 72.3,
CA15-3, and CA-125. 5 Of these the CA 125 ovarian
cancer-associated antigen is present at elevated levels in
the serum of up to 90% of all ovarian cancer patients,
including approximately 50% of patients with early-stage
disease, suggesting its potential utility in the early
detection of ovarian cancer. However, it has been reported
that CA- 125 is elevated in 1% of healthy women, 6-40% of
women with benign masses (e.g., uterine fibroids,
endometriosis, pancreatic pseudocyst, pulmonary hamartoma),
and 29% of women with non-gynecologic cancers (e.g.,
pancreas, stomach, colon, breast) and so false-positive
results are common.6, 7 This high false-positive rate
relative to the low incidence of ovarian cancer has led to
the general consensus that a single CA 125 assessment is not
useful in detecting early-stage ovarian cancer. So serial
measurements may be required.
Also evidence is limited on whether tumor markers become
elevated early enough in the natural history of occult
ovarian cancer to provide adequate sensitivity for screening
in asymptomatic women. Studies of stored sera have found
that about one half of women who developed ovarian cancer
had elevated CA-125 levels (>35 U/mL) 18 months to 3 years 8
before their diagnosis. Further research is needed, however,
to provide more reliable data on the sensitivity of this and
other tumor markers in detecting early-stage ovarian cancer
in asymptomatic women.
It may be possible to improve the specificity of CA-125
measurement by selective screening of postmenopausal women,
modifying the assay technique, adding other tumor markers to
CA-125, requiring a higher concentration or persistent
elevation of CA-125 levels over time, or combining CA-125
measurement with ultrasound. 5
ULTRASOUND
Ultrasound imaging is able to estimate ovarian size,
detect masses as small as 1 cm, and distinguish solid
lesions from cysts. Transvaginal color-flow Doppler
ultrasound 9,10 can also identify vascular patterns
associated with tumors. In screening studies, the reported
sensitivity and specificity of transabdominal or
transvaginal ultrasound are 50-100% and 76-97%,
respectively, but small sample sizes, limited follow-up, and
outdated techniques may limit the validity of the data.9,
10,11
14,356 ultrasound examinations performed over 3 years on
5,489 asymptomatic women over age 45 detected five ovarian
cancers.10 Although the sensitivity and specificity of the
test were excellent (100% and 94.6%, respectively), the
positive predictive value in this low-risk study population
was only 2.6% and follow-up was of short duration.
Another study using transvaginal sonography (TVS) for the
detection of ovarian cancer consisted of 14,469 asymptomatic
women, all of whom were either >/= 50 years of age or >/= 30
years of age with a family history of ovarian cancer,
followed between 1987 and 1999 at the University of
Kentucky.9, 10,11 An abnormal sonogram was defined as one in
which the ovarian volume was greater than 10 cm3 in
postmenopausal women, and greater than 20 cm3 in
premenopausal women, or one in which a papillary or complex
tissue projection into a cystic ovarian tumor was evident.
All women with an abnormal TVS underwent a repeat sonogram
after 4-6 weeks, and if abnormal scans persisted, surgery
was recommended.
Of the 180 patients with persistent TVS abnormalities that
underwent exploratory laparoscopy or laparotomy, 17 ovarian
cancers were detected, 14 of which were stage I or II at
diagnosis. With a mean follow-up of 4.6 years (range, 0.8 ???
9.6 years), all of the patients with early-stage disease
were still alive without recurrence, whereas 2 of the 3
patients with advanced-stage disease had died. Of the group
without evidence of TVS abnormality, 4 patients developed
ovarian or primary peritoneal cancers within 1 year of a
negative scan, 2 of which were early stage and 2 of which
were advanced stage.
In this study, TVS was associated with a sensitivity of 81%,
a specificity of 98.9%, a positive predictive value of 9.4%,
and a negative predictive value of 99.9%. After a total of
46,113 screening years, there have been 3 ovarian cancer
deaths in the annually screened population and a 5-year
survival of 88% for the ovarian cancer patients in the study
population.
These studies show that TVS screening for ovarian cancer in
the general population may be effective at detecting disease
at an earlier, more curable stage, thus improving long-term
survival from this malignancy but it has relatively low
positive predictive value of only 9%, which is probably not
acceptable from the standpoint of cost-effectiveness and
patient acceptance. It should also be noted that this
methodology does not appear to be effective at detecting
primary peritoneal cancer, which is perhaps not surprising,
given the frequent absence of enlarged ovaries associated
with this malignancy. Clearly, further studies of the
utility of TVS in detecting early-stage ovarian cancer are
warranted.
COMBINED MODALITIES
It may be possible to improve accuracy by combining
ultrasound with other screening tests, such as the
measurement of CA-125.12 One prospective study screened
1,010 asymptomatic postmenopausal women over age 45 with
pelvic examination and CA-125 measurement; those with
abnormal results received an ultrasound examination.
Although one ovarian cancer was detected (all three
screening tests were positive in this woman), the study
demonstrated poor positive predictive value with each of the
three screening tests. No abnormality was discovered in 28
of the 31 women with elevated CA-125. Fibroids and benign
cysts were responsible for over half of the 28 abnormal
pelvic examinations. Various studies reported that the
combination of abdominal ultrasound and sequential CA-125
measurements had a sensitivity of 58-79%, a specificity of
about 100%, and a positive predictive value of 27%. 12,13,14
In our own study we have found that pelvic examination gave
a sensitivity of 82.1% and specificity of 73.07%. trans
vaginal ultrasound gave a sensitivity and specificity of 75%
and 76.9% while CA 125 levels had a sensitivity and
specificity of 92.8% and 75% respectively. When a combined
modality was used the sensivity and specificity improved to
95.2% and 94.2%.
GENETIC SCREENING
Women with germline BRCA1 or BRCA2 mutations are at
substantially increased risk for breast and ovarian cancer,
although the risks may not be as high as originally
reported. It appears that both breast and ovarian cancer
risk may be lower among BRCA2 carriers than among BRCA1
carriers, these cancers may occur at later ages, on average,
in BRCA2 carriers, and risk may also vary with the location
of the mutation within the gene. The choice of whether to
undergo genetic testing is a difficult one as it is
expensive, there are several variants to the gene and once
detected there are no definitive prophylactic methods to
prevent the occurrence of the disease. It has also proved to
be very psychologically disturbing to the women.15, 16
Several very large, prospective trials designed to test the
efficacy of this type of multimodality screening in both the
general and high-risk populations are currently under way.
SUMMARY
There is no direct evidence from prospective studies till
date that women with early-stage ovarian cancer detected
through screening have lower mortality from ovarian cancer
than do women with more advanced disease. A large body of
indirect evidence, however, suggests that this is the case.
Conclusive proof will require properly conducted prospective
studies comparing long-term mortality from ovarian cancer
between screened and nonscreened cohorts.
The sensitivity and specificity of available screening tests
for ovarian cancer in asymptomatic women are uncertain and
require further study. Although various tests can detect
occasional asymptomatic tumors, there is currently no
evidence that a particular test or combined approach is
definitely effective for routine screening. The large
majority of women with abnormal screening test results does
not have cancer, yet will require invasive procedures
(laparoscopy or laparotomy) to rule out malignancy. Given
the risks, inconvenience, and substantial costs of follow-up
testing, and the current lack of evidence that screening
reduces morbidity or mortality from ovarian cancer, routine
screening cannot be recommended.
Recommendations of Other Groups
There are no official recommendations to screen routinely
for ovarian cancer in asymptomatic women by performing
ultrasound or serum tumor marker measurements. The American
College of Physicians (ACP), the Canadian Task Force on the
Periodic Health Examination, and the American College of
Obstetricians and Gynecologists recommend against such
screening.
Current recommendations
The current recommendations made are pelvic examination to
be performed with the Pap test every 1-3 years in women aged
18-40 years and annually thereafter. Identified high risk
women or women with presumed hereditary cancer syndrome
should undergo annual pelvic examinations, CA-125
measurements and transvaginal ultrasound.
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