Full Text Review
Please note: In 2003, the CTF updated its Grades of
Recommendations to include an "I Recommendation" for situations where
insufficient evidence exists to allow a recommendation to be made.
(Formerly, these situations were captured under a "C
Recommendation".) This change is not retroactive, and all
"C Recommendations" made prior to 2003 have not been
reevaluated in light of the new "I" recommendation grade. For a
discussion of these recommendation grades, please link to the 2003 article in
the Canadian Medical Association Journal here.
Screening for Ovarian Cancer
Prepared by Cindy Quinton Gladstone, MHSc, MD,
FRCPC, Research Associate, Department of Preventive Medicine and Biostatistics,
University of Toronto, Ontario
These recommendations were finalized by the Task Force in January 1994
Contents
Overview
Ovarian cancer is the leading cause of gynecologic
cancer mortality in North America. The disease has usually spread beyond
the ovary by the time of diagnosis, and is associated with a five-year
survival of 35% or less, as compared with 90% for Stage I tumours. To date,
standard treatments have had little impact on mortality, and attention
has focused on early detection through screening. A review of the evidence
does not support such action. In fact, given the poor positive predictive
value of pelvic examination, abdominal and transvaginal sonography, and/or
serum CA 125
levels for ovarian cancer, as well as the potential harm of laparotomy,
there is fair evidence to exclude such testing from periodic health assessments
in asymptomatic pre- and post-menopausal women. The issue is less clearcut
for high-risk women, with one or more first-degree relative(s) with ovarian
cancer, or with one of the rare hereditary ovarian cancer syndromes. In
such cases, the higher prevalence of disease may outweigh the risks of
screening, although there is insufficient evidence to recommend for or
against such a course of action. In all cases it would be prudent to examine
the ovaries at the time of cervical cancer screening (see Chapter 73),
as well as to refer women with a family history of ovarian cancer to an
academic research center for follow-up.
Burden
of Suffering
Ovarian cancer is the sixth most common female malignancy,
after cancers of the breast, colon, lung, and uterus. The estimated incidence
in Canada in 1993
was approximately 2100
new cases per year, about 4% of all new cancers in women.<1>
Yet, because it is so lethal, it remains the leading cause of gynecologic
cancer mortality in both Canada and the U.S.<2> Sparks suggests that
for populations in which preventive measures have been applied for more
common causes of death, the early detection of ovarian cancer "becomes
the next focus of efforts to reduce premature death among women".<3>
Familial instances account for 5% to 15%
of all ovarian cancers.<4,5> A recent case-control study, conducted
in Alberta, Canada<6> established a relative risk of 2.61
for
individuals with relatives with ovarian cancer. (The 95% confidence interval
for the ratio between the observed and expected number of malignancies
in cases’ and controls’ relatives was 1.12-1.59,
significantly different from 1).
Public health records in the United Kingdom showed that, if two or more
close relatives were affected, the lifetime risk to a sister or mother
of a patient approached 40%.<7> The rarer, hereditary cancer syndromes
include: a) breast/ovary kindreds, b) Lynch II families, where both colonic
and ovarian cancers occur, and c) site-specific cancers, involving only
ovarian tumours. In addition to family history, other risk factors include
advanced age, low parity, and nonuse of the oral contraceptive pill. At
least one case-control report has shown a protective effect after as little
as 3–6 months of oral contraceptive use.<8>
Ninety percent to 95% of ovarian malignancies are
classified as epithelial<9> including serous, mucinous, endometrioid,
clear cell, mixed epithelial, and undifferentiated histologies. Ten percent
to 15% of
these tumours are termed "borderline" or of "low malignant potential" because
of their limited metastatic tendency and much higher 5 year survival rates.
Tumour staging has been standardized by the International Federation of
Gynecology and Obstetrics with Stage I tumours limited to the ovaries,
Stage II including those with pelvic extension, Stage III involving those
with peritoneal disease outside the pelvis and/or positive retroperitoneal
or inguinal lymph nodes, and Stage IV comprising those with "distant" metastases.
At present, because of late and nonspecific symptomatology,
and the relative inaccessibility of the ovaries to physical examination,
only 25% of women with ovarian cancer have disease confined to the ovary
at the time of diagnosis.<10>
While in recent studies the five-year survival rate for this group nears
90%, the comparable rate is 35% or worse for the majority of women, who
have disseminated disease when diagnosed.
The natural history of ovarian cancer is not well
understood. Rare case reports have suggested that malignancy may arise
in benign cystadenomas. To date, however, no preinvasive lesion has been
established. It may be that tumours arise de novo at multiple sites, as
seen with primary peritoneal neoplasias. The problem of understaging due
to inadequate surgery has hampered efforts to further define "typical"
disease progression.
Maneuvers
Pelvic Examination
The sensitivity and specificity of the biannual examination
have not been addressed. Patient size, body habitus, pelvic structure,
and anxiety level would be expected to affect the accuracy of this maneuver,
as would the expertise of the examiner, and the dimensions of the tumour
itself. According to retrospective reports, chart reviews, and case series
on this topic, pelvic examinations have missed from 10%
to 100% of
tumours diagnosed at laparotomy. A particularly high false positive rate
would be expected in pre-menopausal women, given the increased prevalence
of benign adnexal disease in this group.
One prospective comparison of preoperative ultrasound
and pelvic examination in patients with pelvic masses yielded sensitivities
(for detection of any pathology) of 83% and 67% respectively. Specificities
were much higher at 94% and 96%.<11>
The level of "blinding" of the examiners in this study, however, was questionable.
Abdominal Ultrasound
The literature in this area is limited once again to
case series.<12,13>
Campbell and colleagues<14,15>
performed three annual screening scans on 5,479 self-referred, asymptomatic
women over 45 years of age. Of 15,977
scans, 338 were positive. Almost 4% of subsequent laparotomies were negative.
Five primary ovarian malignancies, all Stage I, were diagnosed, for a prevalence
of 0.09%, a specificity of 97.7%, and a sensitivity of 100%.
However, even with these test characteristics, the positive predictive
value in this population was only 1.5%.
Furthermore, there was no independent follow-up of the women with negative
scans.
Clearly, despite the impressive sensitivity and specificity
reported for abdominal ultrasonography, its ability to screen for ovarian
cancer is limited by the low prevalence of such tumours in the general
population.
Transvaginal
Sonography (TVS)
This technique is said to be superior to abdominal ultrasonography,
because the transducer is closer to the area of interest, permitting the
use of higher frequency ultrasound and enhancing the image quality. There
have been three recent case series reported by Van Nagell’s group<2,16>
on screening for ovarian cancer using TVS. Specificity and sensitivity
were calculated at 98.1%
and 100%
respectively. Other investigators have reported similar results.<17>
It has been postulated that transvaginal colour doppler
may increase the specificity of TVS, because changes in tissue vascularity
mediated by angiogenic tumour factors change impedance to bloodflow, even
in Stage I cancers. One case series<18>
supports this claim, with an abnormal colour doppler pattern seen in 0
of 30 normals, 1 of
10
benign masses, and 7 of 8 cancers.
CA 125
This tumour-associated antigen has been proposed for
serologic screening for ovarian cancer. It is an antigenic determinant
on a high molecular weight glycoprotein which is recognized by the monoclonal
antibody OC 125.<19>
Evidence concerning CA 125
screening is limited to 3 case-control studies, several case series,<19-24>
and one "stochastic computer simulation".<25>
When CA 125
levels were evaluated in healthy patients, patients with benign pelvic
masses, and those with malignant masses (including ovarian carcinomas),
a 93.3% sensitivity and 79.7% specificity were achieved, using the usual
threshold of >35 U/ml.<26> As expected, using a higher cutoff increased
specificity with a concomitant reduc-tion in sensitivity.<27> False
positives were seen with leiomyomas, inflammatory masses, endometriomas,
and benign epithelial neoplasms. CA 125
is less sensitive in early stage disease, as well as in borderline and
mucinous tumour types.
The most interesting study<28> involved a "blind"
retrospective analysis of CA 125
levels using sera obtained from the JANUS serum bank, a Norwegian repository
of specimens collected since 1973
from more than 100,000
individuals. CA 125
levels were measured for women who subsequently developed ovarian cancer
and from matched controls. Based on these data, the authors quote a 30-35%
sensitivity (for a threshold value of 35 U/ml) for CA 125
levels drawn 2 years prior to diagnosis. Specificity was 95.4%. Specificity
could be further increased when the doubling of an initially elevated CA
125
value was used as the criterion for positivity.<29>
Combination Screening
When a combination of preoperative clinical examinations,
abdominal ultrasonography, and CA 125
were performed in women with ovarian masses, results in post-menopausal
women suggested much lower sensitivities, but higher specificities for
all maneuvers than reported elsewhere. Test characteristics were poorer
in pre-menopausal women. Using this multimodal approach the authors were
able to increase the positive predictive value of screening to 100%
in post-menopausal women. Clearly this reflects the high prevalence of
disease in this pre-selected population (24% in the pre-menopausal women
and 59% in the post-menopausal group).<30>
Another multimodal screening study<31>
included only post-menopausal volunteers, who underwent a routine pelvic
examination and CA 125
measurement (cutoff 30 U/ml), followed by ultrasonography if indicated.
Only one case of ovarian cancer was detected. As anticipated, specificities
were increased to 99-100%
by the combination of two or three of the maneuvers.
A recent decision analysis, designed to estimate
the effectiveness of an ovarian cancer screening with CA 125
levels and transvaginal sonography in a cohort of 40-year-old women, suggested
that screening increased the average life expectancy in this population
by less than one day.
Costs
There are no randomized controlled trials of screening
for ovarian cancer. The potential costs of screening all women over 45
years of age are prohibitive. The cost in the U.S. to screen the 43 million
eligible women of this age with an ultrasound U.S. ($275 each) and a CA
125
level U.S. ($45 each) has been estimated at over U.S. $13
billion yearly, with no guarantee of a reduced death rate.<5>
Treatment
Efficacy
Surgery Alone
Two recent case series have reported results of a "watch
and wait" approach, without adjuvant therapy, following initial surgery.
In those patients with early stage tumours who had undergone the most extensive
preoperative staging, 100%
5 year disease-free survival was achieved with surgery alone.<32> Prognosis
for early stage tumours with capsular rupture or positive peritoneal washings
was slightly worse.<33>
Chemotherapy
The literature on chemotherapy consists mostly of trials
of single-agent or combination regimens in patients with advanced ovarian
cancer. Trials in early-stage disease are plagued by inconsistencies of
staging and grading. In one study, patients with early stage ovarian cancer
were randomized to receive melphalan or no treatment. Five-year disease-free
survival for the two groups was not statistically different (p>0.05) at
91% and 98%
respectively.<34>
A companion study randomized women with poorly differentiated
Stage I or II tumours to receive either melphalan, or a single dose of
intraperitoneal Chromic Phosphate, a radioisotope. Five year disease-free
survival was 80% for both groups. Overall survival for the two groups was
approximately equal. The authors conclude that Chromic Phosphate is the
preferred treatment, because of the risk of myelosuppression, gastrointestinal
toxicity, and leukemias associated with Melphalan. Both Chromic Phospate
and Melphalan toxicity have been observed by other investigators.<35>
Radiotherapy
There is a scarcity of randomized controlled trials
of radiotherapy. Dembo and colleagues<36> postoperatively randomized
patients with Stage I tumours to "watchful waiting" or pelvic irradiation.
Relapse rates depended more on the degree of differentiation of the tumours
than on treatment received.
Adverse Effects
The unfavourable effects of screening, (including patient
anxiety due to false positive results, and the false sense of security
occasioned by false negative results) have remained largely unquantified.
In those with a family history of ovarian malignancy, the side effects
of prolonged hormonal replacement therapy following prophylactic oopherectomy
must also be considered.
Buchsbaum<37> reported a startling rate of adverse
outcomes of surgical staging of ovarian carcinomas, including 74 complications
in 154 patients
and one postoperative death. Most other authors have noted far fewer adverse
outcomes of diagnostic laparotomy.<38-40>
Diagnostic laparoscopy may offer a less invasive,
and presumably less risky, alternative to laparotomy. However, primary
endoscopic surgery is not generally accepted for routine management of
suspected ovarian cancer, because of the fear of spreading malignant cells.
Guidelines for the pelviscopic management of ovarian masses are currently
under review.
Familial Ovarian
Cancer
Routine screening has been widely advocated in this
population, in which the greater prevalence of disease should markedly
increase the positive predictive value of all detection measures. In a
screening study in asymptomatic women with at least one first degree relative
with ovarian cancer, the prevalence of ovarian cancers was 3.9 per 1,000.
This is much higher than the 0.4 per 1,000
prevalence quoted for the general population. The false positive rate was
also higher, however, because of the higher incidence of benign ovarian
masses. The positive predictive value of ultrasonography under these circumstances
was considerably higher than usual, at 7.7%.<4>
Based on such evidence, many researchers advocate
combination screening in an academic centre for all women with one or more
first-degree relative(s) with ovarian cancer. As tumours tend to develop
at a younger age in this group, it has been suggested that such screening
begin at age 30. In addition to screening, prophylactic oophorectomy is
recommended, particularly where there is a history of hereditary ovarian
cancer. Unfortunately, even this radical prophylaxis does not guarantee
immunity from cancer, as rare case reports of postoperative disseminated
intraabdominal carcinomatosis have been published.
Recommendations
of Others
The U.S. Preventive Services Task Force concluded that
screening of asymptomatic women for ovarian cancer is not recommended.<41>
This group does indicate that it is "prudent" to examine the adnexa, if
a pelvic examination is to be done for other reasons.
For pre- and post-menopausal women without a family
history of ovarian cancer, the American College of Physicians (ACP) does
not recommend screening (ultrasound or CA 125).
For women with a family with hereditary ovarian cancer syndrome, ACP recommends
referral for specialist care. ACP also recommends that for other women
with a family history of ovarian cancer (in one or more relatives), decisions
about screening be made based on other risk factors (age, parity and history
of oral contraceptive pill use).
Conclusions
and Recommendations
There is fair evidence in published clinical research
to exclude screening for ovarian cancer, either by abdominal examination,
pelvic or transvaginal sonography, or CA 125
levels, from the periodic health examination of asymptomatic pre- and post-menopausal
women (D Recommendation).
It would be reasonable to examine the adnexa if a pelvic examination were
being done for another reason, such as cervical inspection or pap smear.
There is insufficient evidence to recommend for or
against screening in individuals with one or more first-degree relatives
with ovarian cancer (C
Recommendation). However, in light of the significantly higher incidence
of ovarian malignancy in such women, expert opinion currently suggests
that they be referred to an academic research centre for regular combination
screening with pelvic examination, ultrasonography, and determination of
CA 125 levels.
There is little evidence concerning the frequency of such screening.
Unanswered
Questions (Research Agenda)
Well-designed clinical trials are needed to elucidate
further the natural history of ovarian cancer, and to assess multimodal
screening for ovarian cancer, to determine whether the combination of pelvic
examination, tumour markers, and transvaginal sonography will lead to reduced
mortality. Further assessment of the test characteristics for these screening
maneuvers in well-defined populations, such as those with a familial risk
of ovarian cancer, would also be of value. The cost-effectiveness of screening
for ovarian cancer will depend on the determination of its effectiveness,
if any.
Evidence
Articles assessing screening for ovarian malignancy
were obtained by a computerized search (MEDLINE from 1975
onwards) using the MESH headings screening, ovarian neoplasms, and one
of either ultrasonography, CA125
antigen, neoplasms-staging, surgery, chemotherapy, or radiotherapy. Only
references in English were retrieved. Review articles, and those dealing
with advanced stages of ovarian cancer or nonepithelial tumours (see below)
were excluded. Content experts were consulted to ensure that all relevant
research was analyzed. A Technical Report (1992)
including a full reference list is available upon request. This review
was initiated in January 1992
and recommendations finalized by the Task Force in January 1994.
Acknowledgements
The Task Force would like to acknowledge the assistance
of J.L. Benedet, MD, FRCSC, Professor, Obstetrics and Gynecology, University
of British Columbia, Vancouver, British Columbia, President of the Gynecologic
Oncology Association of Canada and Head, Division of Gynecologic Oncology
Cancer Control Agency of British Columbia; John F. Jeffrey, MD, FRCSC,
Head, Division of Gynecologic Oncology, Victoria General Hospital, Halifax,
Nova Scotia and Barry Rosen, MD, FRCSC, Assistant Professor, Department
of Obstetrics and Gynecology/Oncology, University of Toronto, Toronto,
Ontario, in the preparation of this manuscript.
Full Citation
Link to Structured Abstract of
this review
Link to Summary Table of this
review
Link to Selected References list of this review
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