Scientists are making headway in detecting ovarian cancer at
an earlier stage.
In 2009, 21,500 women were diagnosed with ovarian cancer, and
14,600 died of the disease. Though far less common than breast
cancer — 192,000 new cases of breast cancer were diagnosed in
2009 and 44,000 people died of the disease — ovarian cancer is
almost three times as deadly.
Urgent need for early detection
Ovarian cancer is so lethal largely because 75% of cases are
diagnosed late, after the cancer has spread beyond the ovaries
and often throughout the abdomen. At that point, the five-year
survival rate is less than 30%. For the 25% of cases that are
diagnosed early, the outlook is very different: a five-year
survival rate of more than 90%.
This large difference in early- and late-stage survival makes
ovarian cancer an ideal target for improved early detection as an
approach to reduce mortality, explains cancer researcher Dr.
Steven J. Skates, at Massachusetts General Hospital in Boston.
"If we can find it in the early stage, then current therapies are
going to cure many women who would have died otherwise."
But early detection is difficult for many reasons. Early-stage
tumors are only rarely found during a routine pelvic exam,
because the ovaries are deep within the body and difficult for a
clinician to feel. In addition, ovarian cancer has no known
precancerous lesion (unlike colon cancer, which produces a
precancerous growth, a polyp, that can be seen and removed during
screening with colonoscopy). And while ovarian cancer may produce
biomarkers — substances in the blood or urine that indicate
something is going on — no biomarker specific to ovarian cancer
has yet been identified. CA-125, the biomarker most women have
heard about, hasn't worked out so far, though the final results
of a large screening trial may change that judgment (see "Ongoing
trials" below). Nor do we know whether any of the other
biomarkers associated with ovarian cancer and now detected at a
late stage are active in the early stages of the disease.
Another approach to early detection is transvaginal ultrasound —
inserting a transducer into the vagina to obtain ultrasound
images of the ovaries. This technique can locate tumors, but most
ovarian tumors aren't cancerous, and surgery is the only way to
tell the difference. Thus, screening with transvaginal ultrasound
alone would result in many unnecessary surgeries for every
ovarian cancer found. By contrast, screening for colon cancer and
cervical cancer (via colonoscopy and a Pap test, respectively)
can identify cancers without major surgery.
No test is perfect, so whatever method is used, some women who
don't have ovarian cancer will end up having surgeries, Dr.
Skates says. "In fact, there's a bar that's been set — and people
may be taken aback by this — but the minimum bar for an
acceptable screening test is that, at most, 10 surgeries can
occur to find one ovarian cancer. Any more than that and the
screening approach would be regarded as unacceptable." So far, no
single strategy comes close to reaching even this low bar.
Where does ovarian cancer start?
Ovarian cancer has traditionally been thought to start on
the surface of the ovary. However, research suggests that
some of it arises in the fimbriae, the fringe-like
extensions at the ends of the fallopian tubes.
What about symptoms?
Ovarian cancer has traditionally been called a "silent killer,"
because symptoms are thought to develop only after the disease
has become virtually incurable. But many women who've had the
disease disagree, reporting they had distinctive abdominal pain
or digestive problems well before they were diagnosed. In a 2007
study, researchers at the University of Washington led by Dr.
Barbara Goff identified a set of physical complaints that often
occur in women who have ovarian cancer. This "symptom index"
formed the basis of a consensus statement released later that
year outlining four symptoms that may be early warning signs:
bloating or distension of the abdomen, pelvic pressure or pain,
difficulty eating or feeling full quickly, and the need to
urinate often or urgently.
Some experts remain skeptical; they think early-stage ovarian
cancer doesn't produce these or any other symptoms, and that the
symptom index serves only to identify treatment-resistant
late-stage cancers. Others worry that these symptoms are too
vague and accompany too many other health problems, such as
irritable bowel syndrome, menstrual difficulties, and bladder
infections. One study found that for every 100 women in the
general population who experienced them, only one would actually
have early-stage disease. Nevertheless, many specialists agree
that they're the best we can do for now, and that women with new,
unexplained pelvic symptoms that persist for a month should see
Two large, controlled trials are under way to find out if ovarian
cancer screening with CA-125 plus vaginal ultrasound improves
survival rates among postmenopausal women at average risk for the
disease. Preliminary findings were reported in 2009, but final
results, including mortality data, aren't expected for several
As part of the National Cancer Institute's Prostate, Lung, Colon
and Ovarian Cancer Screening Trial, more than 75,000 healthy
women were randomly assigned to undergo either usual care or
annual CA-125 testing plus transvaginal ultrasound. If a woman's
CA-125 or ultrasound test was positive, she was referred to a
gynecologist for follow-up. The results so far have been
disappointing. After annual screening for more than four years,
19.5 women on average had undergone surgery for each identified
case of ovarian cancer — far from the aforementioned "bar" of no
more than 10 surgeries to detect one ovarian cancer — and 72% of
the cancers detected were already at a late stage.
The preliminary findings have been more promising in the United
Kingdom Collaborative Trial of Ovarian Cancer Screening, which
Dr. Skates helped design. More than 202,000 women at average risk
for ovarian cancer were randomly assigned either to no screening,
annual transvaginal ultrasound alone (with repeat ultrasounds and
clinical evaluation as needed), or a "multimodal" approach
consisting of annual CA-125 testing followed by transvaginal
ultrasound for selected subjects based on their CA-125 results.
In the multimodal group, if a woman's CA-125 began to rise
significantly above her baseline level, an accelerated schedule
of CA-125 testing or ultrasound kicked in, based on a special
ovarian cancer algorithm, or set of rules. Results from the first
year of screening showed that nearly 50% of cancers detected in
both screening arms were early-stage — a doubling over usual
care, where 25% are found at an early stage. The average number
of surgeries needed to find one cancer in the CA-125 plus
transvaginal ultrasound group was an impressive 2.9; in the
ultrasound-alone group, on the other hand, 35.2 surgeries were
required to find one cancer.
While these first-year findings are encouraging, the final
results of subsequent years of screening are the most important
indicator of the long-term impact of this screening approach.
Until those results are reported, no definite conclusions can be
made. The United Kingdom trial is scheduled to end in 2015.
Although CA-125 is still generally considered a late-stage
marker, Dr. Skates thinks it might serve as an early indicator in
women at average risk as long as the testing is personalized.
That would mean carefully tracking CA-125 values over time and
evaluating fluctuations in relation to a woman's individual
Why CA-125 alone isn't a good screening test
Many women ask to be screened for ovarian cancer with a
CA-125 test. While a CA-125 reading can be a helpful
tool, it doesn't qualify as a good screening test, and
A screening test is a test that's done in a person with
no symptoms in order to find disease early enough for
successful treatment. A good screening test should be
highly sensitive, meaning that it gives a positive result
when the illness is present. In this case, a test that's
100% sensitive would detect all cases of ovarian cancer.
It should also be very specific; that is, the results are
negative when there's no cancer.
CA-125 is a protein often made by ovarian cancer that
circulates in the blood. Levels of CA-125 are elevated in
about 80% of women with advanced ovarian cancer but only
50% of those with early-stage disease. Thus, CA-125 isn't
sensitive enough: it could miss as many as half of all
women with early-stage cancer. It's not specific enough,
either, because it's elevated by many other conditions,
including other cancers, endometriosis, fibroids, and
Specificity is extremely important because only one in
2,500 women develops ovarian cancer every year. To
understand the problem, imagine screening a
representative group of 2,500 women, and suppose our test
is 100% sensitive (it identifies every woman with the
disease). Now suppose the specificity is 99%, meaning
that 1% of the women test will positive even though they
don't have ovarian cancer.
In screening our group of 2,500 women, we would find one
case of ovarian cancer, but we'd also get false positive
results for 25 women. Unfortunately, invasive surgery is
the only way to find out for sure which is which.
Consequently, to locate the one woman in 2,500 who
actually had the disease, we'd have to subject 25 others
to unnecessary abdominal surgery. Now expand the
screening group to include all U.S. women; the number of
unnecessary surgeries would be huge. Thus, the risk of
general screening with CA-125 alone far outweighs the
It's long been thought that most ovarian cancer starts on the
ovary's surface (epithelium), but research by pathologists at
Harvard's Brigham and Women's Hospital in Boston and elsewhere is
changing that picture. It now appears that some ovarian cancer
arises at the end of the fallopian tubes, in the fimbriae, the
finger-like projections that brush the ovary (see the
illustration). This discovery has led some scientists to
speculate that early-stage and late-stage ovarian cancer are
actually two distinct diseases.
Dr. Michael J. Birrer, director of gynecologic medical oncology
at Massachusetts General Hospital, believes fimbrial-end ovarian
cancer may account for the 75% of cases that turn deadly: "It's
because it's sitting out there in the open, sort of flapping
around, that those cells break off and latch on to the ovary, and
more importantly, spread throughout the abdomen very early in
their natural history. That's versus the ‘good' ovarian cancer,
which we think may come from...cysts within the ovary."
Those cancers, he says, "probably evolve into the tumors that
have a longer latency period and can be felt by pelvic exam and
Not everyone agrees that fimbrial-end tumors play such a large
role, but if it turns out that some ovarian tumors are more
aggressive than others for genetic reasons, then genomic
techniques may help identify targets for new therapies. Dr.
Birrer, Dr. Skates, and other scientists are also using advanced
technologies such as mass spectrometry to look for more precise
biomarkers of the disease.
Although research is proceeding apace, the findings haven't
matched the progress that's been made, for example, in breast
cancer research and treatment. But there are certain steps you
Know your risk. CA-125 and transvaginal
ultrasound can be of use in women at high risk for ovarian
cancer. You're at high risk genetically if you have a mother,
sister, daughter, grandmother, aunt, or niece who had the
disease. Carriers of the BRCA1 or BRCA2 gene mutations are also
at increased risk. Most experts recommend combination screening
of high-risk women with CA-125 and transvaginal ultrasound every
six months. Among such women, a positive CA-125 test is more
likely to be a true positive, so the risk of invasive surgery may
be worth taking. High-risk women who are past childbearing may
also want to consider having their ovaries removed — a procedure
that's 90% effective in preventing ovarian cancer.
Pay attention to abdominal symptoms. If
you're at average risk for ovarian cancer, pay attention to new
abdominal or pelvic symptoms that persist for a month or more
even when you've tried such strategies as laxatives, exercise,
and diet change. You know what's normal for you, so if you're
concerned, see your gynecologist for a thorough pelvic exam. If
the pelvic exam raises suspicions, it should be followed up with
transvaginal ultrasound and possibly a CA-125 test.
If you need surgery, it should be performed by a gynecologic
oncologist or other surgeon skilled in ovarian cancer treatment.
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