A guide for ovarian cancer patients

(Article provided by GynecologicCancer Foundation)

Women who are suspected of having ovarian cancer and women who
have been diagnosed with ovarian cancer often receive a blood test to
measure their CA 125 level.
This booklet will take you through the basics of what you need to know
about CA 125 — what it is, what it’s measuring and what the values
mean. And hopefully, this information will help you better understand
how this test is used and interpreted in your treatment and follow-up.
The information in this booklet was originally provided to over 300
women who participated in a free telephone workshop organized by the
Gynecologic Cancer Foundation. Dr. Thomas J. Herzog, Director,
Division of Gynecologic Oncology, Columbia University, and Dr.
Robert L. Coleman, Professor, Division of Gynecologic Oncology, The
University of Texas M. D. Anderson Cancer Center, conducted the
CA 125
CA 125 is a substance found in the blood called a glycoprotein (a sugar
associated protein). It is commonly referred to as a “biomarker” — or
“tumor marker” — because it provides information about the biological
state of a disease (ovarian cancer) and is obtained by a blood sample
from which a level can be measured. But it is more accurately
considered a “tumor associated protein” because elevated CA 125 levels
do not always indicate ovarian cancer, and levels can be misleading.
For instance, CA 125 can be absent when disease is present, or levels can
be high when no disease or no malignant disease exists. Therefore,
CA 125 levels are interpreted with other markers of disease in mind
including symptoms, physical exam findings, and imaging results such
as pelvic ultrasound or CT scan.
The current CA 125 blood test is the second generation of the test that
was first introduced in the early 1980’s as a possible treatment. Based
on early experience with immune therapy for cancer, investigators started
searching for something unique on the surfaces of ovarian cancer
cells that could be used to trigger recognition of tumor cells by the
immune system. After 125 attempts, an antibody was found that seemed
to do the trick. The antibody was termed OC-125 (for the 125th antibody
tested against ovarian cancer) and recognized a tumor cell surface
signal termed CA 125. Unfortunately, attempts to use this antibody in
treatment were not successful. However, creative researchers recognized
an interesting phenomenon about the protein and antibody they were
testing — the levels in the blood seemed to correlate with the status of
the ovarian cancer! New studies were launched to see if CA 125 might
be useful as a test to diagnose and follow ovarian cancer patients.
Eventually, a CA 125 level of 35 units was found to be a useful cutoff
point, with 99% of healthy women having values less than 35. Levels
above 35 units are certainly seen in healthy women, but beyond the cutoff
point of 35, the higher the value, the more likely there is trouble
somewhere in the body. Women with ovarian cancer often have levels
measured in hundreds and even thousands of units.
Early studies quickly identified that as many as 85% of women with
ovarian cancer have elevated values; and, less than 1% of women without
cancer have elevated levels of CA 125. However, there are notable
exceptions: about 50% of Stage I ovarian cancer patients have normal
values and the majority of patients with a certain tumor cell type called
mucinous ovarian cancers have normal values. This means that in the
presence of an ovarian mass, a normal CA 125 does not necessarily
mean that the ovarian growth is benign. In addition, variations
between patients may be substantial even if they have very similar
tumors and, even within the same patient, variations can occur that are
unrelated to the course of the cancer, particularly following surgery or
if there is an infection.
So, the CA 125 test is helpful, but not perfect. Individual values are hard
to interpret, so many physicians focus on the trend in the values over a
course of time rather than any individual value. Time trends help to put
the individual values into perspective to get a “picture” of what might
be going on in a particular situation.
CA 125 and False Elevation
Normal tissues, including ovarian cells, pancreatic and breast cells, and
the lining tissue of the abdomen and chest all make and release low levels
of CA 125. Since the CA 125 test reflects the amount of protein
(often called antigen) released into the blood stream from specific
organs, conditions that “perturb the silence” change the test result.
Ovarian cancer not only increases the number of cells that make CA
125, but also perturbs or inflames the abdominal lining, which contains
“normal” cells that make and release CA 125. So, it’s not surprising that
CA 125 is elevated in ovarian cancer and in some other cancers in the
abdomen. But other, non-cancerous conditions can elevate the CA -125
value, such as inflammatory conditions of the abdomen (diverticulitis,
peritonitis, pelvic inflammatory disease, inflammatory bowel disease
tuberculosis and pancreatitis), liver disease, recent surgery, and benign
gynecologic conditions such as fibroids, endometriosis, ectopic pregnancy,
or a ruptured cyst. In some situations, CA 125 is even used to monitor
the effects of treatment for benign conditions such as endometriosis.
These other diagnoses must be considered in the interpretation of an elevated
CA 125 value.
The CA 125 test is used in a variety of situations during the course of
the diagnosis, treatment and follow-up of ovarian and other closely
related cancers, such as primary peritoneal and fallopian tube cancers.
Four primary roles for CA 125 assessment have been established
with varying degrees of clinical use and reliability. The four major roles are:
Outcome prediction: CA 125 has been studied for its
ability to predict treatment outcome for women with ovarian
cancer and closely related cancers, such as fallopian
tube and primary peritoneal cancer.
Detection: CA 125 is widely employed to detect recurrent
ovarian cancer in women who have been previously treated.
Monitoring: CA 125 is used throughout the course of
chemotherapy to monitor or assess treatment effectiveness.
Screening: CA 125 is often used to screen for ovarian,
primary peritoneal and fallopian tube cancers in high-risk
women, or in women with abnormal findings on examination
or ultrasound.
1. To Predict Outcome
While more study is needed to completely determine how well a CA 125
test can predict the outcome of cancer treatment, several recent studies
have looked at this question. If, during the first time a woman is treated
for ovarian cancer, her CA 125 level returns to “normal,” does this
mean that she will have a better chance of survival?
The answer seems to be “yes,” but with a note of caution. This conclusion
only seems to be true when looking at the trends for large groups
of women. CA 125 levels do not work as well as a predictor for individual
2. To Detect Recurrent Disease
The CA 125 test is most reliable and useful for the detection of recurrent
disease in women previously diagnosed and treated for ovarian
cancer. While there are certainly exceptions to this statement, generally,
rising numbers over a series of tests strongly suggest that a woman is
experiencing a recurrence of her disease. However, some women
develop a recurrence without a rising CA 125 level. On the other
hand, some women have a modest rise in the value but never develop
recurrent disease.
3. To Monitor Treatment
The CA 125 test is a generally reliable tool to use along with a thorough
history and physical exam to assess or monitor if a treatment is working.
However, its usefulness in this case depends on the starting value.
Monitoring treatment results is most accurate when patients have an
elevated initial CA 125 value. Some newer information is emerging suggesting
that the trends of CA 125 values within what is generally considered
the normal range may also provide clues to treatment success. It
is vital to stress that this test represents just a piece of the puzzle and a
number of other factors are considered in determining whether any
given therapy is working to fight the cancer. It is also important to
emphasize that CA 125 values may go up or down for a variety of reasons
and, because of this, the test may not accurately reflect disease status.
This fact is particularly true when the values are in the normal range
or are only minimally elevated. Most clinicians rely on how the numbers
change over time and not on one test alone.
Monitoring trends makes the test useful in treating ovarian cancer for
the first time. Trending CA 125 values over time may also may be useful
in women undergoing treatment for disease recurrence. The most
common non-platinum and non-taxane novel agents used in recurrent
disease treatment, pegylated liposomal doxorubicin (Doxil) and
topotecan (Hycamtin), require thoughtful interpretation of CA 125 levels
during treatment. A significant number of patients ultimately
responding to these drugs can have a rise in their CA 125 values — as
much as 30% — after their first cycle of chemotherapy. Some patients
even had a CA 125 rise after their second or even third cycle, and still
had a favorable treatment outcome. So, CA 125 values can and do fluctuate.
Major treatment decisions, such as changing or discontinuing
treatment, depend on multiple factors that you and your physician will
consider. The trend in your CA 125 values is only one of these factors.
4. To Screen for Ovarian Cancer
As is the case with most cancers, early detection of ovarian cancers leads
to a higher cure rate. Because there is not yet a highly effective screening
test for ovarian cancer, and the symptoms for this cancer are variable,
many women are diagnosed at a later, less curable stage. Successful
screening/early detection could change this fact dramatically. So it’s no
wonder there has been such a concerted investigational effort into
strategies that could achieve this goal.
Unfortunately, the CA 125 test in isolation has proven to be ineffective
in screening for ovarian cancer. As explained earlier, there are many factors
that influence “the number,” making it unreliable as a screening test
for ovarian or any other reproductive cancer. The test misses up to 50%
of those with early ovarian cancer when treatment is most successful.
Furthermore, the test is falsely elevated in a portion of the population
due to conditions unrelated to cancer. CA 125 is especially unreliable in
screening pre-menopausal women because both ovulation and menstruation
can cause elevated levels.
However, research is ongoing to look at other possibilities for ovarian
cancer screening. One option that seems to hold some promise is the use
of a “cocktail,” or panel of markers (also known as “biomarkers”), and
evaluating their changes, over time and in relation to each other. Several
new biomarkers, like the HE4 protein, are being looked at in combination
with CA 125, to see if they can improve upon the ability to catch
the disease early, or at least reduce the number of women who are
referred for surgery because of an abnormal test. This is also known as
a “false positive screen” and is a problem with using limited information,
like a single CA 125 value, in making a decision to further investigate
the abnormal result. While this makes a lot of sense, it is still too
early to know if this approach will prove beneficial in terms of cost and
lives saved.
We urge women diagnosed with ovarian cancer to try to keep in mind
that the CA 125 test is only one indication of how well the treatment is
working. Many other variables need to be considered, and the applications
of CA 125 values need to be individualized. Gynecologic oncologists
are obstetrician-gynecologists with an additional three to four
years of training in the comprehensive treatment of women with gynecologic
cancers and are specifically knowledgeable about how to interpret
what a CA 125 test result means in the treatment of ovarian cancer.
For information on how to find a gynecologic oncologist, and general
information about ovarian and other women’s cancers, please visit the
Women’s Cancer Network Web site (www.wcn.org).
This award-winning Web site of the Gynecologic Cancer Foundation
(GCF) also has a section on clinical trials. The Gynecologic Oncology
Group (GOG), a non-profit cooperative group that conducts most clinical
trials related to reproductive cancers, is working with GCF to make
information on Phase III clinical trials currently accepting enrollment
readily available to women. Each trial is described and women are
offered the opportunity to call GOG at 1.800.225.3053 to learn how to
reach the individual responsible for enrolling women in the nearest trial.
For more information on ovarian and other gynecologic cancers, please
call or e-mail the Gynecologic Cancer Foundation at 312.578.1439 or
info@thegcf.org. The GCF Hotline can be reached by calling



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