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CA-125 and ovarian cancer: benefit, control and anxiety for patients
or clinicians?
A. Coupe, J.-F. Baurain, M. Berlière, T. Connerotte, N. Whenham, L. Duck
Cancer antigen (CA)-125 is considered as a specific tumourmarker of ovarian cancer.
After normalization due to treatment, CA-125 serum increase often precedes clinical
recurrence. The dosage of this marker is linked to great anxiety for both patients and
clinicians. This article provides information about its sensitivity and specificity in determining cancer recurrence. Furthermore, whether or not to re-treat a patient with an
isolated increase of CA-125 without clinical symptoms, is discussed in the light of a
recent phase III MRC/EORTC trial.
(Belg J Med Oncol 2010;4:151-4)
Introduction
Cancer antigen (CA)-125, also known as mucin 16
or MUC16 was first recognized in 1981. MUC16
is a member of the mucin family glycoproteins,
expressed in adult tissue of coelomic epithelial origin.1 CA-125 is applied as a biomarker in the blood
of patients with cancer, especially ovarian cancer.
The serum CA-125 level is elevated in over 80% of
patients with advanced epithelial (papillary serous,
endometrioid, mucinous, clear-cell) ovarian cancer (EOC). Papillary serous carcinoma is the most
frequent type and is often associated with elevated
CA-125. On the other hand, mucinous ovarian carcinomas, ovarian germ cells, and stromal tumors are
not associated with high levels of CA-125. However,
high serum CA-125 level is not specific for advanced
EOC and may also be elevated under other malignant conditions, such as pancreatic, breast, lung,
gastric, and colon cancers and even under various
other conditions, such as pregnancy, endometriosis,
adenomyosis, uterine fibroids, pelvic inflammatory
disease, menstruation and benign cysts.2
CA-125 as a screening tool in healthy
women
Ovarian cancer is well-known for its frequent discovery at an advanced stage. At that stage, chances
to cure the patients are limited. CA-125 is elevated
in less than 50% of stage I ovarian cancers and as
discussed above, the specificity of the test is poor.
Measurement of CA-125 values in an individual
patient over time (rather than a single measurement)
appears to improve the estimation of a patient’s risk
of ovarian cancer.
An algorithm has been developed calculating the
Risk of Ovarian Cancer (ROC) based on serial
CA-125. Value of the algorithm is currently being
Authors: Mrs. A. Coupe, MD, Department of Surgery, Gynaecology, Clinique St-Pierre, Ottignies LLN, Mr. J.-F. Baurain, MD, PhD,
Centre du Cancer, Medical Oncology, Cliniques Universitaires St-Luc, Brussels, Mrs. Berlière, MD, PhD, Centre du Cancer, GynaecologyObstetrics, Cliniques Universitaires St-Luc, Brussels, Mr. T. Connerotte, MD, Mr. N. Whenham, MD, Mr. L. Duck, MD, Department of Internal
Medicine, Onco-Haematology Unit, Clinique St-Pierre, Ottignies LLN, Belgium.
Please send all correspondence to: Lionel Duck, MD, Head of Onco-Hematology Unit, Clinique St-Pierre, Av. Reine Fabiola 9, 1340 Ottignies
LLN, Belgium, e-mail: [email protected]
Conflict of interest: the authors have nothing to disclose and indicate no conflicts of interest.
Key words: CA-125, ovarian cancer, tumourmarker
Belgian Journal of Medical Oncology
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evaluated in a trial with 202,638 postmenopausal
women between the ages of 50 and 74 years deemed
to be at average risk for ovarian cancer (United
Kingdom Collaborative Trial of Ovarian Cancer
Screening). Women were randomized to undergo
annual pelvic examination (control group), annual transvaginal ultrasonography (ultrasonography
group) or annual measurement of CA-125 (evaluated over time with the use of the ROC algorithm) plus
transvaginal ultrasonography in cases with elevated
CA-125 level (multimodality group).
In a preliminary report, multimodality screening
had a significantly greater specificity (99.8% versus 98.2%) and a higher positive predictive value
(35.1% versus 2.8%, p<0.001), as compared to
just ultrasonography. Sensitivity did not differ significantly between the 2 groups. Another large-scale
trial whose results are expected in 2014, is ongoing
(the Prostate, Lung, Colon, and Ovarian (PLCO)
Cancer Screening Trial). So far, no clear recommendation can be made for such a screening, given the
lack of data concerning its cost, its impact on survival, and its potential harmful surgical complications
for women with false-positive results.3,4
CA-125 as a prognostic tool during
primary chemotherapy
Tumour stage, residual disease after initial surgery,
histological type and tumour grade are the most
important clinical-pathological factors related to the
clinical outcome of patients with epithelial ovarian
cancer. If the Response Evaluation Criteria In Solid
Tumors (RECIST)-method is a standard method
for evaluating the response to further treatment,
one may ask if decrease of blood CA-125 may also
serve as a surrogate response marker. According to
Rustin et al., CA-125 monitoring can be valuable
if pre-treatment level was at least twice the normal
upper limit and was performed within 2 weeks prior
to start of treatment.5 A threshold of a 50% reduction in CA-125 level compared to pre-treatment
value can be used as a response criterium. The
response must be confirmed and maintained for
at least 28 days. For patients with advanced ovarian cancer and an elevated CA-125, data also show
that the timing of normalization of CA-125 during
primary chemotherapy is predictive of survival in
patients with epithelial ovarian cancer. In Rocconi et
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152
al., patients achieving normalization of CA-125 by
their third cycle of chemotherapy were compared
to patients failing to achieve normalization by their
third cycle.6 Patients with early normalization demonstrated improved progression-free survival (19
versus 6 months; p<0.001), overall survival (48 versus 27 months; p<0.001) and platinum sensitivity
(78 versus 22%; p<0.001). This survival advantage
was maintained when patients were evaluated by debulking status. However, if CA-125 does not reach
normal values, the importance of early modification
of chemotherapy has to be defined.
CA-125 monitoring after treatment
ESMO guidelines (clinical recommendations) state
that “history and physical examination (including
pelvic examination) should be performed every 3
months for 2 years, every 4 months during the third
year and every 6 months during years 4 and 5 or
until progression is documented. CA-125 can accurately predict tumour relapse (level IA evidence) and
may be performed at follow-up visits. It is unknown,
however, whether the early detection of recurrence
by CA-125 offers any advantage. CT scans should
be performed if there is clinical or CA-125 evidence
of progressive disease. FDG-PET-CT scans may be
superior to CT scans in detecting small volume operable relapses (level IIIB evidence)”.7
Follow-up studies show that elevated CA-125 with
clinical (pelvic) examination has a sensitivity of more
than 90% in detecting EOC recurrence. This percentage is probably lower for non-serous (mucinous
and clear-cell) carcinomas and for CA-125-negative
tumours at diagnosis.
Median time from increased CA-125 to clinical
relapse is 2-6 months.8 But which CA-125 cut-off
value may predict relapse after complete remission?
For the Gynaecologic Cancer Intergroup (GCIG),
CA-125 criteria, doubling in CA-125 from the normal upper limit reliably predicts objective progression. For those patients whose CA-125 had never
fallen back to the normal range, a doubling from the
nadir has been shown to predict progression with a
false-positive rate of <2% and a high sensitivity.9
For some CA-125 non-secreting tumours, diagnosing recurrent ovarian cancer with single-detector spiral Computer Tomography has a sensitivity depending on size, ranging from 25-50% for infracentimetric
volume 4, issue 4, 2010
Key messages for clinical practice
1.
2.
Cancer antigen (CA)-125 can not be used as yet as a standard detection tool in
healthy women.
CA-125 decrease under primary chemotherapy may serve as a predictive tool for
early response to chemotherapy, and as a prognostic factor.
3.
Rising CA-125 is a sensitive and specific surrogate marker of progression, based
on validated criteria (GCIG).
4.
Rising CA-125 may predict early progression in 25-75% of patients before clinical
progression (clinical/CT).
5.
CT (or PET) is not a routine follow-up tool, perhaps except for the follow-up of
poorly secreting CA-125 ovarian tumours.
6.
A recent MRC/EORTC trial did not show a survival advantage for the early treatment of relapse based on CA-125 level alone, versus delayed treatment based on
conventional clinical indicators.
lesions to 85-93% for supracentimetric lesions.
Multidetector CT’s enhance the performance. PET
may help but sensitivity may be very low for subcentimetric lesions and omental lesions. PET is better
for visceral surface lesions, normal-sized nodes and
supradiaphragmatic lesions. PET-CT may reach a
93% sensitivity and 96% specificity when correlated
to imaging and histology.10,11
How to manage first CA-125 increase?
Even if professionals would have been in agreement
on treating patients with both increased CA-125 and
clinical symptoms due to recurrent cancer, it was
still unclear until recently if asymptomatic patients,
even with an elevated CA-125, should immediately
receive treatment.
In the era of Internet, consulting patients are anxious
and wait for their marker, hoping it will stay normal.
Policy of continuation of CA-125 monitoring invites
the major problem of patient “addiction” to CA-125
results. Increase of CA-125 may be felt as drama for
patients. For clinicians, it is sometimes difficult to
decide “what to do next”: re-treat an asymptomatic
patient immediately or wait for symptoms of the disease? For patients relapsing after a long disease-free
Belgian Journal of Medical Oncology
interval (>1 year), the decision seems even harder,
because these patients may be candidates for a secondary surgical cytoreduction (SCR). Complete SCR
and better survival are associated with long diseasefree interval, good performance status, absence of
ascites, low FIGO stage and no residual tumour after
first surgery. Outcome is directly related to volume
of relapsed disease.
Three studies, but not all, show that CA-125 level
before SCR is a factor influencing survival. Some
authors have hypothesized that, in appropriately
selected patients, early identification of macroscopic
recurrent disease may facilitate complete surgical
cytoreduction and even survival; but this hypothesis
should be prospectively validated.12,13
At the 2009 ASCO meeting, a large phase III randomized trial (jointly conducted by the Medical
Research Council and the European Organisation
for the Research and Treatment of Cancer) addressed
this question.14 This study compared early treatment
of relapse based on just CA-125 level to delayed
treatment based on conventional clinical indicators.
Women with ovarian cancer in clinical complete
remission after primary platinum-based chemotherapy and a normal CA-125 were registered. CA-125
was measured every 3 months but patients and
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investigators were blinded to the results, which were
only monitored by the trial units. If CA-125 levels
exceeded twice the upper limit of normal, patients
were randomized to either immediate treatment or
to continue having blinded CA-125 measurements
with treatment commencing when clinical or symptomatic recurrence appeared. From 1,442 registered
patients, 527 were randomized. Patients in the earlytreatment group started secondary chemotherapy
4.8 months earlier than the delayed-treatment group.
The secondary therapy was well balanced over the 2
arms. With a median follow-up of 49 months from
randomization and a total of 351 deaths, there was
no evidence of a difference in overall survival between
the immediate and delayed arms (HR 1.01, 95% CI
0.82-1.25, p=0.91). This study demonstrates that
there is no survival advantage to treating patients
on a rising CA-125 compared to an expectative policy until the development of symptoms. Although
this trial provides strong evidence against frequent
CA-125 testing, some clinicians may still hesitate
to discontinue routine CA-125 measurement: the
trial took place during a 10-year period (1996-2006)
when the options for treatment were relatively limited; trial did not address the issue of early detection
of surgically resectable recurrence. The era of targeted
therapy has now arrived, and thus paradigms of ovarian cancer treatment may change.15
References
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Conclusion
Usually, CA-125 is a sensitive marker for early ovarian cancer progression after primary treatment. Until
recently, clinicians frequently followed CA-125 for
detection of recurrence, and treated patients before
symptoms had developed. The recent MRC/EORTC
OV05/5595 trial clearly showed that frequent CA-125
testing and early treatment, based on CA-125 increase
only, are not useful. Obviously, patients will keep high
expectations concerning their marker, but oncologists
need to inform and educate patients.
Belgian Journal of Medical Oncology
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clinical indicators (MRC OV05/EORTC 55955 trials). J Clin Oncol 2009
ASCO Annual Meeting Proceedings;27:No 18S.
15. Kaye SB. Should Routine CA-125 screening be discontinued? ASCO
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