use of tumor markers in testicular, prostate, colorectal, breast, and ...

Tumor Markers in Ovarian Cancer 55
CA125 is recommended, together with trans-vaginal
ultrasound, for early detection of ovarian cancer in
women with hereditary syndromes as early intervention
may be beneficial [LOE, III; SOR B].
Discrimination of Pelvic Masses
In contrast to its use in early detection, CA125 is more widely
accepted as an adjunct in distinguishing benign from malignant
disease in women, particularly in post-menopausal women
presenting with ovarian masses (407, 408, 422), facilitating
triage for operations by optimally qualified surgeons. Benign
conditions resulting in elevated CA125 levels may be a confounding
factor in pre-menopausal women. In the United
Kingdom, CA125 measurement is an integral part of the risk
of malignancy index (RMI), which forms the basis of patient
pathway guidelines for the management of pelvic masses
and/or adnexal cysts (423). The RMI is calculated as a product
of CA125 concentration multiplied by menopausal status
(1 for pre-menopausal and 3 for post-menopausal) multiplied
by ultrasound score (0, 1, or 3 depending on ultrasound features).
A cut-off of 200 or 250 is frequently used, with patients
with scores above this referred to specialist gyna-oncology
teams. Sensitivities of 71% to 78% and specificities of 75% to
94% have been reported in other studies (414). Elevated concentrations
of CA125 95 kU/L in post-menopausal women
can discriminate malignant from benign pelvic masses with a
positive predictive value of 95% (411). Therefore, based on
current evidence, CA125 is recommended as an adjunct in distinguishing
benign from malignant pelvic masses, particularly
in postmenopausal women. When there is a suspicion of germ
cell tumor, particularly in women younger than 40 years or in
older women where scan features suggest a germ cell tumor,
AFP, and hCG are also important markers for triage, as for testicular
germ cell tumors [see Staging, Risk Stratification, and
Selection of Therapy section p. 6].
NACB Ovarian Cancer Panel Recommendation 3:
CA125 in Discrimination of Pelvic Masses
CA125 is recommended as an adjunct in distinguishing
benign from malignant suspicious pelvic masses, particularly
in postmenopausal women [LOE, III/IV; SOR, A].
Monitoring Treatment
Serial measurement of CA125 may also play a role in monitoring
response to chemotherapy. Declining CA125 concentrations
appear to correlate with treatment response even when
disease is not detectable by either palpation or imaging. In a
meta-analysis, serial CA125 concentrations in 89% of 531
patients correlated with clinical outcome of disease (424-426).
There is general consensus among current guidelines in recommending
that CA125 be used to monitor therapeutic
response but there is no consensus as to how best to define a
CA125-based response (404, 427, 428). The Gynecologic
Cancer Intergroup (GCIG) defines a response as a reduction
of 50% or more in pre-treatment CA125 level that is maintained
for at least 28 days (428-431). The pre-treatment sample
must be at least twice the upper limit of the reference range,
which means that patients with pre-treatment concentrations
between the upper limit and twice the upper limit are nonassessable
by this criterion. The first sample is recommended
within 2 weeks prior to treatment with subsequent samples at
2 to 4 weeks during treatment and at intervals of 2 to 3 weeks
during follow-up. The same assay method is required throughout
and patients who received immunotherapy (ie, mouse antibodies)
cannot be evaluated. In addition to monitoring initial
chemotherapeutic regiments, CA125 measurements may be
useful in monitoring salvage therapy, because a doubling of
values is associated with disease progression and treatment
failure in more than 90% of cases (411). However, disease progression
may also occur without an increase in CA125, and
therefore the presence of tumor should also be assessed by
physical examination and imaging (15). Tuxen et al (427) suggested
that interpretation of changes in serial CA125 levels
should be based on a statistical estimation that takes account
both of the analytical variation of the method used and of the
normal background intraindividual biological variation of the
marker (432, 433). The theoretical background for this statistical
procedure has recently been reviewed in detail (434).
Serial measurement of CA125 to aid in monitoring response
to therapy is a second FDA-indicated use for the marker. Trials
currently in progress, including the UK Medical Research
Council OV05 trial, have been designed to evaluate the benefit
of early chemotherapy for recurrent ovarian cancer, based
on a raised CA125 level alone versus chemotherapy based on
conventional clinical indicators (435). Pending results of these
trials, practice is likely to vary.
NACB Ovarian Cancer Panel Recommendation 4:
CA125 in Monitoring Treatment
CA125 measurements may be used to monitor response
to chemotherapeutic response. The first sample should be
taken within 2 weeks prior to treatment with subsequent
samples at 2 to 4 weeks during treatment and at intervals
of 2 to 3 weeks during follow-up. The same assay
method should be used throughout and patients who
received therapy with anti-CA125 antibodies cannot be
evaluated [LOE, I/II; SOR, A].
CA125 Measurement Postoperatively:
Second-Look Operation
Early studies on CA125 indicated that it was useful postoperatively
in predicting the likelihood that tumor would be found
at a second-look operation, therefore CA125 assays were initially
approved by the FDA for this indication (412, 424).
Elevations of CA125 higher than 35 kU/L after debulking surgery
and chemotherapy indicate that residual disease is likely
( 95% accuracy) and that chemotherapy will be required
(436). Second-look laparotomy is now considered to be