therapy) and by the plasma half-life of the marker
(Bidart
et al.
1999). In the extreme, when a tumor
has been surgically excised in its entirety, the plasma
concentration of the marker will fall exponentially
until a new steady-state is reached. As a rule-of-
thumb, this requires five or more half-lives of the
marker. If the marker is highly tumor-specific, the
plasma concentration of the marker will fall to zero
(that is, below the lower limit of quantification).
The same is true for a marker that is highly organ-
specific if the entire organ is removed as a surgical
approach to treatment of a tumor. In both cases, if
the plasma concentration of the marker remains
measurable, it can be inferred that the tumor has not
been completely excised. These considerations
apply, for instance, to PSA following radical
prostatectomy for prostate cancer. PSA has a plas-
ma half-life of two to three days and becomes unde-
tectable in the plasma by 21 days (seven to ten
half-lives) after a successful prostatectomy (Bidart
et
al.
1999). Persistence of a measurable concentration
of PSA in the plasma indicates the presence of resid-
ual tumor. It is important, when evaluating the
success of a surgical tumor excision, not to measure
the marker concentration soon after surgery while
the marker present in the circulation at the time of
surgery has still not been completely cleared from
the plasma. Similarly, the plasma concentration of a
marker should not be measured too early after treat-
ment by chemotherapy when evaluating the anti-
tumor effect of the therapy because the marker
concentration will not have had time to decline to its
new steady-state. It is even possible to see early
increases in the plasma concentration of a marker if
the marker is released into the circulation from
dying cancer cells. It is also possible to see modest,
transient increases in marker concentration after
several months of therapy, if the chemotherapeutic
agents reduce the clearance rate of the marker due to
liver dysfunction. This happens with CEA occasion-
ally following chemotherapy of colorectal cancer.
Patients may be monitored following therapy in
order to detect recurrence of their cancer if early
detection of tumor recurrence and institution of
therapy will alter the outcome. This is not unlike
periodic screening for the appearance of the cancer
although the monitoring program may have a differ-
ent schedule and dissimilar critical values from those
used in screening because of the higher probability
of disease and because prior therapy can alter the
performance of a plasma marker in detecting
cancerous tissue. In the case of monitoring PSA
following radical prostatectomy, the removal of all
hyperplastic (and normal) prostate tissue eliminates
the high background plasma PSA concentrations that
make the interpretation of PSA concentration in the
screening setting so difficult.
In general, when using a tumor-specific marker
or an organ-specific marker following excision
surgery of the organ, tumor recurrence is indicated
by the return of measurable plasma concentrations of
the marker. The rapidity with which this happens
depends upon the amount of residual tumor from
which the recurrent tumor arises and upon the rate of
growth of the tumor. The amount of residual tumor
is always hoped to be zero, but it can be as large as
that associated with a marker concentration just
below the limit of quantification. Because of the
possibility that, if present, the amount of residual
tumor is just shy of that needed for detection by the
marker, monitoring is begun soon after the comple-
tion of therapy, when even a small amount of tumor
growth will have produced a measurable plasma
marker concentration. This allows for the earliest
possible detection of recurrent disease. The subse-
quent monitoring schedule is based on clinical
experience with the time of appearance of residual
tumor following the particular therapy employed. If
recurrences tend to appear soon after therapy, inten-
sive post-therapy monitoring is appropriate. If
recurrences usually arise sporadically for years
following therapy, monitoring may be less frequent
but will need to continued for many years.
Most markers used in cancer monitoring are not
tumor-specific or even organ-specific, so the detec-
tion of tumor recurrence requires identifying a
plasma marker concentration, or concentration
profile, that can reliably be distinguished from the
background marker concentration arising from the
non-tumor or non-organ sources of the marker.
There are three approaches that can be used in this
setting: (1) establishment of a marker concentration
that serves as a critical value above which the
diagnosis of tumor recurrence is made, (2) use of a
significant difference rule, or (3) use of a clinical
monitoring rule such as the 2
2s
rule and the 4
1s
rule
which can be used to evaluate consecutive monitor-
ing measurements when the findings from the
measurements are of concern but do not exceed the
significance criterion for a concentration difference.
Figure 11.9 (identical to Figure 5.2) shows CEA
concentrations in a patient being monitored for
Cancer
11-18
