In this paper, Dr. Kuban et al address
the use of posttreatment prostatespecific
antigen (PSA) in determining
outcome after radiotherapy. They base
most of their discussion on their own
observations of prostate cancer outcomes
in more than 4,000 patients following
alone.[1,2] I had the privilege of writing
an editorial on their earlier companion
papers, and I made the argument
then that although some definitions
were slightly better than the American
Society for Therapeutic Radiology and
Oncology (ASTRO) definition, the differences
were not impressive enough
to recommend changing the standard
for determining outcome after external-
Dr. Kuban and colleagues raise the
provocative idea that perhaps we could
create "a universal definition of failure
that might be applied to multiple
modalities, including surgery." Rather
than writing another editorial congratulating
these investigators for "a
job well done" and making the point
that "switching to a new [definition]
may not be worthwhile," I will focus
on the question of whether we can
ever have a "universal definition."
In fact, some investigators have
assumed that the ASTRO definition
should be applied to patients treated
with either external-beam irradiation
or brachytherapy, implying that a universal
definition might already exist.[
4,5] Carrying this further, other investigators
have gone so far as to apply
the ASTRO definition to patients treated
with radical prostatectomy. Is this
attempt to use the ASTRO definition
universally appropriate, or should we
adopt a more sensitive definition?
Universal Application of
the ASTRO Definition
We already have a definition of
PSA failure after radical prostatectomy
(0.2 ng/mL) that is likely to be far
more sensitive and specific than the
ASTRO definition, so why not use it
after external-beam radiotherapy? As
Dr. Kuban and coauthors demonstrate,
the specificity of a failure definition
based on a PSA level of 0.2 ng/mL
after external-beam irradiation was
only 9%. This is not surprising because
the day-to-day variability of
PSA values in men with an intact prostate
exceeds the thresholds currently
accepted as highly predictive of recurrence
after surgery. Thus, although
the level to which the PSA declines
correlates roughly with the risk of PSA
failure after treatment, a surgical definition
is too strict for patients treated
with external-beam radiotherapy.
Some investigators have applied
the ASTRO definition to patients with
permanent prostate implants (PPI), but
this approach has not been studied
using the statistical approaches described
by Thames et al for patients
treated with external-beam irradiation.
Although Dr. Kuban's data suggest
that the least reliable definition of
PSA failure following external-beam
radiotherapy involves the use of
threshold values > 0.2 ng/mL, this
may very well not be true for patients
treated with PPI. Because of the ablative
nature of the high doses associated
with this modality, the specificity of
a strict definition is likely to be much
better when applied to PPI-based therapy.
Five years after a patient receives
external-beam irradiation to 45 Gy plus
PPI irradiation to 108 Gy, a persistent
PSA level > 1 ng/mL is likely to reflect
persistent disease. However, after
external-beam radiotherapy to
70 Gy, such a patient is more likely to
have residual benign glands that can
What about applying the ASTRO
definition to patients after prostatectomy?
Such an application might work
if urologists were willing to accept
ultrasensitive assays with a detectable
value (eg, PSA ≥ 0.02 ng/mL) that
rises two or three times consecutively.[
7] Given that the threshold for defining
PSA failure after prostatectomy
has been rising, it seems doubtful that
the urology community will do an
about-face and head toward an ultrasensitive
test. I would argue that
they cannot have it both ways, ie,
require a minimal value > 0.2 ng/mL
or 0.4 ng/mL and then count failure
only after a required number of increases.
Many men with their prostates
in place have PSAs in that range.
How can urologists justify defining a
patient as "cured of prostate cancer"
if he is walking around with a PSA
well into the normal range?
Perhaps the most promising approach
for developing a universal definition
(in patients not receiving
hormonal therapy), would be to use
the slope of the PSA over a specified
recent period of time. With this
approach, bouncing PSA values can
be "self-neutralized." This occurs because
upward bounces are offset by
downward bounces, thus eliminating
the noise associated with random PSA
fluctuations while capturing consistent
PSA progression even if the increases
are not consecutive.
Unfortunately, the problem is far
more complex than Dr. Kuban or I
have addressed thus far. This is due to
the fact that patients who are most
likely to have a rising PSA are those at greatest risk of recurrence
at the time of treatment. Many, if not all of these patients,
should have received hormonal therapy as part of their initial
therapy. Although it is less problematic to compare groups of
patients receiving hormonal therapy for the same duration, it is
more problematic to define recurrences using PSA if the duration
is not standardized. For this reason, I would argue that we are a
long way away from developing a universal definition.
PSA values are extremely sensitive to hormonal manipulations,
and there is great variability between patients in the rate at
which they recover their testosterone, which is complicated by
variations in the duration of hormonal therapy. Thus, I would
doubt that one size will ever fit all.
To define PSA failure in this setting, I consider the patient's
risk of recurrence, his testosterone level, how far out he is, his
age, and his pretreatment PSA. On some occasions, I also consider
his prior history of prostatitis, the presence of local symptoms
and all of his PSA trends, and then I use my own judgment to
decide whether I think his disease has recurred. The bottom line is,
we are not close to developing a truly "universal definition" that
can replace good judgment. In other words, although I can't define
it for every type of treatment, "I know it when I see it."
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analysis of stage T1-T2 prostate cancer treated with radiotherapy in the PSA
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2. Thames H, Kuban D, Levy L, et al: Comparison of alternative biochemical
failure definitions based on clinical outcome in 4839 prostate cancer patients
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prostate-specific antigen supports cure of patients with long-term followup
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