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A Publication of the James Buchanan Brady
Urological Institute Johns Hopkins Medical Institutions
Volume VI, Winter 2003
Mixing Apples and Oranges:
Using Two Standards to Determine Cure with
Surgery and Radiation Therapy
"Did
the treatment work?" For men with prostate cancer,
this is the million-dollar question. And yet, this is the one question
that remains elusive for many men who undergo radiation treatment
for prostate cancer—because depending on how a man’s follow-up results
are interpreted, he may never formally fail treatment, even if all
evidence suggests that his cancer is back, and growing.
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For men who undergo radical prostatectomy,
the definition for success is simple —an undetectable level of PSA,
of 0.1 ng/ml or lower. With radiation, however, there is no such
“line in the sand”—no definitive PSA cutoff point between success
and failure. Most radiation studies hinge on the concept of PSA
nadir—the lowest point PSA reaches after treatment —and any subsequent
rise in PSA. (For
an explanation, see side story.)
In 1997, the American Society for
Therapeutic Radiology and Oncology (ASTRO) defined relapse, or “biochemical
failure,” as three consecutive rises in PSA after it reaches its
nadir. One difficulty with this is that the PSA increases are not
always consecutive. A man’s rise in PSA with one test might be followed
by a transient decrease in the next, followed by another increase.
Under the ASTRO guidelines, even
though there is still what in a radical prostatectomy patient would
be considered evidence that cancer may be present, the treatment
would be considered a success.
The ASTRO guidelines suggest that
a man should have a PSA test every three or four months during the
first two years after treatment, and every six months after that.
The theoretical date of failure is
then backdated—to the midpoint between the PSA nadir and the first
of the three consecutive rises. But it may take years for PSA to
fall to its lowest point, and then— if the treatment didn’t work—several
more years before failure is declared. During that time, the cancer
may be growing, and the opportunity to kill it while it’s still
localized may slip away.
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Double Standard
Why is
the PSA cutoff used to define success or failure after radical
prostatectomy?
The reasoning is this: If all the prostate cells are removed
from the body, then there should be no PSA in the body. Zero
PSA—technically, less than 0.1 nanograms per milliliter— equals
cure. Conversely, the presence of PSA—detectable levels over
0.1 ng/ml—means that there are still some PSA-making prostate
cells somewhere in the body. After radical prostatectomy,
a PSA of 0.2 signals a recurrence of cancer. The great benefit
of this cut-and-dried rule is that, if the treatment did not
get all the cancer, the doctor and patient can know about
it as soon as possible and plan further treatment accordingly.
Why is
the PSA nadir so important after radiation therapy?
This is because radiation’s effect is gradual; it generally
takes two or even three years for PSA to hit rock bottom.
Some men reach this nadir quickly, as soon as three months.
Rarely, it can take much longer—as long as 10 years. Ideally,
once PSA has reached its lowest level, it should stay there.
Some doctors consider a man cured if he has a PSA between
1.0 and 1.5; others even assume that a man has been cured
if his PSA after radiation is in the “normal” range— lower
than 4.0. But a PSA of 1.0 to 1.5 means that 10 to 15 grams
or more of viable prostate tissue could still be there in
the body (because the PSA level in the blood is about 10 percent
of the weight of the prostate). Theoretically, even if there
is no cancer in this tissue, it could still become cancerous
in the future. Thus, after any form of radiation, the PSA
level should eventually fall to less than 0.5, and ideally,
to less than 0.2.
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What would happen if the ASTRO criteria were applied to radical
prostatectomy patients?
In a recent study, published in
the Journal of Urology, Hopkins scientists did just this: They
applied a double standard, using the surgical criteria—the cut-and-dried
PSA level of 0.2 or above—as a sign of cancer recurrence, and
then interpreting those same results using the ASTRO criteria.
In this study, the scientists retrospectively evaluated
2,691 men who underwent radical prostatectomy at the Brady Urological
Institute between 1985 and 2000, and who were followed with PSA
tests and rectal exams every three months for the first year,
every six months for the second year, and then annually. The average
follow-up time was six years; none of the men in the study underwent
radiation therapy or hormonal therapy, unless cancer recurred.
Using the surgical criteria for failure, at five
years after surgery, 85 percent of the men were cancer-free; at
10 years, 77 percent were, and at 15 years, 68 percent were cancer-free
(see graph).
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These
lines show the same men.
How many are cancer-free?
According to the ASTRO criteria, nearly all of them—90
percent—are. But the surgical criteria tell a more
sobering story—68 percent are cancer-free—giving
the men whose PSA has started to climb a chance to seek
further treatment as soon as possible.
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But using ASTRO criteria—requiring three consecutive
rises in PSA, and backdating failure to the midpoint between nadir
and the first PSA—90 percent of those same men were cancer-free
at five, 10, and 15 years.
“Applying the ASTRO criteria artificially
improved the patients’ probability of being free from cancer at
15 years from 68 percent to 90 percent,” says Urologist-in- Chief
Patrick C. Walsh, M.D., lead author on the study. “Because most
men with prostate cancer are being diagnosed when the disease
is curable, and because there are more choices for treatment than
ever, it is essential that they make the best decision they can
about treatment. Should he have his cancer surgically removed,
treated with external-beam radiation or brachytherapy (implanted
radiation seeds), or left alone and followed closely?
“Today, many men are told that
radiation therapy cures everyone—that 90 percent of men are cured,
and no one fails after five years. But unfortunately, these results
are based on the ASTRO guidelines, which grossly overestimate
the probability of cure. Thus, men must be cautious in interpreting
any comparison of these therapies based on ASTRO criteria, because
they may be misleading.”
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