A Publication of the James Buchanan Brady Urological Institute Johns Hopkins Medical Institutions

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.

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.

The 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.

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).

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.

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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