Low PSA Nadir After Radiation Can Predict Freedom From Prostate Cancer Return

After external beam radiation for prostate cancer, this study finds, a longer period of PSA fall and lower PSA nadir predicts higher chance of disease-free survival. Higher dose of radiation (at or above 70 Gy) significantly improves this chance.

March 16, 2006. Prostate cancer patients who have a lower prostate specific antigen (PSA) nadir after external beam radiation therapy to treat their prostate cancer are less likely to have the cancer return or spread to other parts of their body than patients with a higher PSA nadir. The longer the PSA continues to fall and the lower its ultimate lowest point (nadir) the better the patient's chances of disease-free survival.

In addition, patients treated with a higher dose of radiation have a better chance of achieving a lower PSA score and are less likely to see their prostate cancer return.

These findings about nadir and dose might seem obvious but the first study to demonstrate them by clinical investigation has just been published in the March 15, 2006, issue of the International Journal of Radiation Oncology / Biology / Physics. The study was conducted on nearly 5,000 patients treated with radiation therapy in nine academic radiation oncology departments across the United States.

After receiving radiation, most patients experience a decline in their PSA blood test score. Doctors measure the PSA level at intervals after radiation to monitor treatment response. If the PSA steadily decreases (except for a widely seen event called PSA "bounce") and if after reaching a nadir (low point) the PSA stays relatively level, the treatment is considered a success; but if the PSA reaches a nadir then steadily rises, the patient is judged to be experiencing systemic recurrence and additional treatments such as hormonal blockade may be prescribed.

In the current standard of care, doctors are less interested in the actual PSA score than in whether the PSA rises after treatment. A rise is used to gauge whether the cancer will likely return.

In this study researchers set out to find out what PSA nadir and time to reach PSA nadir can predict about the likelihood that a patient's prostate cancer will return or spread.

The doctors found that a lower PSA nadir was associated with a dramatic decrease in both prostate cancer recurrence and the spread of cancer among patients across all risk categories. The patients were separated into different categories, based on their PSA nadir after radiation. The patients with the lowest PSA scores experienced an eight year disease-free survival (PSA-DFS) rate of 75 percent, compared with only 18 percent for those with the highest PSA scores. Patients who had the lower PSA scores also had a 97 percent distant metastasis-free survival (DMFS) rate, compared with 73 percent for those with the highest PSA scores.

The 8-year PSA-DFS and DMFS rate for patients with PSA nadir (nPSA) was calculated as follows:

PSA Nadir & 8 Year Survival

PSA Nadir (n PSA)	PSA Disease-Free Survival Rate	Distant Metastasis-Free Survival Rate
Conclusion	Lower PSA nadir increases PSA free and distant metastasis free survival.
<0.5 ng/mL	75%	97%
=1.0 but <2.0 ng/mL	40%	90%
=2.0 ng/mL	17%	73%

Time to PSA nadir (T nPSA)
& 8 Year Survival

T n-PSA	PSA Disease-Free Survival Rate	Distant Metastasis-Free Survival Rate
Conclusions	A shorter T nPSA was associated with decreased PSA-DFS and DMFS, regardless of the nPSA. Both nPSA and T nPSA were significant predictors of PSA-DFS and DMFS in multivariate models incorporating clinical stage, Gleason score, initial PSA level, and RT dose. The significance of nPSA and T nPSA was supported by landmark analysis, as well as by analysis of nPSA and T nPSA as time-dependent covariates. A dose =70 Gy was associated with a lower nPSA level and longer T nPSA in all risk categories, and a greater dose was significantly associated with greater PSA-DFS and DMFS in multivariate analysis. Higher clinical stage, Gleason score, and initial PSA were associated with a greater nPSA level.
<6 months	27%	66%
≥6 but <12 months	31%	85%
≥12 but <24 months	42%	94%
=24 months ng/mL	75%	99%

Of note, the study found that although some authors "have suggested that specific nPSA levels might be used to define treatment failure or success," absolute cutpoints are not useful below a certain level:

For this analysis, nPSA cutpoints of 0.5, 1.0, and 2.0 ng/mL were selected on the basis of previous reports. Although this analysis validated the general principle that a lower nPSA is predictive of improved outcome after RT, our CART analysis clearly reaffirmed the conclusion of the 1996 American Society for Therapeutic Radiology and Oncology consensus panel. Although nPSA is a useful prognostic factor, a single nPSA cutpoint cannot separate successful from unsuccessful treatment. No threshold of post-RT PSA level exists that defines, or is required for, total tumor cell eradication. nPSA alone provides valuable prognostic information, of the “biochemical failure” definition.

"While there is no magic number for the PSA that guarantees that prostate cancer has been cured in an individual patient, in general, the lower the PSA number, the better chances that the cancer will not return or spread," said Michael E. Ray, M.D., Ph.D., lead author of the study and a radiation oncologist at the University of Michigan Medical Center.

"In addition," Dr. Ray said, "the study showed that the longer time that the PSA continues to decline after radiation, the less likely the cancer will recur or spread."

"Our findings about PSA nadir level and the time to reach PSA nadir level suggest that patients who have more advanced and aggressive cancer (for example extracapsular disease or subclinical metastatic disease) generally do not achieve low PSA nadir levels and usually reach their nadir quickly and then start to rise again." Ray said. "So higher nPSA and shorter TnPSA are both associated with worse outcomes."

"Regardless of how low the ultimate nPSA went, longer TnPSA was better," Ray said, "when we looked at specific groups of patients, we found that those general trends applied to patients in all risk categories (in other words, patients with low stage, Gleason and PSA levels all the way up to patients with high stage, Gleason and PSA levels). Furthermore, when we looked at patients treated with higher radiation doses, they seemed to get
lower nPSA and have longer TnPSA, suggesting that higher radiation doses are beneficial."

"These findings may help us to identify high risk patients early," he said. "This may allow their doctors to consider other adjuvant or salvage therapies to hopefully increase their chances for survival."

During the time period covered by this study, standard doses for external beam radiation of the prostate were at or below 60 Gy. Today, with the introduction of 3-dimensional conformal radiotherapy and Intensity modulated radiation therapy or IMRT (and some use of proton and neutron beam), doses are often at or well above 70 Gy.

The participating institutions included the University of Michigan in Ann Arbor, Mich.; the M.D. Anderson Cancer Center in Houston; Fox Chase Cancer Center in Philadelphia; Cleveland Clinic Foundation in Cleveland; William Beaumont Hospital in Royal Oak, Mich.; Mallinckrodt Institute of Radiology in St. Louis; Mayo Clinic College of Medicine in Rochester, Minn.; Massachusetts General Hospital in Boston and Memorial Sloan-Kettering Cancer Center in New York.

This article posted March 16, 2006 by J. Strax, last edited March 17.

For more information on radiation therapy for prostate cancer, visit www.rtanswers.org. and www.astro.org/patient/treatment_information/ for a free brochure.