Does early salvage radiation save lives?

Several studies have tried to address the issue of whether adjuvant radiation actually increases prostate cancer survival in the long term compared to waiting. They all showed that biochemical progression-free survival could be improved by earlier treatment, but it remained questionable whether that would eventually translate into a survival benefit.

After 10 years of follow-up, the randomized clinical trial ARO 96-02 found that neither metastasis-free survival nor overall survival was significantly improved by adjuvant radiation. However, the study was underpowered to reliably detect those results.

After 10 years of follow-up, the randomized clinical trial EORTC trial 22911 found that adjuvant radiation did not significantly improve overall or metastasis-free survival, although there may be benefit for men less than 70 years of age, or those with positive margins.

There was only one study, SWOG S8794, which after 12.6 years of follow-up, demonstrated a significant improvement in both overall and metastasis-free survival among patients who had adjuvant radiation compared to patients who waited. However, the difference did not hold up when patients who received adjuvant radiation were compared to those who received salvage radiation. The difference was possibly attributable to the fact that very few patients in the wait-and-see arm ever got salvage radiation.

None of those three studies used radiation doses that are now considered to be adequate for curative adjuvant or salvage radiation.

So, with highly equivocal findings from the best studies we have available so far, how is the patient to make a decision as to whether it is worthwhile to undergo the potential side effects of early salvage radiation? This is the question that Hsu et al. at the University of California San Francisco set out to answer by looking for evidence in their large CaPSURE database. They identified 305 patients who had radiation after surgery, and who had such high-risk features on their surgery pathology report as:

• ·      Positive surgical margins, or
• ·      Gleason score 8-10, or
• ·      Stage T3 or T4

In that group, they found

• ·      76 men who had undetectable PSA and received adjuvant radiation within 6 months of surgery.
• ·      229 men who had salvage radiation after reaching a PSA>0.1 ng/ml, or after 6 months post-surgery. This group comprised:

o   180 who had early salvage radiation before PSA reached 1.0 ng/ml

o   49 who had late salvage radiation after PSA reached 1.0 ng/ml

After a median elapsed time of over 6 years after surgery, the researchers found:

• ·      Overall, 98% were still alive.
• ·      Overall, 12% had progressed to metastases or death.
• ·      Adjuvant and salvage radiation patients had comparable high-risk features.
• ·      Men who had salvage radiation had an all-cause mortality rate 2.7 times higher than men who had adjuvant radiation.
• ·      Men who had salvage radiation had a prostate cancer-specific mortality rate 4.0 times higher than men who had adjuvant radiation.
• ·      Ten year estimated prostate cancer-specific mortality was:

o   12% among men who had adjuvant radiation.

o   16% among men who had early salvage radiation.

o   29% among men who had late salvage radiation.

• ·      Late salvage radiation carried increased risk of prostate cancer-specific mortality and all-cause mortality.
• ·      Early salvage radiation had about the same mortality risk as adjuvant radiation.

The conclusion is that early salvage radiation, while PSA is still below 1.0 ng/ml, had the same survival benefit as adjuvant radiation, but without the risk of overtreatment. However, waiting until after PSA reached 1.0 ng/ml significantly increased the risk of metastases and prostate cancer mortality.

The PSA threshold used in this study, 1.0 ng/ml, is quite high and well beyond the limit used for the definition of biochemical recurrence (0.2 ng/ml). It may turn out to be the case that this higher threshold is a more useful definition of biochemical recurrence than the current definition. However, the follow-up period here is short (median 6 years), as it may require 20 or 30 years for a survival benefit to show up when a lower threshold is used. It should also be noted that the definition of “adjuvant” radiation used in this study included therapy begun anytime before PSA reached 0.1 ng/ml, while there may be greater survival advantage when adjuvant radiation is begun at a lower level measured on an ultrasensitive PSA test.

While this study provides evidence for early salvage radiation, its retrospective nature makes it subject to selection bias: there may have been specific reasons why the patients were selected to receive adjuvant, early salvage or late salvage radiation. The abstract of the study makes no mention of the radiation doses used, whether androgen deprivation was used along with the radiation, the use of radiation to pelvic lymph nodes, or whether age and co-morbidities were significantly different. We await the results of ongoing randomized clinical trials to provide more reliable information.