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.