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Intermittent Androgen
Deprivation: Promising Theory, Results Pending. (References available)
The honeymoon period of PSA depression that results from initial androgen
deprivation conceals progressive subclinical cellular adaptations that
eventually culminate into androgen insensitive prostate cancer. These are
the adaptations that a strategy of intermittent androgen deprivation (IAD)
strives to repress and postpone. Considerable research has focused on
these adaptations and the results from the many Phase II trials have been
instructive.
After the initial wave of apoptotic death of prostate cancer cells
resulting from the initial steep decline of testosterone, the surviving
cells promptly activate their survival "applications." The paucity of
testosterone immediately upregulates genes expressing Bcl-2 and clusterin,
anti-apoptotic proteins that promote cell survival; the testosterone
deprived environment effects an increase in cell surface androgen
receptors and greater cellular sensitivity to the diminished, residual
testosterone; and cells resourcefully explore new signaling pathways by
mutating the androgen receptor to widen its ligand preferences and lay the
groundwork for alternative proliferative signaling via protein kinase A
and the troublesome IL-6. The theory and hope underlying IAD is that the
periodic pattern of testosterone restoration in IAD will abrogate these
events, thereby prolonging disease control.
What has been learned from research and Phase II trials?
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IAD is feasible, and
most likely is associated with survival outcomes similar to continuous
androgen suppression. Validated questionnaires document a modest benefit
in "quality of life".
-
Initial treatment
durations (the "on" periods) of 9 months or even >1 year produce the
longest "off" periods.
-
The most appropriate
candidates for IAD are men whose PSAs fall to <.2 ng/ml (preferable
"undetectable") after the initial "on" period of AD.
-
Younger men; men with
higher Gleason sums, or higher baseline PSAs are less successfully treated
with IAD. The duration of the initial no-treatment time (the "off' period)
appears to be shortened relative to higher baseline levels of serum PSA
and less deep PSA nadirs, and these features are associated with higher
Gleason scores (Bruchovshy).
-
A single 3 month depot
Lupron results in a median castrate level of testosterone of 6 months.
-
The duration of "off"
treatment periods gradually shorten and vary with the factors listed
above, but initial "off" periods of 9 to 16 or more months are common.
-
The PSA signal for
restarting AD set forth in the different protocols varies widely from 3 ng/ml
to 20 ng/ml PSA.
-
Bruchovsky studied the
relationship of testosterone and PSA in cycles of AD and found that the
recovery of testosterone precedes the rise of PSA by approximately 6
months. He observed that if the PSA rise precedes the testosterone
recovery then androgen insensitivity is likely developing.
-
Under study is the
possibility that continuous finasteride will lengthen the "off" period,
and in some studies finasteride prolonged the no-treatment period from 24
weeks (without the medication) to 80 weeks. There is some evidence that
rapid re-exposure to testosterone of an androgen deprived cell will
reawaken apoptotic potential (Bruchovsky) and this area is under study as
a technique to maintain cell sensitivity to AD and prolong remission.
The currently active
nationwide omnibus Phase III randomized protocol (i.e., SWOG
9346, & ECOG, et.al.) tests IAD in men with metastatic disease. Activated
in May 1995 with a goal of more than 1500 registrants, it prescribes the
combination of Zoladex and Casodex for all men for a period of 7 months.
Participants achieving a PSA of < 4 ng/ml are randomized between IAD or
continuous androgen deprivation. For the IAD group a PSA of >20 ng/ml is
the signal for restarting 7 more months of treatment with cycles repeating
as long as the study requirements are met. The results are several years
away.
At the AUA meeting in May 2003 a German group reported preliminary results
from the first randomized prospective trial comparing IAD to
continuous (C) treatment. The protocol design compared Lupron administered
either intermittently or continuously in men experiencing their first PSA
relapse (PSA > 1 ng/ml) following radical prostatectomy, 82 men (IAD) v.
68 (C). All men initially received Lupron for 6 months, and those who
achieved a PSA <0.5 ng/ml were then randomized between the two arms of the
study. In the IAD group treatment was restarted when the PSA levels became
3 ng/ml. The median pretreatment PSA in the IAD group was 3.5 and the mean
off-treatment period in the IAD group was 9.9 months in cycle #1 and 6.1
months in cycle #2. Normal testosterone levels were regained in the IAD
group 4 months after treatment cessation. At a current median follow-up of
24 months there is no significant difference between the two groups in
time to disease progression. However, this is much too short a period of
follow-up to support any overall conclusions.
Bottom Line: An intermittent androgen deprivation treatment
strategy in relapsed PC offers important theoretical advantages, but
superiority over continuous androgen deprivation has not yet been
established.
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