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Intermittent Vs Continuous Androgen-Deprivation Therapy: Two Reports
From ASCO 2006
(November 2006)
Numerous studies in
recent years have compared intermittent androgen deprivation (IAD) with
continuous treatment, and generally suggest that IAD is not inferior
in terms of disease progression and survival, but have found that IAD
does provide substantial therapy "off-periods" during which the side
effects of androgen suppression lessen, albeit "off-periods" of
decreasing lengths. Although basic science studies suggest that there
may be benefits at the molecular level associated with IAD that
forestall transition into androgen refractoriness, clinical evidence
supporting this potential advantage has as yet not been identified.
Two abstracts presented
at ASCO 2006 addressed intermittent treatment. In abstract 4513 Da Silva
presented results based on 626 study participants (31% metastatic, 69%
stage T3 or T4; baseline PSA > 4 ng/mL) who achieved a PSA drop to <
4ng/mL or 80% below baseline after initial treatment for 3
months with a regimen of cyproterone and a GnRH agonist, at which time
they were randomization to continuous CAB or IAD with CAB. An overall
observation was that the amount of time off therapy was determined by
the nadir value of the post-induction PSA decrease.
Of the 312 men in the
IAD arm 50% were able to be off treatment for at least 52 weeks
following the induction period, and 29% of them had an an initial
off-therapy time of >36 months. The initial off-treatment period for the
197 men who achieved a nadir PSA of <2 ng/mL was a median of 74 weeks,
and this group experienced a median of 82% of their total study
time off of therapy. The abstract did not detail the protocol
instructions for re-starting treatment after an "off" period.
"In the intermittent
arm, 41% were sexually active at 9 months, 40% at 15 months, and 35% at
21 months".
Conclusion: "Estimated
5-year survival for the IAD cohort was 53.8%, and 51% in the continuous
group."
The second abstract,
4517 (Southwest Oncology Group Trial 9346), was a interim report on 1134
men who achieved a PSA of < 4 ng/mL after an induction period of
7 months of ADT and then were randomized to IAD or continuous therapy.
Eligibility required D2 disease and baseline PSA > 5 ng/mL. The
median baseline PSA for the group was 76.1 ng/mL, 38% with bone pain,
and 47% with Gleason sum >7.
The subject of this
report was not a mature comparison of survival between the intermittent
and continuous cohorts, but rather an examination of whether the
duration of survival was related to the nadir of the PSA achieved at the
end of the 7 month induction period. The answer: a resounding "yes".
"After adjusting for significant independent risk factors", the median
survival for those who achieved a post-induction PSA < 0.2 ng/mL
was 75 months; for a PSA between 0.2 and 4.0, 44 months; and for PSA
> 4 ng/mL, 13 months. Commenting in ONCOLOGY, OCT 2006, Drs. Kantoff
and Appleman cautioned that until the final results of this important
study are known, IAD should be considered investigational in metastatic
disease.
Of note is a small
study reported In J. Urol, 2006 May, "Intermittent use of testosterone
inactivating pharmaceutical [IAD] using finasteride prolongs the time
off period". This strategy builds on the fact that even when serum
testosterone is in the castrate range (< 50 ng/mL), the intratumoral
levels of DHT and testosterone are sufficient to drive the androgen
receptor. Their schema randomized 60 men to received 5 mg of finasteride
during the time-off periods, and 41 received none. Their findings were
suggestive of usefulness of 5-alpha reductase inhibition: the median
time-off therapy for the finasteride group was 31 months compared to 15
months without finasteride.
Bottom Line:
Study results are converging to suggest equivalency between IAD and
continuous ADT therapy with the duration of time-off treatment in the
IAD regimen determined by the PSA nadir after induction therapy. There
is suggestive evidence that finasteride administered during IAD
off-periods can increase their duration.
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