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Intermittent Androgen Deprivation: Very Likely An Idea Whose Time Has
Come
(July 2007)
Although the final
judgment about the comparative effectiveness of IAD to continuous
treatment awaits the completion of two ongoing major randomized trials,
nonetheless there is substantial early support for IAD's equivalency of
outcome with clear benefits for quality of life (QoL). In his review of
IAD (BJU Int, Jan 2007) Dr. Tunn, Frankfurt, Germany, points out that
"It can be used in any clinical situation where continuous AD (CAD)
treatment could be applied." Additionally, "The potential advantages of
IAD over CAD therapy are an improved QoL, a prolonged period of androgen
independence, a reduced incidence of the side-effects normally
associated with AD therapy, and a decrease in the cost of care." At the
recent AUA meeting he presented data from a 244 man study that showed no
significant difference in the 2-year rate of progression to androgen
independence between CAD, 6%; and IAD, 8.3%. Both strategies showed a
similar time to eventual PSA progression - about two years. At the
meeting Dr. Gleave, UBC, indicated a desire for stronger data, which may
in fact come partly from the contribution from his own Vancouver group's
participation in the North American cooperative trial in which this
issue is under study in 1300 men .
The Vancouver team
published (Bruchovsky, CANCER, MARCH 1, 2007) useful data about
the dynamics of IAD that will inform the usage of this management
strategy: "Locally Advanced Prostate Cancer - Biochemical Results from a
Prospective Phase II Study of Intermittent Androgen Suppression for Men
With Evidence of Prostate-Specific Antigen Recurrence After
Radiotherapy."
Their regimen: When the
PSA rose to >4 ng/mL, a 4-week lead in with an anti-androgen was
followed by Lupron for a total treatment time of 36 weeks. Therapy was
then discontinued in those 103 men whose PSA dropped to below 4 ng/mL at
both 24 and 36 weeks. Therapy was resumed when the PSA level reached
> 10 ng/mL. Cycle 1 was initiated in the 103 man cohort; and cycle 2
was initiated in 86 patients; cycle 3 in 56; cycle 4 in 26; and cycle 5
in 7 patients.
What was learned?
1) The mean value of
PSA at the start of Cycles 1 through 4 ranged from 18.5 ng/ml to 11.9,
but regardless of the PSA value the PSA fell by a average reduction
of 95.2% in every cycle, and followed the characteristic bi-phasic
pattern with the steep initial drop followed by the slow longer gradual
decrease. The initial sharp drop they believe "represents an initial
inhibition of PSA syntheses over the first 8 to 10 weeks, after which
apoptotic cell loss accounts for the further [slower] reduction in serum
PSA." This recurring pattern led to the suggestion that the 36 week
treatment period could plausibly be lessened.
2) The duration of the
time-off-treatment was inversely proportional to the PSA at the start of
AD. The optimal example was seen in the group starting treatment with a
PSA in the range of 4 - 10 ng/ml wherein the time-off-treatment was 90.7
weeks for Cycle 1; 66.5 weeks, Cycle 2; 26.2 weeks, Cycle 3; and 22.7
weeks, Cycle 4. Groups with higher baseline PSA values had shorter
time-off periods. Correspondingly, the duration of time-off was related
to AD induced nadir of PSA: in Cycle 1 for a PSA nadir of < 0.2
ng/mL the duration of time-off was 75.7 weeks; for PSA nadir of 0.2 to
1, 53.5 weeks; for nadir 1 to 2, 37.2 weeks; and for a nadir of >2, 36.5
weeks.
The recovery of
testosterone to low normal level was seen in 75% of men in cycle 1
within 5 months, but this percentage decreased in Cycles 2, 3, and 4 to
50%, 40%, and 30%, respectively. The recovery, however, was sufficient
to restore hemoglobin to normal levels in successive cycles.
Bottom Line:
It is likely that intermittent androgen deprivation will be found to be
a validated alternative to continuous therapy. The details of the
dynamics of IAD provided by the Vancouver group will usefully inform the
application of this strategy.
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