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Testosterone-Based LHRH Dosing;
Intraprostatic Androgens During Androgen Suppression; Dutasteride and
Intraprostatic Androgens, and Intermittent Androgen Deprivation
Combined with Finasteride
(Sept 2007)
As noted by a group of authors from the Department of
Urology, Kaiser, Los Angeles, (title above) in J.UROL, June 2007,
the manufacturer's recommended dosing of a 22.5 mg Lupron Depot at 3
month intervals is not evidence based. Five percent of patients so dosed
do not achieve castrate testosterone (T) levels (50 ng/dl or less), and
the majority only rise above that level in several to many months beyond
a 3 month period. These researchers sought to individualize dosing based
on a patient's serum testosterone level and retreated with 22.5 mg of
Lupron only when the serum T level exceeded 50 ng/dl.
Forty-two men naive to hormone intervention were studied
(3 were metastatic based on a positive bone scan): median age, 78.5
years; median pretreatment T, 15.5 ng/ml; average Gleason score, 7; and
median post-induction PSA, 0.745 ng/ml. The regimen was initiated with 2
consecutive 3-month 22.5 mg Lupron doses, and if serum T level fell to
castrate range, then the serum T level was monitored monthly, and
re-treatment was administered only when the serum T exceeded 50 ng/dl.
"If there were 3 consecutive increases in PSA despite serum testosterone
of 50 ng/ml or less," the patient was considered hormone refractory,
removed from the study, and referred to medical oncology. During the 18
month follow-up 3 patients were considered hormone refractory.
The study measured the duration of castrate levels of T
for each patient "based on the time from the last [induction] injection
to the first non-castrate serum T level (more than 50 ng/dl)."
Findings: "...the most significant finding of this study
is that not a single patient required dosing of the LHRH agonist more
frequently than 5 months." The median duration was 6 months, and
(abstracted from the graph) 27 were retreated at 7 months, 12 at 8
months, and "One patient had prolonged castration and had a dosing
interval of 12 months."
The authors calculated
the significant savings that would accrue from this regimen. At Kaiser a
22.5 mg Depot Lupron costs $1878.26 (considerably less than in the
private sector!). The average annual cost of the T-based regimen was
$7,316 vs. $3,973 for 3-month dosing.
An EDITORIAL COMMENT in
the article added perspective by noting that "Although of interest, this
[T-based] approach is being overshadowed by the use of intermittent ADT
[see July/August PCa Commentary for discussion of intermittent androgen
deprivation therapy]." Cited was the JCO ASCO Annual Meeting
Proceedings, Abst. 5125 which reported at 2.8 years of follow-up an
estimate that 82% of the 854 men on the intermittent arm remained free
of therapy for one year, and 60% therapy-free for 2 years. "Patients
with [pre-therapy] PSA < 1 ng/ml are off therapy for 2.5 years while 60%
of patients with PSA 1-4 ng/ml are off therapy for 1.5 years." The study
was too immature for progression or survival data.
Quality Of Life Issues Related To Testosterone-Based
Dosing And Intermittent Androgen Deprivation (Iad)
Since the strategy of testosterone-based re-dosing,
albeit at 6 months or longer, effectively achieves continuous castrate
levels of serum testosterone, associated symptoms of androgen
deprivation are not avoided by this strategy. Oefelein (J UROL 2003,
Jan) made this conclusion in his small control-crossover trial of
testosterone-based re-dosing: "However, by study completion overall
health related quality of life was equivalent regardless of dosing
method."
A regimen of IAD does yield benefits in quality of life
as a consequence of withholding the subsequent administration of (say)
Lupron until a PSA of 4, 10, or even 20 ng/ml is reached - various
studies have used different trigger points. This target PSA trigger for
re-treatment lies well beyond - many months, and possibly over a year -
the point at which a man exceeds the castrate level of serum T and then
slowly regains a functional T level. Oefelein nicely documented the time
relationships of the rise of T following a single 3-month
administration of and LHRH agonist in his study of 13 men, median age 65
years. The baseline T was 400 ng/ml. The testosterone levels at
3,6,7,9,12,15 and 18 months after therapy were 0.1, 0.2, 0.7, 1.8, 1.9,
2.1, and 2.3 ng/ml, respectively. The median duration of suppressed
serum T (20 ng/ml or less) was 6 months. However, "The median duration
of hot flashes and sweats was 13.6 months."
Da Silva et al.[cited
above in EDITORIAL COMMENT] reported QOL aspects of their study of
intermittent vs. continuous MAB and noted, "After randomization, sexual
activity increases in the intermittent group to 32% (6 months), 32% (12
months), 24% (24 months), while in the continuous arm the corresponding
percentages are 19%, 20%, 6%, respectively. In their earlier 2006
report, abst. 4513, they reported hot flashes at 30% in the continuous
arm vs. 20% in the IAD group. Their conclusion: "There is no evidence
that intermittent therapy leads to a significant elevated hazard of
dying (p=0.79) or greater subjective or objective progression (p=0.52)
and with less impact on quality of life and less medication. Patients
with PSA <2 ng/ml at randomization have spent a median of 82% of their
time receiving no therapy.
Standard Androgen Suppression Does Not Fully Ablate
Intraprostatic Androgens
Somewhat surprisingly, castrate levels of serum
testosterone do not produce rock bottom androgen levels within
the prostate, with BPH or cancer. The intraprostatic T and
dihydrotestosterone (DHT) levels are only reduced to 20% to 30% of
normal, and those amounts are quite sufficient to drive the androgen
receptor. Page et al. (J Clin Endocrinol Metab. 2006 Oct.)
reported that with androgen suppression by an LHRH agonist "The mean
decrease in serum T was 94%, whereas prostatic T and DHT levels were 70%
and 80% lower" [than normal, respectively] ... [and] "there were no
detectable differences in prostate epithelial proliferation, apoptosis,
prostate-specific antigen, and androgen receptor (AR) expression."
Similar findings were reported by Mostaghel et al. (Cancer Res.
2007, May). After neoadjuvant ADT of 1 and 9 month periods the tissue
androgen levels in the subsequent prostatectomy specimen were reduced by
75% and many androgen-responsive genes, including the AR and PSA genes,
were not suppressed after both periods of ADT. The authors
speculated that "Suboptimal suppression of tumoral androgen activity may
lead to adaptive cellular changes allowing prostate cancer cell survival
in a low androgen environment."
What is the source of
this 20% residual intraprostatic DHT that survives androgen suppression?
This was studied by Suzuki et al. in "Importance of the intracrine
metabolism of adrenal androgens in androgen-dependent prostate cancer" (Prostate
Cancer Prostatic Dis. 2007 Mar) in which they showed that "adrenal
androgen precursors do not directly interact with androgen receptors (ARs)
but are converted to DHT via the intraprostatic metabolic pathways [i.e.
by 5alpha-reductases]." Consideration of this mechanism "suggests the
use of combined therapies that target ARs and prevent the formation of
DHT within prostate cancer cells to achieve optimal therapeutic
efficiency."
Would Concomitant Dutasteride Strengthen Standard Adt?
Although the 5alpha-reductases might be considered weak
compared to LH-RH agonists and anti-androgens, Wurzel et al. (Prostate
Cancer Prostatic Dis, 2007, Oct.) found that the dual
5alpha-reductase inhibitor, dutasteride at 0.5 mg/day, reduced
intraprostatic DHT by 94% in association with reducing serum
DHT by 93%, although there was a slight reciprocal increase in
intraprostatic T. (On the contrary, serum testosterone
increases during dutasteride treatment with one study showing
an increase of 19%.) The Wurzel data was accrued in a study of 43 men
who received dutasteride vs. placebo for 3 months prior to surgery.
Andriole et al. (J Urol. 2004 Sep) found that 5.0 mg [the usual clinical
dose is 0.5 mg] of dutasteride led to a 97% reduction in DHT compared to
placebo after a 6 - 10 week course prior to surgery. A decrease in
microvessel density and an increase in apoptosis caused the authors to
ponder whether dutasteride "can cause regression of some cancers."
The importance of reducing intraprostatic DHT to the
lowest achievable level was emphasized by Singh et al. in "Combinatorial
androgen receptor targeted therapy for prostate cancer" (Endocrine-Related
Cancer, 2006,13). "Prostate cancer cells express modest levels of
type two 5alpha-reductase [inhibited by finasteride] but have
significant expression of the type one 5alpha-reductase." Dutasteride
inhibits both types one and two 5alpha-reductase isoenzymes.
Singh points out that although the intraprostatic T is significantly
lowered by LHRH agonists,"the low level of testosterone remaining can be
amplified by the conversion of testosterone to DHT catalyzed by
intraprostatic 5alpha-reductase." Singh finds validity in "the use of a
5alpha-reductase inhibitor, such as dutasteride, in combination with a
LHRH analog to further lower DHT levels within prostate cancer", and
this approach is currently being tested by GlaxoSmithKlne in men with
metastatic cancer who had a rising PSA level while on LHRH monotherapy.
Suggestive research is developing indicating that
dutasteride, unlike finasteride, may address prostate cancer directly
(in addition to depleting DHT). McCrohan's work (CANCER 2006 Jun) along
with other researchers have found that dutasteride "induced a
dose-dependent increase in apoptosis in [some of] the androgen-sensitive
prostate cell lines ... and in the androgen-expressing PC3 (AR2) cell
line."
Intermittent Androgen Deprivation With An
5alpha-Reductase Used In The "Off Treatment" Period
An effort to prolong the duration the "off treatment"
period has been under study using finasteride by a variety of
researchers. Scholz et al, (J Urol. 2006 May) retrospectively
analyzed 101 men treated with IAD over a 9-year period, 60 of whom
received finasteride during the time off period, and 41 with no
finasteride. The mens' clinical stages were T1c-T2a in 51, T1b-T3b in
11, PSA relapse in 29, and T3c, D0 or D1 in 10. Median PSA was 7.6,
median Gleason score was 3 + 4, and the median follow-up was 8.75 years.
It's worth presenting the methodology of this study since
the schema employed may serve to inform future protocols using
dutasteride. Induction was achieved with an LHRH agonist combined with
either 50 mg/qd bicalutamide or flutamide 250 mg TID, and continued
until the PSA was below 0.1 ng/ml, usually requiring 13 months of
therapy. Time off therapy was measured from the date at which the PSA
first exceeded 0.1 ng/ml until re-administration of ADT. The PSA trigger
of re-treatment was arbitrarily chosen at PSA of 2.5 ng/ml for the
finasteride group (in acknowledgment of the 50% reduction in PSA
associated with a 5alpha-reductase inhibitor) and 5.0 ng/ml for the
control group. To be eligible for analysis a man's testosterone had to
recover above 150 ng/dl by 12 months from the point at which the PSA
first exceeded 0.1 ng/ml. "AIPC [androgen insensitive prostate cancer]
was defined as failure to attain an undetectable PSA of less than 0.1 ng/ml
with the reinstitution of [ADT] while testosterone remained less than 50
ng/dl."
Study findings: Median time off therapy for the
finasteride group, 31 months; and for the control group, 15 months.
As yet there are no
published trial results of intermittent androgen deprivation using
dutasteride in the "off periods". However, this regimen is an idea whose
time has come because of its sound basis in science. We should look
forward to a protocol studying it in the near future.
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