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Are there alternatives to Lupron or
Zoladex for primary hormonal intervention? A discussion of Proscar in
combination with either Casodex or Eulexin.
(February 2003)
This section arose from a question from
a colleague who asked about the role of Casodex, 150 mg daily, as
monotherapy. By coincidence, while I was addressing this topic a patient
called for advice. He had had a brief, and biochemical successful exposure
to both Lupron and Zoladex, but discontinued therapy because of
debilitating side effects. His PSA is rising again. The question: what are
his options?
Two very acceptable options are: 1) Bicalutamide (Casodex) 150 mg daily
and 2) finasteride ("Proscar") 5 mg once or twice daily combined with and
either flutamide ("Eulexin") 125-250 mg TID or bicalutamide 50 mg daily.
Both of these regimens result in an increase in testosterone while at the
same time depriving the PC cell the key stimulating molecule
dihydrotestosterone. Bicalutamide as monotherapy at 50 mg daily is
insufficient to achieve the desired result. As a consequence of this
elevation of serum testosterone physical capacity, sexual interest, and
bone density are preserved.
The most recent and comprehensive discussion of bicalutamide therapy
appears in UROLOGY Vol.60 (Supplement 3A) pp.64-71 by Dr. Peter Iverson,
University of Copenhagen, Denmark: "Antiandrogen Monotherapy: Indication
and Results." There is an extensive literature on this subject mostly
coming from Europe where this regimen is extensive used. Mature data is
available combining results from two large randomized trials (480
patients) studying men with locally advanced, nonmetastatic disease (stage
M0). The comparison regimens were LHRH agonists or castration or
bicalutamide, 150 mg daily. In studies of the M0 group, bicalutamide, 150
mg daily, and castration shared an essentially similar in survival outcome
yielding a 46% survival for both with a median follow up of 6.3 years. (By
checking "Prostatecalculator.org", which shows the outcome of Zoladex in
the non-metastatic situation, it can be seen that the Casodex 150 mg
regimen is similar.) The outcome of this comparison for M1 (metastatic)
disease favored castration. At a median follow up of 1.9 years the
mortality was 43% with a 6-week advantage for castration. However, in
patients with PSAs <400 the outcome was equivalent. Quality of life issues
favored bicalutamide with libido maintained 40% vs. 15% and in men
sexually active before treatment erectile function was preserved 31% vs.
7%, and hot flashes occurred in 13% vs. 50%. The unwelcome side effects of
bicalutamide were gynecomastia 49.4% and breast pain 40.1%. Studies are in
progress to evaluate if pretreatment breast irradiation can lessen these
consequences. (flutamide and nilutamide have not been sufficiently studied
to allow comparable evaluation to bicalutamide) Cost can be an issue;
Casodex runs about $13per 50 mg pill, hence 90 pills per months costs
roughly $1200.
The second applicable option is the finasteride/antiandrogen regimen. This
regimen has been less well studied and the supporting literature is older.
The rationale is based on the combined physiologic actions of both agents.
The initial step in androgen activation of prostate cells is the inward
diffusion of testosterone. At this point testosterone is converted into
the 20X more potent form, 5alpha-dihydrotestosterone by the enzyme
5alpha-reductace. Finasteride inhibits this enzyme. The antiandrogen (flutamide
or bicalutamide) upregulates the corepressor mechanism restraining
signaling via the androgen receptor thereby further reducing the androgen
stimulation. The serum testosterone rises >50%, the serum
dihydrotestosterone falls by 74%. In a study of 13 men (UROLOGY 1996 Dec;
48:901-5) the PSA fell 91% with 85% of men showing a nadir of PSA >4 and
46% achieving levels .2 ng/mL or less. In another study the PSA drop was
97.6%. In a small group followed for more than 2 years the antineoplastic
effect was sustained. The patients treated with this regimen experienced
the same benefits in quality of life as mentioned for bicalutamide
monotherapy. The regimen I have preferred uses finasteride 5 mg BID and
bicalutamide 50 mg daily. (The serum half-life of bicalutamide is 7 days
allowing once-a-day dosing, whereas with a half-life of 5-6 hours
flutamide requires TID dosing, and flutamide induces more diarrhea). I've
heard Dr. David Crawford favorably refer to this regimen. He was at that
time unsure if an LHRH agonist could be successfully used as a rescue when
the combined regimen faltered."Proscar", 5 mg, runs about $3 each. At two
pills daily per month the cost is roughly $175. By adding the cost of
Casodex, 50 mg daily, at roughly $400, the monthly total for the regimen
rises to about $575.
Bottom Line: Several useful options are available for primary androgen
suppression and clinicians may choose among them to best meet the
individual requirements of patients.
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