|
Interaction Of Finasteride (Proscar) And Psa: A Potential Problem In
Diagnosis
It has been well documented that when 5 mg of finasteride is used for the
treatment of BPH the total PSA falls by 50%. Less clear is the
interpretation of the change in the percent free PSA (%fPSA) in instances
wherein patients are under treatment with finasteride. A clinical example
serves to point up important issues associated with this not uncommon
diagnostic challenge.
Consider the following: A 70+ year old man's total PSA (tPSA) results on
5/1996 were 3.6 ng/ml, %fPSA 18%; on 7/2000 the tPSA was 4.2 ng/ml, %fPSA
25%; on 10/2002 tPSA 6.7 ng/ml, %fPSA 21%. Because of urinary symptoms
from an enlarged gland, he was prescribed finasteride 5 mg. On 5/2003 the
tPSA was 3.9 ng.ml, a 42% reduction, and the %fPSA was 7.9%. What to
think?
The next reasonable step would be to recheck the results. The national
press gave widespread coverage to the recent JAMA article, "Variation of
Serum Prostate-Specific Antigen Levels", which essentially reframed the
carpenters' old adage - "Measure twice, cut once", suggesting that a
physician considering a biopsy on the basis of a upward change in PSA
should recheck the PSA result. With reference to the example above, the
values were rechecked yielding the following results: tPSA was 2.5 ng/ml
with %fPSA of 7.7%. When tested again with a different assay: tPSA 2.1; %fPSA
13.7%
A brief review of the biology underlying the secretion of PSA and the
genesis of the percentage of "free" PSA in the serum offers a useful
background for analyzing this issue. The related biology was nicely set
forth in the review, "Biology of Prostate-Specific Antigen" by Bubley and
Balk in JCO, January 15, 2003. They explain that as a result of androgen
stimulation, mainly by dihydrotestosterone (DHT), the prostatic secretory
epithelium secretes a 224-amino acid precursor protein, proPSA, into the
ductal lumen where seven amino acid residues are immediately cleaved, thus
creating the active mature proteolytic enzyme, PSA, whose purpose is
liquifying semen. A modest proportion of this active enzyme is inactivated
within the duct by enzymatic cleavage. As a consequence of various
intraprostatic factors, a small proportion of both the active and inactive
PSA leaks into the adjacent prostate vasculature where the active PSA is
immediately complexed with an inhibitor of its enzymatic potential, alpha
1-antichymotripsin. However, as a result of cleavage alterations, the
inactive form is not bound by this inhibitor and becomes the
so-called "free PSA". Disturbances in normal glandular anatomy results in
increasing amounts of PSA entering the systemic circulation. These factors
may include increased internal pressure from BPH, and disruption of
basement membrane and internal glandular architecture resulting from
malignancy. Because the PSA isoforms that enters the circulation as a
result of these disturbances have bypassed transit through the
ductal lumen where "inactivation" occurs (the geneses of "free"
PSA), a smaller proportion of the PSA leaking into the circulation is in
the "free" form.
Finasteride, a steroidal analog of testosterone, functions as a reversible
competitor to testosterone as the the substrate for type II
5-alpha-reductase, whose customany function is to convert testosterone
into the 10 times more potent DHT. This competitive inhibition results in
"a 75% decrease in serum DHT levels, an 80% decrease in intraprostatic DHT,
and a 10% increase in serum testosterone,... finasteride's serum half life
is about 8 hours,... and single doses as low as 0.2 mg depress serum DHT
levels persisting for up to 4 days." (Brawley, Urologic Oncology Seminars,
21, 2003)
It is generally recognized that in men (who are not taking finasteride)
and whose PSAs are between 4 and 10 ng/ml, a fPSA/tPSA ratio of >25% is
associated with an 8% risk of PC, whereas a ratio <10% raises the risk to
56%. However, the focus of this article is upon the effect of
finasteride upon the fPSA/tPSA ratio. This issue has been addressed in the
literature in several ways.
Various authors have validated the observation that finasteride reduces
the tPSA level by an average of 50% without changing the
fPSA/tPSA ratio (Partin and Pannek, J UROL, Feb 1998, "Influence of
finasteride on free and total serum prostatic specific antigen levels in
men with benign prostatic hyperplasia" [emphases mine].
Kaplan, (Urology, Sept 2002, "PSA response to finasteride challenge in men
with a serum PSA greater than 4 ng/ml and a previous negative prostate
biopsy, preliminary study"), analyzed the change in total PSA in men who
took 5 mg finasteride for one year. Results: no cancer was found on
subsequent biopsy in men whose tPSA decreased 50% or more. In 19 men
showing a decline in tPSA of only between 33% and 50% 6 cancers were
diagnosed, and when the tPSA decline was <33%, 5 of 9 men (56%) showed
cancer.
The article which addresses our example most specifically (Tarle,
ANTICANCER RESEARCH 23, 2003) reported a study which involved 37 men who
were prescribed 5 mg finasteride daily because of urinary symptoms
resulting from enlarged glands of >60 cc. The fPSA/tPSA ratio was measured
pre- and post-treatment. Twenty five men showed a mean reduction of 53% in
tPSA (8.1 to 4.3 ng/ml) and their fPSA/tPSA ration was unchanged
at 25%, consistent with the observation that in BPH the tPSA and fPSA
should decline by a similar proportion. No cancer was found in this group
during a 8-26 month follow-up. The baseline mean PSA of another 12 men was
9.9 ng/ml and their baseline mean fPSA/tPSA ratio was 20.1%. After 6
months of treatment the tPSA had only dropped to 7.2 ng/ml (a 28.3%
reduction). However, the fPSA/tPSA ratio showed only a 14%
reduction (20.1% to 17.4%) and in this group during a 4-19 month follow-up
cancer was diagnosed in seven men (58%).
The proposed explanation for these observations is that in the presence of
increasing BPH the benign tissue's contribution to tPSA increasingly
overshadows the less conspicuous perturbation of the fPSA/tPSA ratio
resulting from a concomitant, but comparatively smaller volume of prostate
cancer. Finasteride effects shrinkage of the BPH tissue, thus diminishing
its contribution to tPSA, and thereby unmasks the worrisome signature of
possible prostate cancer.
Bottom Line: Analysis of the changes in the fPSA/tPSA ratio
resulting from finasteride treatment can alert the physician to an
increased risk of prostate cancer.
«
Back to Article List |
