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Does Finasteride Alter The Pathology Of
The Prostate And Cancer Grading - Yes? No? ... Maybe? (October
2005)
The landmark article “The Influence of Finasteride on the
Development of Prostate Cancer”, NEJM July 17, 2003, by Ian Thompson et
al. reported a 24.8% finasteride related reduction in the seven-year
period-prevalence of cancer and was a source of optimism for the
prevention of this disease. It was, however, also a source of a vexing
controversy that still evades a definitive answer. The heading of this
Commentary article is the title of the analysis of this issue by David
Bostwick et al. published in Clinical Prostate Cancer, March 2004. But
first, a review of the facts.
Of the total of 18,882 men in the Prostate Cancer
Prevention Trial, Gleason grade 7, 8, 9, or 10 was found in 37% of the
tumors diagnosed in men on the finasteride arm (280/757), which
represented 6.4% of the 4368 men taking the drug. In contrast, of the
tumors found in the 4692 men in the placebo group, only 22% were
high-grade (237/1068), or 5.1%; P=0.005 for the comparison between the two
groups. In a commentary on the trial, Talcott (JCO, Oct 10, 2005) pointed
out that the nearly 25% reduction in cancers (24.4% reduced to 18.4%, an
absolute reduction of 6%) was comprised of tumors of Gleason score <
6. Gleason 7 tumors were equally represented in both arms, while there was
a 27% increase in cancers with Gleason score 8 - 10, and with the
inclusion of Gleason 7 tumors this was an absolute overall increase of
1.3%.
If this higher proportion of Gleason 8, 9, and 10 cancers
was an actual biologic consequence of the relatively weak (compared to an
LHRH agonist) intraprostatic androgen deprivation resulting from
finasteride, a type II 5-alpha-reductase inhibitor, what mechanisms might
be operative? By competitive enzyme blockade, finasteride decreases
intraprostatic DHT by > 90%, and presumably this reduction swamps the
effect of a seven-fold increase in intraprostatic testosterone. It isn’t
unreasonable to speculate that the DHT reduction inhibits the
proliferation of premalignant and androgen dependent prostate cancer, and
commensurately favors the growth of cells with more aggressive histology,
which are thought to be both less growth dependent on DHT and less
“hormone sensitive”. Additionally, it is well known that one of the
consequences of androgen deprivation is an associated alteration in the
pattern of gene expression leading to increased transcription of the
anti-apoptotic enzymes Bcl2 and survivin and other unwelcome gene products
that may transform cells toward a higher grade.
One important result of finasteride’s 5-alpha-reductase
inhibition is a 25% reduction in gland size over about two years, an
effect which would compress the gland density and actually should
relatively increase the positive biopsy yields in finasteride treated
prostates.
Does androgen deprivation lead to histologic alterations
that artifactually confound pathologic grading? Epstein et al. addressed
this issue in UROLOGY 53(4)1999: “Does long-term finasteride therapy
affect the histologic features of benign prostatic tissue and prostate
cancer on biopsy?” He commented “Leuprolide induces marked atrophy of
prostate carcinoma cells, which sometimes makes pathologic diagnosis of
cancer difficult, although evaluation at radical prostatectomy is easier
than at biopsy”. The more marked histologic alterations that result from
Lupron treatment and castration has led to a consensus that Gleason
grading should not be used after these treatments. The Epstein study
addressed grading after finasteride and compared 53 biopsies showing
cancer from 35 men treated with finasteride, and 18 on placebo, and
concluded there were “no significant histologic differences” between the
groups and that cancer could reliably be identified after finasteride
treatment.
Kattan, Scardino et al. extended observations on this issue
in BJU Int 95, 2005: “Gleason grade remains an important prognostic
predictor in men diagnosed with prostate cancer while on finasteride
therapy”. They studied 45 men who had been on finasteride for > 6 months
before the diagnosis of prostate cancer and reported the outcome after a
median of 23.6 months of follow-up. The Kattan post-prostatectomy nomogram
predicted a 5-year PFS of 85%. The real-life actuarial PFS was 86%.
Conclusion: “Finasteride does not appear to compromise the assignment of
Gleason grade for use in prediction tools before or after RP... “.
In the Epstein study the numbers were too small to allow
detection of a difference in Gleason scores that might have developed in
their two groups as a result of finasteride therapy. And, likewise, the
Kattan study of 45 men did not address that point, and was underpowered to
do so.
Drs. Eric Klein, Ian Thompson et al.(JCO, Oct. 2005)
presented an innovative analysis, “Assessing Benefit and Risk in the
Prevention of Prostate Cancer: The Prostate Cancer Prevention Trial
Revisited”, in which several absolute benefit/absolute risk ratios were
calculated based on assumptions that the higher Gleason scores were
produced to various extents ( e.g., 0%, 10%, 25%, or 50% of cases) by a
hormone induced artifact from finasteride and were, therefore, not
biologically consequential. The benefit/risk ratio assuming no artifact
(e.g. entirely due to a biologic effect) was 4.6:1 and increased to 9.2:1
if artifact accounted for 50% of the higher Gleason scores. The Klein
article led to a rather insightful rejoinder commentary by James Talcott
in the same JCO issue wherein the reader was reminded of “type I and type
II errors of inference” and, simply put, argued that in the case of the
PCPT it was much more important to avoid interpretations that, if in
reality were incorrect, would lead to harm (e.g discounting the possible
consequence of the more aggressive Gleason scores). He cautioned that
greater potential harm resulted from focusing on reductions in the more
“benign” cancers, which characteristically are slower to develop and are
better treated, and thereby miss the chance to intervene in what might be
more aggressive cases.
We now return to a brief summary of the Bostwick, Civantos
review, the title of which is the lead for this Commentary article. Their
conclusion: “The Gleason grading system should not be used after
finasteride treatment as it is not validated in this setting and is likely
to overestimate the biologic potential of high-grade cancer observed after
therapy”. They clearly imply that the histologic changes that have raised
such concern are hormone induced artifacts, and that chemoprevention
trials using agents that alter morphology should not rely on Gleason
grading as a endpoint, but instead focus on survival outcome (an endpoint
that will eventually emerge from the PCPT data). They noted that the
histopathologic alterations were less prominent than following LHRH
agents, but “Finasteride treatment created small clusters of shrunken
acini morphologically similar to post atrophic hyperplasia and atypical
adenomatous hyperplasia” with “variable distribution throughout the
prostate ... strikingly reminiscent of lobular carcinoma of the breast”.
Their conclusion regarding artifactual alteration was supported by their
observation that “the relative over-interpretation of Gleason score >
7 in the finasteride arm was more pronounced in years 1 and 2 of the PCPT
and thus more likely caused by treatment-induced architectural changes
rather than to the de novo development of more aggressive cancer.”
Dutasteride, a dual inhibitor of the 5-alpha-reductases, is
replacing finasteride in many urologic practices and is the agent under
study in the placebo-controlled chemoprevention trial, “REDUCE”. Bostwick,
Andriole et al. addressed the histologic effects of this newer drug in
“The dual 5-alpha-reductase inhibitor dutasteride induces atrophic changes
and decreases relative cancer volume in human prostate”, UROLOGY
65(1)2005. In a treatment period of 5 - 10 weeks 17 men took dutasteride
and 18 placebo. Results: tumor volume was significantly reduced in the
dutasteride group, the percentage of atrophic epithelium increased, and
the stromal/gland ratio was doubled. If these post-dutasteride
architectural changes, similar to those following finasteride therapy, are
associated with Gleason upgrading in the REDUCE trial, Bostwick and others
will likely offer the same caveats to the interpretation of the REDUCE
trial as they posited for the PCPT.
Bottom Line:
Although the evidence is still being weighed, currently the preponderance
of evidence suggests that finasteride treatment does not lead to the
development of more aggressive prostate cancer.
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