Finasteride
Dick Smith
reported in Time a couple months ago. Dr Catalona was very kind and
emailed me back an attachment of his thoughts. I believe it will go
into his Quest newsletter soon.
I'm still trying to digest it, but will admit I don't understand parts
of it, but it *sounds* like the problem with Finasteride is that if
you at the early stages of prostate cancer Finasteride can hide the
rise in the PSA and therefore delay a biopsy when the cancer is most
likely curable.
I'm interested in any thoughts on Finasteride.
Thanks.
The Finasteride Controversy
Questions About Safety Remain
by William J. Catalona, MD
An article in the New York Times (June 15, 2008) suggested that men
might be well advised to take finasteride (Proscar) every day to
prevent prostate cancer.
I believe that important, unanswered questions remain about the safety
and efficacy of finasteride for prostate cancer prevention.
I currently do not recommend its off-label use for prevention to my
patients.
Theoretical Basis
The US Food and Drug Administration (FDA) approved Finasteride
(Proscar) for the treatment of benign prostate enlargement. A similar
drug approved for this purpose is dutasteride (Avodart).
The most potent male hormone called dihydrotesosterone is associated
with enlargement of the prostate. Dihydrotestosterone is created
from the male hormone, testosterone, through enzyme activity. The
rationale for using these drugs is they block the conversion of
testosterone to dihydrotesosterone and therefore reduce or prevent
prostate enlargement. The PSA levels in men taking finasteride for
treatment of benign prostate enlargement usually decrease by 30% to
70% after one year and even more after more prolonged treatment.
The theoretic basis for using finasteride for prevention of prostate
cancer is that almost all prostate cancer cells are responsive to male
hormones (androgens). Because androgens might stimulate the change of
normal prostate cells into prostate cancer cells and because androgens
stimulate growth of prostate cancer cells after they have become
malignant; then, the argument goes, if finasteride or dutasteride can
slow or prevent the production of dihydrotesosterone, they might slow
or prevent the development and progression of prostate cancer.
The Study
A Prostate Cancer Prevention Trial was conducted to test whether
finasteride could prevent prostate cancer over a relatively short 7-
year study interval. Approximately 18,000 men were randomized to
receive 5 mg per day of finasteride or placebo. Of these men, only
4,800 and 5,100, respectively, were included in the analysis of the
results of the study, in my opinion, compromising to some extent the
validity of the results. Prostate biopsy was recommended for men with
abnormal PSA or digital rectal examination screening results during
the study.
Overall, the incidence of prostate cancer in men who received
finasteride was 25% lower, a seemingly good result.
But a surprising and alarming 26% increase in high-grade tumors
(Gleason score of 7-10) was reported for those on finasteride and
diagnosed with prostate cancer.
That finding raised questions about whether finasteride actually
induced high-grade prostate cancer. In fact, if the endpoint of the
study had been the incidence of aggressive, high-grade prostate
cancer, the conclusion would have been that finasteride was associated
with an increased risk for life-threatening cancer.
In reviewing what happened during the study that might account for
this surprising result, it was found that fewer biopsies had been
recommended and performed for “abnormal” PSA results in the group
taking finasteride. Also, among men who were advised to have a
biopsy, those taking finasteride had a lower compliance rate. I
presume this was so because their PSA levels had decreased.
Other Findings Should Cause Concern
Overall, among the men who were recommended to have a biopsy “for
cause” (PSA or digital rectal examination findings), 26.5% in the
finasteride group were diagnosed with prostate cancer as compared with
29.5% in the placebo group.
This far-lower 10% difference in cancer incidence in the men who
actually underwent a biopsy in clinical setting where biopsies are
normally performed because of an abnormal screening test is, in fact,
not statistically significant for prevention of prostate cancer.
Study participants who never had abnormal screening tests during the
study were offered “end-of-study” biopsies, and of those who agreed to
have the biopsy, 10% in the finasteride group and 15% in the placebo
group were positive for cancer. Not unexpectedly, the tumors diagnosed
because of abnormal screening results were more aggressive and more
advanced, e.g., 48% in the finasteride group were high grade versus
29% in the placebo group.
Of concern was that in this “end-of-study” biopsy group who were found
to have prostate cancer, 25% were high-grade in the finasteride group
and 16% were high-grade in the placebo group.
Of even more concern is that these “end-of-study” cancers would not
have been detected at the time in a real-world setting where biopsies
are only recommended when screening tests are considered abnormal.
Interpretations Vary
The interpretation of the Prostate Cancer Prevention Trial has been
widely debated.
The initial arguments for using finasteride were that by reducing the
overall cancer detection rate, it might reduce the number of men
diagnosed with prostate cancer and prevent unnecessary testing,
biopsies, and treatment and its side effects.
These arguments resonate with certain segments of the medical
community who are concerned that current widespread prostate cancer
screening methods detect many cancers that would be best left
undetected. By preventing or delaying the detection of prostate cancer
with finasteride, they believe that over-diagnosis and over-treatment
of prostate cancer might be partially remedied.
But in my interpretation of the study results, they resonate wrong.
Questioning Off-label Use
Arguments questioning the recommendation for off-label use of
finasteride for “prevention” of prostate cancer are too strong to
ignore.
Finasteride inconsistently reduces PSA levels in different men, making
it difficult to track what the “true” PSA values are over time.
Finasteride fails to reduce PSA velocity (increases) in men with high-
grade prostate cancer and fails to induce objective responses in men
with metastases.
Finasteride’s so-called “preventive” effects in the Prostate Cancer
Prevention Trial occurred far too early and did not increase much over
time.
One of the most appropriate conclusions to be directly drawn from the
Prostate Cancer Prevention trial is that finasteride prevents PSA-
prompted biopsies, not prostate cancer. And that situation can result
in diagnosis and treatment of prostate cancer when it’s too late for
cure.
Position of Original Investigators
In fairness to the investigators of the Prostate Cancer prevention
Trial who disagree with my position, they have completed several
extensive post-hoc analyses. These studies reported several possible
countervailing features of finasteride therapy that they claim
overcome the intrinsic biopsy bias.
These include: improved sensitivity of PSA for overall and high-grade
cancer detection, improved sensitivity of digital rectal examination
for cancer detection, and more accurate grading of high-grade cancer.
Thus, they reported that that shrinkage of the prostate induced by
finasteride may enhance the performance characteristics of PSA and
rectal examination testing and increase the likelihood of a biopsy
detecting a small cancer or a high-grade cancer.
They reported that Gleason scores may be more accurate in the
finasteride arm than in the placebo arm because a greater proportion
of the prostate is being sampled and that patients who developed
prostate cancer in the finasteride group had a lower tumor volume and
other potential aggressive features across all tumor grades compared
with the placebo group.
They took the results from the 25% of the men in the study who
underwent radical prostatectomy and used them in statistical models
that included assumptions that may or may not accurately reflect
reality to impute what the results would have been if all men had
undergone radical prostatectomy. By this method, they arrived at the
opposite conclusion that finasteride actually did not increase the
risk of high-grade prostate cancer but rather decreased the risk. They
concluded that men aged 55 years or older have no need to be concerned
about the risk of high-grade prostate cancer with finasteride.
Questions Left Unanswered
However, I believe that too many fundamental questions are still left
unanswered.
Any treatment that reduces androgen effects is considered “hormonal
therapy,” because many, but never all, prostate cancer cells cease to
proliferate or die when androgenic stimulation is substantially
reduced.
A central question, therefore, is whether taking finasteride is true
“chemoprevention” or whether it is merely a weak form of early
hormonal therapy that masks and delays the detection of prostate
cancer.
An alternative hypothesis to finasteride providing true
chemoprevention of prostate cancer that is consistent with the
available data is as follows:
(1) Finasteride cannot prevent prostate cancer; it merely delays
progression of low-grade prostate cancer;
(2) Finasteride suppresses the growth of normal prostate tissue,
benign prostate hyperplasia tissue, and low-grade prostate cancer
cells, but cannot control aggressive, high-grade cancer, and
eventually, if given time, high-grade cancer will emerge.
It is possible that in a clinical trial with longer follow-up (15 to
20 years), it might turn out that “masking” of high-grade prostate
cancer by finasteride until it is too late for cure might outweigh any
benefits from delaying or preventing the detection of lower-grade
cancers.
If a prostate cancer chemoprevention study has a limited time span of
7 years, a delay in cancer detection would produce the appearance of a
decrease in cancer incidence. However, with longer follow-up, this
apparent benefit would substantially diminish or disappear.
This situation was, in fact, the case in the Prostate Cancer
Prevention Trial in the patients who had a biopsy procedure “for
cause”. Seven years after randomization, when they had biopsied 7.1 %
of men in the placebo arm and 7.0% in the finasteride arm, they
diagnosed a nearly equal number of cancers (124) in the placebo arm
and in the finasteride arm (122); however, 64 (52%) of the cancers in
the finasteride arm were high-grade as compared with only 38 (31%) in
the placebo arm.
Until further information is available, I recommend only the FDA-
approved use of finasteride in men with severe symptoms from a benign
enlarged prostate gland that have not responded to alpha-blocker
therapy (such as Flomax) and do not want to undergo surgery for relief
of urinary obstruction.
I warn them that finasteride might mask high-grade prostate cancer.
I perform a prostate biopsy to rule out cancer before starting
finasteride, and I recommend a repeat biopsy if the PSA rises while
the patient is on finasteride treatment after I have ruled out other
possible causes for the PSA increase.
A Hypothetical Patient
A man who has benign prostate enlargement as well as not yet detected
prostate cancer – that is largely composed of low-grade cancer cells
but also contains a small proportion of high-grade cancer cells – is
started on finasteride therapy for cancer prevention.
With the initiation of finasteride therapy, the normal prostate cells
regress, decreasing the PSA contribution from normal prostate
tissue.
The benign enlargement tissue also regresses, additionally decreasing
the PSA from the benign hyperplasia component. And the low-grade
prostate cancer regresses, further decreasing the PSA level.
However, the high-grade prostate cancer cells continue to grow
unchecked and, because high-grade prostate cancer produces less PSA
per cell, PSA levels might not increase until regression of benign and
low-grade cancer is near complete.
Therefore, by the time the PSA begins to rise or reach the threshold
for biopsy, most of the remaining prostate cancer is composed of
aggressive, high-grade disease that has less favorable prognosis.
In contrast, if this man were not taking finasteride, his PSA would
not decrease but rather would continue to rise and reach the biopsy
threshold sooner.
Moreover, men with a rising PSA would be more likely to comply with
the recommendation for a biopsy, and the biopsies would be found to
contain relatively more low-grade and less high-grade prostate cancer.
Lud
Thanks for the post.
Lud
I.P. Freely
> I emailed Dr Catalona regarding the Finasteride study that was
> reported in Time a couple months ago. Dr Catalona was very kind and
> emailed me back an attachment of his thoughts. I believe it will go
> into his Quest newsletter soon.
>
> I'm still trying to digest it, but will admit I don't understand parts
> of it, but it *sounds* like the problem with Finasteride is that if
> you at the early stages of prostate cancer Finasteride can hide the
> rise in the PSA and therefore delay a biopsy when the cancer is most
> likely curable.
>
> I'm interested in any thoughts on Finasteride.
> The Finasteride Controversy
> Questions About Safety Remain
> by William J. Catalona, MD
>
>
> An article in the New York Times (June 15, 2008) suggested that men
> might be well advised to take finasteride (Proscar) every day to
> prevent prostate cancer.
> I believe that important, unanswered questions remain about the safety
> and efficacy of finasteride for prostate cancer prevention.
> I currently do not recommend its off-label use for prevention to my
> patients.
SNIP
Johns-Hopkins’ October “Health After 50” newsletter article titled “Does
Proscar prevent PC?” addresses the same study. its opening statement was
essentially, “Men who took finasteride were 25% less likely to be
diagnosed with prostate cancer … but those who did develop PC were 68%
more likely to develop high-grade disease”. My immediate reaction was
“Isn't it obvious that artificial PSA suppression => fewer biopsies =>
later detection => more advanced PC?”
yada yada yada followed, subsequently opposed by Walsh with “finasteride
=> PSA reduction => fewer biopsies => less and/or later detection =>
more advanced cases.”
You and I, and probably everyone here, were in good company and probably
right with our rather obvious initial interpretation.
I.P.
Steve Jordan
> I emailed Dr Catalona regarding the Finasteride study that was
> reported in Time a couple months ago. Dr Catalona was very kind and
> emailed me back an attachment of his thoughts. I believe it will go
> into his Quest newsletter soon.
>
> I'm still trying to digest it, but will admit I don't understand parts
> of it, but it *sounds* like the problem with Finasteride is that if
> you at the early stages of prostate cancer Finasteride can hide the
> rise in the PSA and therefore delay a biopsy when the cancer is most
> likely curable.
That issue was addressed in a May 18, 2008 article in Cancer Prevention
Research published online. Perhaps Catalona had not seen it.
The article, "Finasteride Does Not Increase the Risk of High-Grade
Prostate Cancer: A Bias-Adjusted Modeling Approach," concluded, "These
collective results suggest that the observed, unadjusted higher risk of
high-grade disease with finasteride seems to have been due to
facilitated diagnosis resulting primarily from increased biopsy
sensitivity with finasteride."
See, http://cancerpreventionresearch.aacrjournals.org/ where a PDF of
the article can be downloaded.
It's interesting to note that the New York Times published, on June 15,
2008, an article entitled, "New Take on a Prostate Drug, and a New
Debate." It cites the famous uro Peter Scardino as follows, "Dr. Peter
Scardino, chairman of the department of surgery at Memorial
Sloan-Kettering Cancer Center, originally thought finasteride was
dangerous but now recommends its use." This is the article that Catalona
criticises.
As my cardiologist says with a grin, "welcome to medicine."
Well, I'm not hyperventilating in alarm over it. The May 18 article has
good foundation, IMO as a non-medic just like the others on this thread.
Regards,
Steve J
Steve Jordan
> That issue was addressed in a May 18, 2008 article in Cancer Prevention
> Research published online. Perhaps Catalona had not seen it.
Oops. Obviously, C. had seen it.
Regards,
Steve J