Finasteride & Promotion of High-Grade Prostate Cancer

Science Other Studies
#1

Finasteride (Propecia) and the Promotion of High-Grade Prostate Cancer

PDF: content.karger.com/ProdukteDB/pr … =87057.pdf

[Archives of Dermatology 2004;140:885–886]

W.R. Pitts, Jr.
Associate Clinical Professor (Urology), New York Presbyterian/Weill Cornell Medical College, New York, NY, USA

Correspondence: The phase 1 trials of finasteride (Propecia/Proscar; Merck) have shown that finasteride at 1 mg (Propecia) as well as finasteride at 5 mg (Proscar) blocks 5a-reductase.

The genetic, biochemical, epidemiological, experimental, and clinical reasons for my warning [1, 2] 3 years ago that use of finasteride promotes prostate cancer have been confirmed by the findings of a finasteride chemoprevention trial [Prostate Cancer Prevention Trial (PCPT)] involving 18,882 men followed up for 7 years.

The trial was stopped after 9,060 men underwent biopsy during the trial or at the end of 7 years. It was found that ‘finasteride prevents or delays the appearance of prostate cancer’ by 24.6% [fi nasteride, 803/4,368 (18.4%); placebo, 1,147/4,692 (24.4%)] but ‘increased the risk of highgrade prostate cancer’ by 67% [finasteride, 280/757 (37%); placebo, 237/1,068 (22.2%) (p 0.001)] in men diagnosed as having prostate cancer.

At 7 years 52% of the tumors in the finasteride treated men were high grade vs. 31% in the placebo group… If one looks at the positive biopsy rate in the patients with an elevated PSA (prostate-specific antigen) or abnormal digital rectal examination (DRE) (i.e. biopsied ‘for cause’), finasteride only reduced the positive biopsy rate in those patients by 10% (29.5% placebo vs. 26.5% finasteride).

The ‘end of study’ biopsies of the men who did not undergo biopsy during the 7 years (no PSA 4.0 ng/ml, no induration on DRE) showed a 60% increase in high-grade prostate cancer [finasteride, 92/364 (25.3%); placebo, 89/564 (15.8%) (p 0.001)].

Even with intensive screening, high-grade prostate cancer was promoted without warning by finasteride (Propecia). The suggestion by Dr. Peter Scardino in his editorial in the New England Journal of Medicine that young men (35 years old) might have the ‘added benefit of cancer prevention’ is not correct, as these men will have the added risk for promoting high-grade prostate cancer for over 50 years while using finasteride, 1 mg (Propecia, 1 mg).

Principal investigator Ian M. ‘Thompson, MD, also confused the issue of low dose finasteride (Propecia, 1 mg) and high-dose finasteride (Proscar, 5 mg) (Oncology Times, July 25, 2003, and August 10, 2003). The PCPT was stopped in March 2003 because finasteride promoted high-grade (Gleason scores 7, 8, 9, 10) prostate cancer.

Dermatologists should heed the warnings of the PCPT and cease using Propecia (finasteride) and nonprescription blockers of ‘the bad body chemical DHT [dihydrotestosterone]’ (e.g., Hair Advantage, Avocor) for alopecia.

1 Pitts WR Jr: Chemoprevention of urological cancer (letter). J Urol 2000;163:1260–1261.

2 Pitts WR Jr: Prostatic intraepithelial neoplasia and putative precursor lesions of prostate cancer: a clinical perspective (letter). BJU Int 2001;88:
985–986.

#2

Finasteride reduced prostate cancer but led to more high grade tumours and sexual side effects

British Medical Journal
ebm.bmj.com/cgi/reprint/8/6/183.pdf

Attached PDF.
Finasteride reduced prostate cancer but led to more high grade tumours and sexual side effects.pdf (69.5 KB)

#3

The influence of finasteride on the development of prostate cancer

Ian M. Thompson, M.D.,New England Journal of Medicine 2003;
349:215-224 (July 17th)

To date, the management of prostate cancer, has focused on early diagnosis and treatment.

However, the development of prostate cancer is a long-term process involving multiple steps, and it has been suggested that prevention may be a more effective approach The Prostate Cancer Prevention Trial was undertaken to determine whether finasteride can reduce the prevalence of prostate cancer among initially healthy men during a seven-year study period.

Finasteride, an inhibitor of 5a-reductase, inhibits the conversion of testosterone to dihydrotestosterone, the primary androgen in the prostate, and therefore may reduce the risk of prostate cancer.

At entry 18,882 men 55 years of age or older who were considered to have a low risk of prostate cancer, (as indicated by a normal digital rectal examination and a serum PSA level of no more than 3.0ng per millilitre) were randomly assigned to treatment with finasteride (5 mg per day) or placebo for seven years. Prostate biopsy was recommended if the annual PSA level, adjusted for the effect of finasteride, exceeded 4.0 ng per milliliter or if the digital rectal examination was abnormal.

It was anticipated that 60 percent of participants would have prostate cancer diagnosed during the study or would undergo biopsy at the end of the study. The primary end point was the prevalence of prostate cancer during the seven years of the study. Prostate cancer was detected in 803 of the 4368 men in the finasteride group who had data for the final analysis (18.4 percent) and 1147 of the 4692 men in the placebo group who had such data (24.4 percent), for a 24.8 percent reduction in prevalence over the seven-year period (95 percent confidence interval, 18.6 to 30.6 percent; P<0.001).

Tumors of Gleason grade 7, 8, 9, or 10 were more common in the finasteride group (280 of 757 tumors [37.0 percent], or 6.4 percent of the 4368 men included in the final analysis) than in the placebo group 237 of 1068 tumors [22.2 percent], P<0.001 for the comparison between groups; or 5.1 percent of the 4692 men included in the final analysis, P=0.005 for the comparison between groups). Sexual side effects were more common in finasteride-treated men, whereas urinary symptoms were more common in men receiving placebo.

The authors concluded that finasteride prevents or delays the appearance of prostate cancer, but this possible benefit and a reduced risk of urinary problems must be weighed against sexual side effects and the increased risk of high-grade prostate cancer.

The accompanying editorial points out that although finasteride reduced the cumulative incidence of cancer in the PCPT trial, the reduction was relative to the incidence in a control group in which biopsy was recommended for all men, regardless of risk factors — an approach that is destined to lead to the overdetection of histologically identified cancers of little clinical significance.

In the placebo group, cancer was detected four times as often as was expected ( in 24.4 percent rather than 6 percent of the men.) As the malignant potential of such cancers is unknown, there is no evidence to suggest that any benefit would be worth the risk associated with treatment.

Furthermore, the study results suggest that finasteride may accelerate the growth of highgrade cancers, which may pose a threat to life and health if they are not treated successfully (5.1 percent of men in the placebo group and 6.4 percent of those in the finasteride group had a cancer with a Gleason score of 7, 8, 9, or 10 which contain poorly differentiated components that are known to behave aggressively.)

Finally, the effects of finasteride on sexual function lessen the attractiveness of the drug as a preventive agent.

#4

This should put some minds at ease:

This was taken from Reuters 9/11/07
reuters.com/article/health-S … 12?sp=true

Prostate drug cleared of causing aggressive tumors
By Maggie Fox, Health and Science Editor

WASHINGTON, Sept 11 (Reuters) - A hair-loss drug that can also prevent prostate cancer may offer a third benefit by helping doctors detect the most aggressive prostate tumors earlier, U.S. and Israeli researchers reported on Tuesday.

They said they could dispel fears that finasteride might somehow cause the high-grade tumors.
Two studies published in the Journal of the National Cancer Institute show that the drug appears to be keeping the prostate gland small, making it easier to find dangerous tumors inside or on the surface.

“It appears that a man concerned about prostate-cancer risk, who is having a PSA test on a regular basis, will not only reduce his risk of prostate cancer if he takes finasteride, but will help find the cancers that pose the highest risk,” Dr. Ian Thompson of the University of Texas Health Science Center at San Antonio said in a statement.

An estimated 219,000 U.S. men will this year be diagnosed with cancer of the prostate, a walnut-sized gland that makes fluid for semen, and 27,000 will die of it, according to the American Cancer Society.

Finasteride, available generically but also sold as a hair loss drug by Merck and Co (MRK.N: Quote, Profile, Research) under the brand name Propecia, can reduce the risk of prostate cancer by 25 percent.

Diagnosing prostate cancer is tricky. The gland can enlarge naturally, and it also produces a protein called prostate specific antigen or PSA.

Doctors can feel an enlarged gland with a finger, or can measure PSA in the blood. PSA goes up as the prostate enlarges, but it also rises if there is a tumor in the gland.

A biopsy can find cancer, but doctors take samples randomly and can easily get several pieces of healthy tissue instead of a nearby tumor.

When finasteride was studied for its potential in preventing cancer, researchers noticed that the men who did get cancer were slightly more likely to have aggressive tumors.

It was feared that finasteride itself somehow made cancer worse if it was already present, although it lowered the overall risk of cancer by nearly 25 percent. Yael Cohen of Gamida Cell in Jerusalem and colleagues found that prostate size in the finasteride group was 25 percent smaller than in men who got placebos – making it easier to find the tumors.

Dr. Scott Lucia of the University of Colorado Health Sciences Center in Denver and colleagues made similar findings.

“This report … should help lessen fears that finasteride somehow causes more aggressive prostate cancer,” Dr. Frank Meyskens at the University of Texas Southwestern, who helped coordinate the original trials, said in a statement.

#5

Hormonal treatment for male-pattern hair loss: implications for cancer of the prostate?

blackwell-synergy.com/doi/fu … 02.03003.x

Conclusions:

"The idea of taking a pill to conquer MPHL is attractive and will almost certainly meet with great demand from a grateful audience of men. This is surely a welcome development. However, the possible implications for prostate cancer diagnosis and management may not be known for years, and this must be entirely appreciated by both the patient and the doctor when prescribing this medication.

PSA assays are usually given to one or two decimal places; the danger of losing this accuracy by converting the result to a ‘best-guess’ approximation has to be fully considered and is not acceptable as good science. Long-term studies into PSA reduction by finasteride 1 mg are lacking but are clearly warranted; many of the current studies into PSA changes are relatively short-term and funded by the pharmaceutical industry, therefore raising the issue of possible bias. Regular symptomatic enquiry, with a DRE of the prostate and long-term monitoring of PSA for patients on finasteride 1 mg, should be considered until such details are established."

#6

Validation of the Pitts unified theory of prostate cancer, late-onset hypogonadism and carcinoma: the role of steroid 5a-reductase and steroid aromatase

www3.interscience.wiley.com/cgi- … 4/PDFSTART

Selected bits…

"… Without steroid 5
α-reductase (5AR) I and
II mRNA in Gleason 4, 5 prostate cancer
there is no 5AR I and II in such disease [1].
Genetic and epigenetic factors lower 5AR
and are associated with increased deaths
from prostate cancer deaths.

Pitts predicted
[2–5] that finasteride (Prostate Cancer
Prevention Trial, PCPT) and, in 2005 [6],
dutasteride (Reduce with Dutasteride
Cancer Events) would increase Gleason
4, 5 prostate cancer by lowering 5AR by
70–90%.

The PCPT [7–11] used finasteride
to lower 5AR by 70% and reported a 68%
increase in the incidence and a 200%
increase in the prevalence of Gleason 4, 5
prostate cancer (n.b. predicted prognosis of
grade 4, 5 prostate cancer same with/without
finasteride: “finasteride”/“native” prostate
cancer equally malignant).

The PCPT validated
the ‘Pitts unified theory of prostate cancer’,
i.e. Gleason 4, 5 prostate cancer is promoted
by low 5AR and increased steroid aromatase"

… "Decreasing 5AR by
90% results in DHT decreasing by 35 times,
testosterone increasing by 20 times, and
oestrogen increasing by 19 times. The same
changes are found in Gleason 4, 5 prostate
cancer.

Oestrogen plus testosterone increases
the oestrogen proliferation by a factor of 100.
Low 5AR results in unchecked prostatic
epithelial cell proliferation from increased
oestrogen without the apoptosis mediated by
DHT (i.e. carcinogenesis)"

"… In obesity the adipose tissue has steroid
aromatase that produces a high oestrogen
level, which down-regulates the
hypothalamic-pituitary gonadal axis, and
both testosterone and sperm production
decrease.

Blocking the steroid aromatase
conversion of testosterone to oestrogen
with anastrozole lowered serum oestrogen
in obese (BMI >35 kg/m2) infertile men,
from 46.0 to 28.9 pg/mL, increased
testosterone from 295 to 445 mg/dL, and
increased the testosterone/oestrogen ratio
(255%:stuck_out_tongue_winking_eye: <0.001 for all differences) without
increasing bone turnover or osteoporosis
from oestrogen/testosterone deprivation
by LHRH agonists or orchidectomy [29–33].

Late-onset hypogonadism (decreased
androgen and sperm production) could be
treated by ‘resetting’ LHRH by lowering
oestrogen and increasing testosterone
with aromatase inhibitors, which would block
the adverse effects of increased testosterone
on incidental prostate cancer [12,13]."

#7

Kinda effed up because proscar is designed to stop BPH.

#8

Symposium on Androgen Action in Prostate Cancer
cancerres.aacrjournals.org/cgi/c … 64/19/7178

[b]There appears to be a link between blood androgen levels and risk of prostate cancer; this has been supported by the finasteride chemoprevention trial wherein finasteride, a 5-reductase inhibitor, reduces the overall risk of prostate cancer by 25%.

The finding from this trial that those treated with finasteride have a 20% increased likelihood of developing high-grade prostate cancer is supported by findings from the Health Professionals’ Follow-up Study. This study suggests that individuals with lower testosterone levels years before diagnosis who develop prostate cancer are more likely to develop high-grade prostate cancer. [/b]

Androgen deprivation therapy remains the mainstay of therapy for men with advanced prostate cancer. The use of androgen-deprivation therapy in early prostate cancer has been established in men with locally advanced and high-risk prostate cancer when radiation therapy is used but not before surgery. The optimal duration of androgen-deprivation therapy has yet to be determined.

Whereas earlier androgen-deprivation therapy appears to prolong survival, this has not been rigorously demonstrated in men with recurrent prostate cancer, nor has optimal timing been established. Because this is the case, one needs to consider the side effects of androgen-deprivation therapy as well in this population.

Whereas the androgen receptor appears to play a key role in all aspects of prostate and prostate cancer development, many fundamental aspects of its function and its interaction with other molecules are unknown but under study.

Of particular note is the continued presence of androgen receptor in the hormone-refractory state. Multiple mechanisms to support continued androgen receptor function can be demonstrated. This includes the persistence of low levels of androgen in the hormone-refractory prostate gland, the amplification of androgen receptor, the overexpression of androgen receptor, and in some cases, the mutation of androgen receptor giving rise to either constitutively activated androgen receptor or mutated androgen receptor that responds to nonandrogen ligands. There is evidence for androgen receptor activation through altered expression of coregulatory molecules and through other signaling pathways.