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DjinTonic 01-09-2020 05:02 AM

5α-Reductase Inhibitors (e.g., finasteride) and PCa risk/benefit
 
This topic came up in a recent thread. Here are some recent publications I had flagged on the question of the risks/benefits of these meds for PCa, plus a couple that turned up with a very quick search.

[b]Risk of Prostate Cancer in Men Treated With 5α-Reductase Inhibitors—A Large Population-Based Prospective Study[/b] [2018, Full Text]

https://academic.oup.com/jnci/article/110/11/1216/4935092

[QUOTE]Results
Of the 333 820 men in the cohort, 23 442 (7.0%) were exposed to 5-ARI at some time during the study period of eight years. Treatment with 5-ARI decreased the risk for overall PC, and the effect was larger with longer time of exposure (0.1 to 2 years: hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.71 to 0.93; 2 to 4 years: HR = 0.39, 95% CI = 0.32 to 0.47; 4 to 6 years: HR = 0.40, 95% CI = 0.31 to 0.52; and 6 to 8 years: HR = 0.31, 95% CI = 0.16 to 0.60). Specifically, 5-ARI decreased the risk for PC with Gleason Scores 6 and 7 but did not statistically significantly affect the long-term risk of being diagnosed with a PC with a Gleason Score of 8 to 10 with up to eight years of treatment.

Conclusions
Treatment with 5-ARI for lower urinary tract symptoms is safe with respect to prostate cancer risk.[/QUOTE]

[b]Reduced Risk of Prostate Cancer With 5α-Reductase Inhibitors[/b] [2018, Editorial on above study]

https://academic.oup.com/jnci/article/110/11/1159/4935098

[QUOTE]The unique contribution of the study from Wallerstadt et al. that cannot be addressed by prior randomized studies of 5-ARIs is the study population, including men with PSA levels greater than 3.0 ng/mL. The lack of an increase in diagnosis of high-grade PCA should provide reassurance to patients/physicians who are receiving/prescribing 5-ARIs for management of LUTS. Ultimately, however, it will require long-term follow-up of phase III clinical trials of these agents to confirm the true impact of these agents on risk of PCA morbidity/mortality.[/QUOTE]

[b]Association between 5α-reductase inhibitors therapy and incidence, cancer-specific mortality, and progression of prostate cancer: evidence from a meta-analysis[/b] [2019, Full Text]

http://www.ajandrology.com/preprintarticle.asp?id=270594

[QUOTE]Conclusion
Our results indicated that 5-ARI treatment exhibited a protective role on the incidence of low-grade and intermediate-grade prostate cancer, but not high-grade cancer. The results also showed that there was no close link between 5-ARI treatment and prostate cancer-specific mortality. In addition, it is important to note that 5-ARI treatment has a protective role that has a dramatic benefit by delaying the progression of low-risk tumors.[/QUOTE]

[b]Association of Treatment With 5α-Reductase Inhibitors and Prostate Cancer Mortality Among Older Adults[/b] [2019 Research Letter]

https://jamanetwork.com/journals/jamanetworkopen/article-abstract/2753244

[QUOTE]Discussion
This cohort study found that 5-ARI users presented with higher adjusted PSA levels and PC disease burden. They also had worse PCSM and ACM, but not worse noncancer mortality. These results are consistent with our recently published findings3 that observed that among US veterans, 5-ARI use was associated with worse PCSM (subdistribution HR, 1.39; 95% CI, 1.27-1.52; P < .001) and ACM (HR, 1.10; 95% CI, 1.05-1.15; P < .001). Like other studies,3-6 we found that comorbidities, unmarried status, old age, low income, and black race were risk factors for PCSM, which adds validity to our findings. One study limitation included the possibility of misclassification bias, in which 5-ARIs were not used as prescribed.

Our results suggest a need for increased awareness of 5-ARI–induced PSA suppression, clearer guidelines for early PC detection, and systems-based mechanisms to help improve care for men using 5-ARIs.[/QUOTE]

[PC-specific mortality (PCSM), all-cause mortality (ACM)]

[b]Association of Treatment With 5α-Reductase Inhibitors With Time to Diagnosis and Mortality in Prostate Cancer[/b] [2019]

https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2732119?widget=personalizedcontent&previousarticle=2752854

[QUOTE]Conclusions and Relevance Results of this study demonstrate that prediagnostic use of 5-ARIs was associated with delayed diagnosis and worse cancer-specific outcomes in men with prostate cancer. These data highlight a continued need to raise awareness of 5-ARI-induced PSA suppression, establish clear guidelines for early prostate cancer detection, and motivate systems-based practices to facilitate optimal care for men who use 5-ARIs.[/QUOTE]

(This study sparked a back-and-forth of letters to the editor and author replies, but I don't have ready access to them.)

[b]Prostate Cancer Prevention and Finasteride: A Conversation with NCI’s Dr. Howard Parnes[/b] [2019 Blog Interview]

https://www.cancer.gov/news-events/cancer-currents-blog/2019/prostate-cancer-prevention-finasteride-parnes

[QUOTE]There was a 25% relative reduction in prostate cancer risk in PCPT. Were you surprised by the large reduction?

The finding that finasteride decreased the 7-year period prevalence of prostate cancer by 25% was actually very much in-line with our expectations.[/QUOTE]

[Prostate Cancer Prevention Trial (PCPT)]
____________________

As I mentioned in the other thread, I don't think we've seen the last word on this topic.

Just a reminder that even a reduced dose of finasteride (e.g. Propecia for hair loss) causes the same (approx. 50%) reduction in PSA (in time) as the full dose prescribed for BPH symptoms.

Djin

IADT3since2000 01-09-2020 05:26 AM

Re: 5α-Reductase Inhibitors (e.g., finasteride) and PCa risk/benefit
 
Djin,

Thanks for your diligent work putting this together!

Most of the findings are in line with what I understand about these drugs - finasteride/Proscar and dutasteride/Avodart, one of the other of which I have been taking since the fall of 2000 as part of my anti-prostate cancer program: these drugs lower risk of getting low-risk prostate cancer (such as GS-6 and below), don't have much effect except improved detection on GS-8 - 10, and have a doubtful effect on GS-7, meaning not much eliminated, if any, but improved detection.

I hope to get time to look at the few studies suggesting an adverse influence, such as a seeming increase in prostate cancer specific mortality, of 5-ARI drugs; this is out-of-line with most research, which indicates a substantial favorable influence. One sad circumstance is that some doctors do not understand how these drugs lower the PSA baseline, and, while that improves the value of the PSA signal for cancer, if misunderstood (ignorance) can result in a delayed diagnosis which often means increased risk.

Jim

- - - - - - - - - - - - - - - - - - - - - - - -
[SIZE="1"]Diagnosis Dec 1999 PSA 113.6 (first ever), age 56
Gleason 4+3=7 (J. Epstein, JHU), all cores +, most 100%; "rock hard" prostate with ECE - stage 3, PNI, PSADT determined later 3-4 months; technetium bone scan and CT scan negative; prognosis 5 years.
Later ProstaScint scan negative except for one suspicious small area in an unlikely location. ADT Lupron as first therapy, in Dec 1999, then + Casodex in March 2000, then + Proscar and Fosamax in Sep 2000. Rejected for surgery January 2000; offered radiation but told success odds were low; switched to ADT only vice radiation in May 2000, betting on holding the fort for improved technology; PSA gradual decline to <0.01 May 2002. Commenced intermittent ADT3 (IADT3) with first vacation from Lupron & Casodex. Negative advanced scans in 2011 (NaF18 PET/CT for bone) and 2012 (Feraheme USPIO for nodes and soft tissue). With improved technology, tried TomoTherapy RT, 39 sessions, in early 2013, plus ADT 3 in support for 18 months (fourth round of IADT3), ended April 2014. Continuing with Avodart as anti-recurrence shield. Current PSA remarkably low at <0.01; apparently cured.. Supportive diet/nutrition, exercise, supportive medications during this journey, as well as switches in antiandrogen, 5-ARI, and bone drugs.
[/SIZE]

Prostatefree 01-09-2020 05:55 AM

Re: 5α-Reductase Inhibitors (e.g., finasteride) and PCa risk/benefit
 
Do any studies address the use of these hormone treatments in precipitating smaller higher risk cancer in the users?

DjinTonic 01-09-2020 06:01 AM

Re: 5α-Reductase Inhibitors (e.g., finasteride) and PCa risk/benefit
 
[QUOTE=Prostatefree;5499817]Do any studies address the use of these hormone treatments in precipitating smaller higher risk cancer in the users?[/QUOTE]

Yes, I believe most of them do, but you'd have to go through them to learn the details other than what I've quoted. I had thought the current opinion was that, although there was initial concern, there is no increased risk of higher-grade PCa, but that may not be a unanimous view. The increased mortality rates cited in some of the studies would occur, I presume, as the results of an increase in high-grade cases.

(I would bring up the caveat that we are learning that a high-risk for metastasis potential cuts across [I]all [/I]Gleason scores.)

Djin

saros 01-09-2020 06:08 AM

Re: 5α-Reductase Inhibitors (e.g., finasteride) and PCa risk/benefit
 
Thanks. Here's one comment on the article:

[QUOTE]Re: Association of Treatment with 5α-Reductase inhibitors with Time to Diagnosis and Mortality in Prostate Cancer
Patrick C. Walsh European Urology Vol. 76, Iss. 5, November 2019

Expert’s comments:
We are told that 5-ARIs prevent prostate cancer and do not
increase the risk of high-grade disease. If this were true,
why did the men in this study who were treated with 5-ARIs
develop high-grade, lethal disease? Sadly, this is because we
have not been told the full truth. There is no 5a-reductase
enzyme in normal or malignant prostatic epithelial cells; it
is located in the stroma. Because higher-grade cancers
(Gleason >6) have little stroma, 5-ARIs have no effect in
reducing Gleason 7–10 disease. 5-ARI treatment reduces the
production of PSA by the stroma in benign prostatic
hyperplasia. To correct for this effect, men treated with a
5-ARI must multiply their level by 2.0 for the first 2 yr, by
2.3 for years 2–7, and by 2.5 after year 7 [3]. If patients do not
know this, they will not realize they may need a biopsy and
might miss the opportunity of being diagnosed with curable
disease. This explains the findings in this study.

In the original publication from the Prostate Cancer
Prevention Trial, which was a randomized, placebo controlled =
trial evaluating finasteride for the prevention
of prostate cancer, the authors reported a 25% reduction in
prostate cancer prevalence and a 68% increase in high-grade
disease [2]. Although the authors have argued that the
increase in high-grade disease was an artifact, in 2011 the
US Food and Drug Administration reported on their
independent reanalysis of the study and found that the
original published article was severely flawed [4]. They
concluded that in the clinical setting, if 150–200 men were
treated with a 5-ARI, there would be a reduction in only
three to four Gleason 6 cancers, no reduction in Gleason 7,
and an increase in one new case of Gleason 8–10 disease.
Sarkar et al [1] suggest that their results “include the
possibility that 5-ARIs inherently increase the risk of highgrade cancer”.

When I first prescribe 5-ARIs, I explain to patients the
importance of having their PSA measured regularly for as
long as they are taking the drug. I tell them why they need to
know those numbers and if their PSA ever increases they
need a biopsy. In patients taking a 5-ARI, PSA levels should
continue to go down for as long as they are taking them. If
their PSA ever goes up at all, the risk of cancer is increased
by a factor of three and the risk of high-grade disease by a
factor of six [5]. Urologists need to know the full truth about
drugs that have lethal potential.[/QUOTE]

DjinTonic 01-09-2020 06:14 AM

Re: 5α-Reductase Inhibitors (e.g., finasteride) and PCa risk/benefit
 
I question Walsh's statement: "In patients taking a 5-ARI, PSA levels should
[B]continue to go down for as long as they are taking them[/B]."

[Emphasis mine]

I believe that, assuming no PCa) after a number of months on one of these meds, men's PSA bottoms out at roughly 50% of their starting PSA, but does [B]not [/B]continue to decrease. A continuing decrease would be a heavy lift for a drug -- especially if one's BPH is continuing to produce more PSA-producing prostate tissue, as is often the case.

I note that Walsh attributes this family of meds with "lethal potential" yet continues to prescribe them, so the risk/benefit issue is with us.

Djin

IADT3since2000 01-09-2020 07:44 AM

Re: 5α-Reductase Inhibitors (e.g., finasteride) and PCa risk/benefit
 
[B]The Potential of Prostate Cancers Scored GS-6 and Lower to Metastasize: Dr. Klotz Says It's Extremely Low[/B]

At 9:20 today you wrote:

[QUOTE=DjinTonic;5499818]...

(I would bring up the caveat that we are learning that a high-risk for metastasis potential cuts across [I]all [/I]Gleason scores.)

Djin[/QUOTE]

My understanding is that [I]true[/I] Gleason 6 and lower cancers have an extremely low risk for metastasis. ("True" here means that a the cancer scored 6 was not underscored and that higher scoring cancer was not overlooked.) Dr. Klotz of Toronto has done research that backs that up, convincingly to me. Is there a credible research finding out there that that may not be the case?

Jim

- - - - - - - - - - - - - - - - - - - - - - - -
[SIZE="1"]Diagnosis Dec 1999 PSA 113.6 (first ever), age 56
Gleason 4+3=7 (J. Epstein, JHU), all cores +, most 100%; "rock hard" prostate with ECE - stage 3, PNI, PSADT determined later 3-4 months; technetium bone scan and CT scan negative; prognosis 5 years.
Later ProstaScint scan negative except for one suspicious small area in an unlikely location. ADT Lupron as first therapy, in Dec 1999, then + Casodex in March 2000, then + Proscar and Fosamax in Sep 2000. Rejected for surgery January 2000; offered radiation but told success odds were low; switched to ADT only vice radiation in May 2000, betting on holding the fort for improved technology; PSA gradual decline to <0.01 May 2002. Commenced intermittent ADT3 (IADT3) with first vacation from Lupron & Casodex. Negative advanced scans in 2011 (NaF18 PET/CT for bone) and 2012 (Feraheme USPIO for nodes and soft tissue). With improved technology, tried TomoTherapy RT, 39 sessions, in early 2013, plus ADT 3 in support for 18 months (fourth round of IADT3), ended April 2014. Continuing with Avodart as anti-recurrence shield. Current PSA remarkably low at <0.01; apparently cured.. Supportive diet/nutrition, exercise, supportive medications during this journey, as well as switches in antiandrogen, 5-ARI, and bone drugs.[/SIZE]

DjinTonic 01-09-2020 09:08 AM

Re: 5α-Reductase Inhibitors (e.g., finasteride) and PCa risk/benefit
 
[QUOTE=IADT3since2000;5499826][B]The Potential of Prostate Cancers Scored GS-6 and Lower to Metastasize: Dr. Klotz Says It's Extremely Low[/B]

At 9:20 today you wrote:


My understanding is that [I]true[/I] Gleason 6 and lower cancers have an extremely low risk for metastasis. ("True" here means that a the cancer scored 6 was not underscored and that higher scoring cancer was not overlooked.) Dr. Klotz of Toronto has done research that backs that up, convincingly to me. Is there a credible research finding out there that that may not be the case?

Jim[/QUOTE]

Jim, you may have missed a post of mine in another thread where a statement of mine wasn't clear or was misinterpreted. I'll paste it here.

-------------
I didn't mean to say G6 metastasizes when I said G6 disease (i.e., men with only G6 lesions) can progress and lead to metastatic PCa, i.e., higher-grade lesions can arise and they can metastasize.

There are a couple of separate issues regarding G6 status and metastases.

1) As mentioned, even though a biopsy finds nothing higher than G6, there could well be higher G lesions present. Those could metastasize.

2) [COLOR="RoyalBlue"][B]G6 themsleves [I]do not metastasize[/I].[/B][/COLOR] In every case where a man with a G6 post-op grade went on to metastatic PCa, when they went back and re-examined the prostate, they found higher-grade lesions that were missed.

AFAIK there has been one very instructive case of confirmed G6 metastasis! That is, all the metastases themselves were found to be G6. However, when they investigated the genetics of the mets, they found that the patient had pattern 3 adjacent to pattern 4 or 5 (I don't remember) in his prostate and a G6 cell(s) picked up the genetic material from the higher-grade that allows it to "go metastatic." So in this highly exceptional case, it was just a fluke that the G4 or 5 present didn't metastasize, but this "weaponized" G6 did.

Genetic studies have found that in the majority of cases all of one's metastases originate from a single lesion!
https://www.nature.com/articles/nm.1944

3) We know PCa is a heterogeneous disease. We see this all the time in biopsy reports. It it not known conclusively how higher-grade lesions form. One theory is that there are precursor cells, which give rise to a lesion with a certain G profile. There could be a change in these precursors that cause them to form higher-grade lesions.

Lesions seem to put out filament or tendril-like outgrowths that can lead to separate lesions. Perhaps pattern 3 can further mutate on division to a higher-grade, giving rise to pattern 4 or 5 clones elsewhere.

[I]The statement "G6 doesn't metastasize" can lead to a false sense of security, in that there is no guarantee that higher-grade lesions won't form, by whatever mechanism.[/I] These higher-grade lesions may have or develop the ability to metastasize. [I]This is reflected in the fairly large percentages of G6 men whose Decipher met-risk score comes back intermediate or high.[/I]

Back to AS. The figures I've seen show that although many men have to abandon AS because their G6 status has changed to G7, the number who slip through programs and actually have metastatic PCa at the time they abandon AS is [I]extremely[/I] small.
------------------------------

See Table 2 of this important Decipher study on the distribution of met risk across both G scores and pT staging at the time of RP:

[b]Decipher correlation patterns post prostatectomy: initial experience from 2342 prospective patients[/b]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133268/

Genomic testing is being stressed for G6 men contemplating AS not for the reason that their G6 needs a second look because it may actually be a G7 or higher. They are at risk because they have genetic markers that predict higher-grade lesions may arise, and[I] those lesions[/I] may metastasize.

See also:

[b]The Heterogeneity of Prostate Cancer: A Practical Approach[/b] [2018, Full Text]

https://www.karger.com/Article/FullText/477852

A figure there shows the "ancestor clone" hypothesis.

And

[b]When Can Patients With Gleason 6 Prostate Cancer Safely Undergo Active Surveillance?[/b] (Roundtable discussion with J. Epstein and others)

https://www.ascopost.com/issues/july-25-2018/when-can-patients-with-gleason-6-prostate-cancer-safely-undergo-active-surveillance/

[QUOTE]I explain to patients that nothing is 100% guaranteed. Even though we may tell patients that there is an 80% to 90% chance their cancer will not progress, it’s not 100%. But I reassure them that if they are closely monitored and we do regular repeat biopsies,[COLOR="Red"][b] if their cancer starts to advance in terms of grade or tumor volume[/b][/COLOR], they can elect to undergo therapy, either radiation or radical prostatectomy, and it is rare that their cancer will not be cured. It’s not 100%, but it’s rare.[/QUOTE] [J. Epstein]

[Emphasis mine]

Dr. Epstein is using "progress" as I was: you now have a lesion(s) of a grade >6.

Djin

IADT3since2000 01-09-2020 01:04 PM

Re: 5α-Reductase Inhibitors (e.g., finasteride) and PCa risk/benefit
 
[COLOR="Blue"][U]Finasteride for Prevention of Prostate Cancer? The December 1, 2010 FDA Advisory Committee Hearing[/U][/COLOR]

I am about to reply to saros’s post of 9:08 am today, but I first want to provide this resource which is an excellent way to understand what was presented at the hearing, including the visual images. I viewed the hearing, which was held in the DC metro area, live on a simulcast all day while I was on vacation in LA. I really wished I could have been there to speak in favor of finasteride.

By this time I had already been on the drug for more than ten years and was having great success with my intermittent triple androgen deprivation therapy (IADT3). I was well aware that Dr. Walsh, who vigorously opposed use of finasteride for prevention at the hearing, had an ingrained opposition to early use of ADT, including finasteride, which was precisely the approach that was proving successful for me.

While Dr. Walsh is justly revered for his pioneering surgical contributions and operating skill in prostate cancer circles, I, and a number of prominent medical oncologists and researchers (including some of Dr. Walsh’s Johns Hopkins colleagues), as well as many empowered patients, have long felt that he had/has an inadequate and misleading view of the roles drugs should play, especially ADT. To me, his presence at the hearing, which I believe was facilitated by the hearing chairman, was, to borrow a thought from “The Untouchables” movie, like bringing a knife to a drug fight. :mad:

Major doctors in the prostate cancer world took part in the hearing, and they formed two sharply opposed sides. From memory, some among the prominent doctors on the pro finasteride side were Drs. Ian Thompson from MD Anderson, Scott Lucia (U. of Colorado), Peter Scardino (MSKCC), Mark Garnick (Beth Israel Deaconess Medical Center, Boston), David Penson (Vanderbilt U.), Gerald Andriole (Washington U. St. Louis), Christopher Logothetis (MD Anderson), and others. Dr. Walsh of Johns Hopkins was the major figure on the other side. Dr. Mario Eisenberger, an eminent Johns Hopkins medical oncologist also presented, but I don’t recall which side he was on.

My view is that the FDA advisory committee did not fully understand the significance of key points and did not resolve key issues. These hearings are a tough arena; they usually take place on just one day, thought presentation materials are typically available in advance. It is a lot to absorb and process at this quick pace, even for talented doctors and researchers on the committees. I am convinced the votes, majorities against finasteride, should have been for finasteride, or at least neutral. :( Recent much longer-term follow-up from the Prostate Cancer Prevention Trial, which was critical evidence for the hearing, supports those who favor finasteride use (https://pubmed.ncbi.nlm.nih.gov/29534197-using-medicare-claims-to-examine-long-term-prostate-cancer-risk-of-finasteride-in-the-prostate-cancer-prevention-trial/?from_term=%22Prostate+Cancer+Prevention+Trial%22+AND+2018+%5Bdp%5D&from_filter=simsearch1.fha&from_size=10&from_pos=3). :cool:

The following URL addresses provide the recorded record of the hearing, except for the live visual aspect. Powerpoints are included. Time permitting, I am willing to discuss questions resulting from this material.

The following FDA site, page 2 etc., is the agenda for the FDA hearing I’ve referred to, which took place on December 1, 2010: https://wayback.archive-it.org/7993/20170404153830/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM236781.pdf

The following FDA site, after the introductory pages, is the “quick minutes” for the December 1, 2010 hearing: https://wayback.archive-it.org/7993/20170404153837/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM239355.pdf

The following FDA site, after the introductory pages, has the detailed and informative power pointslides presented by the advocates for finasteride (Proscar) (94 pages): https://wayback.archive-it.org/7993/20170405223934/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM236788.pdf

The following FDA site, after the introductory pages, has the full and complete 396 page transcript of the hearing, blow-by-blow (sometimes almost literally; it got heated, but that may not be clear from the transcript; it was in-your-face clear during the simulcast): https://wayback.archive-it.org/7993/20170404153834/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM237498.pdf I was really angry at the uninformed and misleading role played by Dr. Patrick Walsh, MD, the truly great surgical pioneer for prostate cancer from Johns Hopkins, and others, including the chairman, at this meeting. :mad: If you load both the powerpoint and the transcript on a split screen, it may be easier to comprehend.

The following FDA site, https://wayback.archive-it.org/7993/20170405223941/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM236790.pdf, after the introductory pages, has 87 pages of powerpoint presentations at the Dec. 1, 2010 hearing by Dr. Peter Scardino, MD, the famed prostate cancer surgeon from Memorial Sloan Kettering Cancer Center in NYC, and by Dr. Patrick Walsh, MD, the famed pioneering prostate cancer surgeon from Johns Hopkins, starting on page 38.

Jim :wave:

- - - - - - - - - - - - - - - - - - - - - - - -
[SIZE="1"]Diagnosis Dec 1999 PSA 113.6 (first ever), age 56
Gleason 4+3=7 (J. Epstein, JHU), all cores +, most 100%; "rock hard" prostate with ECE - stage 3, PNI, PSADT determined later 3-4 months; technetium bone scan and CT scan negative; prognosis 5 years.
Later ProstaScint scan negative except for one suspicious small area in an unlikely location. ADT Lupron as first therapy, in Dec 1999, then + Casodex in March 2000, then + Proscar and Fosamax in Sep 2000. Rejected for surgery January 2000; offered radiation but told success odds were low; switched to ADT only vice radiation in May 2000, betting on holding the fort for improved technology; PSA gradual decline to <0.01 May 2002. Commenced intermittent ADT3 (IADT3) with first vacation from Lupron & Casodex. Negative advanced scans in 2011 (NaF18 PET/CT for bone) and 2012 (Feraheme USPIO for nodes and soft tissue). With improved technology, tried TomoTherapy RT, 39 sessions, in early 2013, plus ADT 3 in support for 18 months (fourth round of IADT3), ended April 2014. Continuing with Avodart as anti-recurrence shield. Current PSA remarkably low at <0.01; apparently cured.. Supportive diet/nutrition, exercise, supportive medications during this journey, as well as switches in antiandrogen, 5-ARI, and bone drugs.[/SIZE]

IADT3since2000 01-09-2020 01:46 PM

Re: 5α-Reductase Inhibitors (e.g., finasteride) and PCa risk/benefit
 
Hi again saros,

I'm responding to your post below, which is a current comment from Dr. Patrick Walsh, MD, the famed prostate cancer surgery pioneer from Johns Hopkins, and a staunch opponent of finasteride in the prevention setting. I have long thought he was misguided. In a post a few minutes ago on this thread I have provided a way of getting a detailed look at the December 1, 2010 FDA advisory committee hearing on finasteride for prevention, during which Dr. Walsh played a critical, and to me most unfortunate, role. :(

[QUOTE=saros;5499821]Saros 9:08 AM

Re: Association of Treatment with 5α-Reductase inhibitors with Time to Diagnosis and Mortality in Prostate Cancer
Patrick C. Walsh European Urology Vol. 76, Iss. 5, November 2019

Expert’s comments:
We are told that 5-ARIs prevent prostate cancer and do not
increase the risk of high-grade disease. If this were true,
why did the men in this study who were treated with 5-ARIs
develop high-grade, lethal disease? …[/QUOTE]

The answer is simple. It's because 5-ARIs have proven to be ineffective at eliminating high-risk disease especially GS-8 - 10(in sharp contrast to their partial effectiveness against GS 6 and lower disease), although they have also been proven to increase efficiency in biopsy detection of high-risk disease. [I][COLOR="Blue"]Follow-up research has demonstrated that 5-ARI use does not foster high-risk disease; they do not increase risk of developing such disease.[/COLOR][/I] For example, see https://pubmed.ncbi.nlm.nih.gov/29534197-using-medicare-claims-to-examine-long-term-prostate-cancer-risk-of-finasteride-in-the-prostate-cancer-prevention-trial/?from_term=%22Prostate+Cancer+Prevention +Trial%22+AND+2018+%5Bdp%5D&from_filter= simsearch1.fha&from_size=10&from_pos=3 . :cool:


[QUOTE]In the original publication from the Prostate Cancer
Prevention Trial … the authors reported a 25% reduction in
prostate cancer prevalence and a 68% increase in high-grade
disease [2]. Although the authors have argued that the
increase in high-grade disease was an artifact, in 2011 the
US Food and Drug Administration reported on their
independent reanalysis of the study and found that the
original published article was severely flawed [4]. They
concluded that in the clinical setting, if 150–200 men were
treated with a 5-ARI, there would be a reduction in only
three to four Gleason 6 cancers, no reduction in Gleason 7,
and an increase in one new case of Gleason 8–10 disease.
Sarkar et al [1] suggest that their results “include the
possibility that 5-ARIs inherently increase the risk of highgrade cancer”.[/QUOTE]

I haven't reviewed reference 4, but expect that it summarizes the December 1 hearing analysis. I am confident that the "severe flaw" was itself faulty. The "possibility that 5-ARIs inherently increase the risk of highgrade cancer” has been debunked.

[QUOTE]When I first prescribe 5-ARIs, I explain to patients the
importance of having their PSA measured regularly for as
long as they are taking the drug. I tell them why they need to
know those numbers and if their PSA ever increases they
need a biopsy.[/QUOTE]

These days, while such an increase in PSA is a pretty strong and valuable signal that there may be significant cancer and a biopsy needed, thereby making "finasteride challenge" an excellent in-depth "screening" technique, we have other tools, such as mpMRI and a number of tests that could filter the need for a biopsy.

[QUOTE]In patients taking a 5-ARI, PSA levels should
continue to go down for as long as they are taking them.[/QUOTE]

That is simply false and widely known to be false. The widely accepted fact is that PSA should go down until it hits a low point, and it should be stable at that point unless cancer or infection/inflammation, mainly, but not BPH (which finasteride counters, at least partially and stabilizes), cause it to increase. PSA should not be expected to continue to drop indefinitely. I'm really surprised that Dr. Walsh does not know this, but he probably devotes most of his attention to surgical developments, and he is not the kind of prostate doctor that has a lot of drug expertise; those doctors are "medical oncologists."

[QUOTE]If their PSA ever goes up at all, the risk of cancer is increased
by a factor of three and the risk of high-grade disease by a
factor of six [5].[/QUOTE]

I don't know the basis for this statement. It may be true, but it would be an example of finasteride making the detection of high-grade disease more efficient and not an example of finasteride causing high-grade disease.

[QUOTE]Urologists need to know the full truth about drugs that have lethal potential.
[/QUOTE]

I will certainly agree with that, both for urologists and all doctors. Ditto for side effects, where I have learned that urologists are often light in the kind of knowledge we would like them to have. However, that statement does not apply at all to finasteride! :mad:

Dr. Walsh deserves his exalted reputation for his surgical contributions, but I hope he sticks to his day job!

I hope this helps, and I would be glad to respond to follow-up.

Jim :wave:

- - - - - - - - - - - - - - - - - - - - - - - -
[SIZE="1"]Diagnosis Dec 1999 PSA 113.6 (first ever), age 56
Gleason 4+3=7 (J. Epstein, JHU), all cores +, most 100%; "rock hard" prostate with ECE - stage 3, PNI, PSADT determined later 3-4 months; technetium bone scan and CT scan negative; prognosis 5 years.
Later ProstaScint scan negative except for one suspicious small area in an unlikely location. ADT Lupron as first therapy, in Dec 1999, then + Casodex in March 2000, then + Proscar and Fosamax in Sep 2000. Rejected for surgery January 2000; offered radiation but told success odds were low; switched to ADT only vice radiation in May 2000, betting on holding the fort for improved technology; PSA gradual decline to <0.01 May 2002. Commenced intermittent ADT3 (IADT3) with first vacation from Lupron & Casodex. Negative advanced scans in 2011 (NaF18 PET/CT for bone) and 2012 (Feraheme USPIO for nodes and soft tissue). With improved technology, tried TomoTherapy RT, 39 sessions, in early 2013, plus ADT 3 in support for 18 months (fourth round of IADT3), ended April 2014. Continuing with Avodart as anti-recurrence shield. Current PSA remarkably low at <0.01; apparently cured.. Supportive diet/nutrition, exercise, supportive medications during this journey, as well as switches in antiandrogen, 5-ARI, and bone drugs.[/SIZE]

IADT3since2000 01-09-2020 01:50 PM

Re: 5α-Reductase Inhibitors (e.g., finasteride) and PCa risk/benefit
 
[QUOTE=DjinTonic;5499831]Jim, you may have missed a post of mine in another thread where a statement of mine wasn't clear or was misinterpreted. I'll paste it here....[/QUOTE]

Great post!

Jim

IADT3since2000 01-09-2020 02:05 PM

Re: 5α-Reductase Inhibitors (e.g., finasteride) and PCa risk/benefit
 
[QUOTE=Prostatefree;5499817]Do any studies address the use of these hormone treatments in precipitating smaller higher risk cancer in the users?[/QUOTE]

Yes, and "these hormone treatments" - meaning finasteride (Proscar) and dutasteride (Avodart) - have been vindicated! :D (Some doctors have not gotten the word. Heads up Dr. Walsh! :(

For other hormonal treatments, the older drugs in the antiandrogen class - flutamide, bicalutamide/Casodex, and nilutamide - often, after many years of use in lower-risk patients, a few years in advanced patients - may cause mutation of the cancer so that it is then able to use these drugs to [I]fuel[/I] the cancer, a phenomenon known as Androgen Receptor Mutation (ARM). (After many years of use, I myself switched from Casodex to flutamide (an older, less effective and much less convenient drug) to counteract a suspected ARM. The switch worked well for me. It works for many patients, but sometimes for a short period.)

Some of the exciting new and often highly effective (and expensive!) drugs, including the antiandrogen Xtandi (enzalutamide) and probably its more recently approved cousins (apalutamide, daralutamide) and Zytiga (abiraterone acetate), sometimes stimulate cancer cells to switch to a more virulent form known as endometrial (from the cell's resemblance to female anatomy) or small-cell prostate cancer. I have not tracked research and recent developments, but a few year ago, the recently retired expert medical oncologist Dr. Charles "Snufffy" Myers, MD, had come to believe that giving men doses of transdermal estrogen, in order to preserve bone mineral density in the face of severe androgen deprivation, was associated with preventing and countering this transformation.

Jim

- - - - - - - - - - - - - - - - - - - - - - - -
[SIZE="1"]Diagnosis Dec 1999 PSA 113.6 (first ever), age 56
Gleason 4+3=7 (J. Epstein, JHU), all cores +, most 100%; "rock hard" prostate with ECE - stage 3, PNI, PSADT determined later 3-4 months; technetium bone scan and CT scan negative; prognosis 5 years.
Later ProstaScint scan negative except for one suspicious small area in an unlikely location. ADT Lupron as first therapy, in Dec 1999, then + Casodex in March 2000, then + Proscar and Fosamax in Sep 2000. Rejected for surgery January 2000; offered radiation but told success odds were low; switched to ADT only vice radiation in May 2000, betting on holding the fort for improved technology; PSA gradual decline to <0.01 May 2002. Commenced intermittent ADT3 (IADT3) with first vacation from Lupron & Casodex. Negative advanced scans in 2011 (NaF18 PET/CT for bone) and 2012 (Feraheme USPIO for nodes and soft tissue). With improved technology, tried TomoTherapy RT, 39 sessions, in early 2013, plus ADT 3 in support for 18 months (fourth round of IADT3), ended April 2014. Continuing with Avodart as anti-recurrence shield. Current PSA remarkably low at <0.01; apparently cured.. Supportive diet/nutrition, exercise, supportive medications during this journey, as well as switches in antiandrogen, 5-ARI, and bone drugs.[/SIZE]

saros 01-09-2020 05:11 PM

Re: 5α-Reductase Inhibitors (e.g., finasteride) and PCa risk/benefit
 
Wow, a lot of information there which I am not well versed in (to put it mildly) but not surprising that the years-long debate is heated, as Dr. Walsh seemed to come across a bit edgy with comments like "sadly, this is because we have not been told the full truth" and "lethal potential." Seems kinda loaded. Fraud and malpractice?

Not that I know the biology of practically anything about the prostate really, but his description of epithelial cells, stroma, the enzyme involved and the action of finasteride is interesting. But is the mechanism of how the 5-ARI biochemistry affects cancer formation and growth really known? I mean, to say things like 5-ARIs can't affect GS7 cancer since those cells have little stroma/5-AR?

DjinTonic 01-09-2020 06:06 PM

Re: 5α-Reductase Inhibitors (e.g., finasteride) and PCa risk/benefit
 
Jim mentioned the SpaceOar gel:[QUOTE]These days IMRT patients will probably get SpaceOAR gel to protect the rectum prior to radiation, which should reduce rectal side effects below their already very low rates.[/QUOTE]

Patients considering it should be aware that there have been serious complications. I would discuss these with your doc, so you know they are aware, and they can reassure you.
----------------------------------------------------------------
[b]Major Complications and Adverse Events Related to the Injection of the SpaceOAR Hydrogel System Before Radiotherapy for Prostate Cancer: Review of the Manufacturer and User Facility Device Experience Database[/b] [2019]

https://www.ncbi.nlm.nih.gov/pubmed/31452385
----------------------------------------------------------------
[b]Late toxicities of prostate cancer radiotherapy with and without hydrogel SpaceAOR insertion[/b][2019]

https://www.ncbi.nlm.nih.gov/pubmed/31520465

(This study showed [I]benefit [/I]from the gel).
----------------------------------------------------------------
[b]COMPLICATIONS OF THE SPACEOAR HYDROGEL SYSTEM[/b] [2019]

https://www.auajournals.org/doi/abs/10.1097/01.JU.0000557137.58284.00
----------------------------------------------------------------
Djin

IADT3since2000 01-17-2020 08:16 AM

Re: 5α-Reductase Inhibitors (e.g., finasteride) and PCa risk/benefit
 
Mechanism of 5-ARI (Proscar/finasteride, Avodart/dutasteride) Effect on Cancer Formation and Growth

[QUOTE=saros;5499857]... But is the mechanism of how the 5-ARI biochemistry affects cancer formation and growth really known? I mean, to say things like 5-ARIs can't affect GS7 cancer since those cells have little stroma/5-AR?[/QUOTE]

Hi again.

I need to update my knowledge of this area with recent research, but here is what I have learned from the past:

1. These drugs severely curtail the conversion of testosterone into DHT (dihydrotestosterone), which is a far more potent fuel for prostate cancer. The reduction by finasteride is 70% in the blood and 80-90% in the prostate; the reduction by dutasteride is 98% in the blood ("A Primer on Prostate Cancer", p. 136, 2002, Strum and Pogliano) and about 94% in the prostate per my somewhat hazy recollection. However, that means that, if used without testsoterone suppression drugs/orchiectomy, testosterone will be higher since less is converted to DH. My layman's understanding is that the balance of effect on cancer of using 5-ARI drugs alone will be less fueling of the cancer than without these drugs but still plenty of fuel for some cancer growth, though at a reduced rate. Yet, these drugs do seem to eliminate some GS 2-6 cancer, possibly decrease some GS 7 cancer, and maybe even decrease some GS 8-10 cancer (based on decrease in incidence after long use in a Swedish study), though I believe the balance of expert opinion is that there is limited effect, if any, on GS 7 and no impact on GS 8-10.

2. These drugs reduce blood supply to the prostate, and apparently this also reduces blood supply to prostate tumors, and tumors need a blood supply to grow.

3. These drugs shrink the prostate. Perhaps, guessing here, that reduces incidence of prostate cancer by providing less territory for it to grow.

Jim :wave:

- - - - - - - - - - - - - - - - - - - - - - - -
[SIZE="1"]Diagnosis Dec 1999 PSA 113.6 (first ever), age 56
Gleason 4+3=7 (J. Epstein, JHU), all cores +, most 100%; "rock hard" prostate with ECE - stage 3, PNI, PSADT determined later 3-4 months; technetium bone scan and CT scan negative; prognosis 5 years.
Later ProstaScint scan negative except for one suspicious small area in an unlikely location. ADT Lupron as first therapy, in Dec 1999, then + Casodex in March 2000, then + Proscar and Fosamax in Sep 2000. Rejected for surgery January 2000; offered radiation but told success odds were low; switched to ADT only vice radiation in May 2000, betting on holding the fort for improved technology; PSA gradual decline to <0.01 May 2002. Commenced intermittent ADT3 (IADT3) with first vacation from Lupron & Casodex. Negative advanced scans in 2011 (NaF18 PET/CT for bone) and 2012 (Feraheme USPIO for nodes and soft tissue). With improved technology, tried TomoTherapy RT, 39 sessions, in early 2013, plus ADT 3 in support for 18 months (fourth round of IADT3), ended April 2014. Continuing with Avodart as anti-recurrence shield. Current PSA remarkably low at <0.01; apparently cured.. Supportive diet/nutrition, exercise, supportive medications during this journey, as well as switches in antiandrogen, 5-ARI, and bone drugs.[/SIZE]


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