Bipolar Androgen Therapy in Prostate Cancer.

[pjoshea13]

New review from Italy, below [1].

I can't readily access the review itself, but I liked that the authors explain the rationale for BAT more clearly than I may have done in the past:

"New-generation hormone therapies improved overall survival in castration-resistant prostate cancer. More recent trials showed a further increase in overall survival when enzalutamide or abiraterone are associated with androgen deprivation therapy in hormone-sensitive disease. However, a higher clonal pressure may lead to the upregulation of alternative pathways for cancer progression and to dedifferentiated diseases that would probably respond poorly to subsequent treatments."

This is nothing new, of course. The reason that I did not want to start Lupron 16 years ago was that it would probably fail within 2 years & leave me with less manageable disease.

I get the impression that many men are rushed into short-term palliative therapies that lead to 'treatment-emergent' disease states with no Plan B.

{Primum non nocere (first, do no harm)?}

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/324...

Review Crit Rev Oncol Hematol

. 2020 May 24;152:102994. doi: 10.1016/j.critrevonc.2020.102994. Online ahead of print.

Bipolar Androgen Therapy in Prostate Cancer: Current Evidences and Future Perspectives

Gianmarco Leone 1 , Consuelo Buttigliero 2 , Chiara Pisano 1 , Rosario Francesco Di Stefano 1 , Fabrizio Tabbò 1 , Fabio Turco 1 , Francesca Vignani 3 , Giorgio Vittorio Scagliotti 1 , Massimo Di Maio 3 , Marcello Tucci 4

Affiliations collapse

Affiliations

1 Division of Medical Oncology, San Luigi Gonzaga Hospital, Department of Oncology, University of Turin, Regione Gonzole 10, 10043 Orbassano, Turin, Italy.

2 Division of Medical Oncology, San Luigi Gonzaga Hospital, Department of Oncology, University of Turin, Regione Gonzole 10, 10043 Orbassano, Turin, Italy. Electronic address: [e-mail].

3 Division of Medical Oncology, Ordine Mauriziano Hospital, Department of Oncology, University of Turin, Via Magellano 1, 10028 Turin, Italy.

4 Division of Medical Oncology, Cardinal Massaia Hospital, Department of Oncology, University of Turin, Corso Dante Alighieri 202, 14100 Asti, Italy.

PMID: 32480269 DOI: 10.1016/j.critrevonc.2020.102994

Abstract

Testosterone suppression by androgen deprivation therapy is the cornerstone of prostate cancer treatment. New-generation hormone therapies improved overall survival in castration-resistant prostate cancer. More recent trials showed a further increase in overall survival when enzalutamide or abiraterone are associated with androgen deprivation therapy in hormone-sensitive disease. However, a higher clonal pressure may lead to the upregulation of alternative pathways for cancer progression and to dedifferentiated diseases that would probably respond poorly to subsequent treatments. In this contest, new strategies that could be able to delay or even revert resistance are needed. The bipolar androgen therapy is an under-investigation treatment that consists in periodical oscillation between castration levels and supraphysiological levels of testosterone in order to prevent the adaptation of prostate cancer cells to a low-androgen environment. This review aims to underline the biological rationale of bipolar androgen therapy and gather evidences from the most recent clinical trials.

Keywords: Androgen; Bipolar; Cancer; Prostate; Review; Therapy.

Copyright © 2020 Elsevier B.V. All rights reserved.

[tango65]

Link to the full article. Hope it works.

sci-hub.tw/https://www.scie...

[cesanon in reply to tango65]

Thanks for the link.

"Highlights

 Testosterone at high levels can induce apoptosis in prostate cancer cells

 Bipolar androgen therapy may prolong response in prostate cancer

 Many mechanisms, including DNA damage, are involved in cells death

 Clinical trials have shown some benefit from bipolar androgen therapy

 Combinations with immunotherapy and PARP inhibitors are under investigation"

The most interesting point is: "Testosterone at high levels can induce apoptosis in prostate cancer cells

"

[pjoshea13 in reply to tango65]

Thanks Tango, your link does work - yet when I paste the title into sci-hub, I get "не найдена в базе | article not found"

Interesting read!

-Patrick

[tango65 in reply to pjoshea13]

It is one of my russian hackers responding.

The search should be done using DOI or the url for the article. Try pasting :

sciencedirect.com/science/a...

[pjoshea13 in reply to tango65]

Useful to know. You are a resourceful guy! -Patrick

[tango65 in reply to pjoshea13]

Best of luck, Patrick.

[LearnAll]

pubmed.ncbi.nlm.nih.gov/291...

The above article explains Adaptive therapy cancept beautifully.

Thank you ..Patrick for bringing fresh and new perspective to cancer therapy discussion of use of Bipolar ADT and Intermittent ADT.

Some brave and smart researchers are now declaring this important fact that BAT as well as IADT can keep cancer cells more sensitive to ADT for longer span of time and delay resistance significantly.

It would be interesting to know ...Are there any cases which quickly started getting worse when high dose of testosterone was given? Dont know how to find the answer to this...and that" s the reason I am currently staying with Intermittent ADT and letting T level rise slowly.

[kaptank in reply to LearnAll]

I think Denmeade noted in a few interviews that they had found generally patients were no worse off. ie worst case was disease progressing pretty much as before. No cases of huge increases after supraT.

[kaptank in reply to kaptank]

Oh. And I should add that you should not take a PSA test for at least a month after first supraT shot. That can result in a large, alarming rise that is actually meaningless.

[noahware in reply to LearnAll]

I believe there are SOME (few) cases which quickly started getting worse when testosterone was given, going way back to the early observations on the 1940s and 50s. But doctors also observed some quickly getting BETTER, sometimes much better. I don't think there is much recent data, since high-T has become so little studied in a variety of PC patients, for FEAR of doing POTENTIAL harm (along with not generating $).

I do know that Dr. Bob Liebowitz thought that avoiding castrate resistance should become a goal of patients (if not doctors), because that form of cancer amounts to a slow-death sentence. He thought high-T was a great follow-up to initial ADT/chemo and he had many documented successes, though less is known about his failures (which surely existed).

[LearnAll in reply to noahware]

My concern is that you inject High T and your PCa responds with quick increase in PSA....what do you do now? You can not pull the injected T back out.

[noahware in reply to LearnAll]

That would seem to be a very real risk... but ask, why WOULD the dose of T cause the PC to run wild? It is true that PSA might rise quickly, but does that necessarily mean the cancer itself is progressing just as rapidly, without recourse?

The only person I know of who really explored this was Dr. Bob. He basically asked, are you scared of your PC or of your PSA? We use PSA as proxy for PC, but that's all it is. Many of his patients still had prostates, and would get nervous (as would he) when PSA rose with T-therapy. But he reported that initial rises of PSA would commonly level off and even decrease as high T-levels were sustained.

These were not controlled studies, so at some level they remain purely anecdotal. One has to trust that they were recorded and reported accurately. But I think the answer is, if PSA rises and rises and there is also other evidence of progression, then you simply bail out of the T-therapy. I don't know of any data that says you would then have trouble getting benefits from other treatments as a result of trying high-T.

The alternative is that you stick to meds that you KNOW will fail, and that you KNOW will ultimately lead to mCRPC. Sometimes, the unknown seems more attractive?

[LearnAll in reply to noahware]

Thanks...good logical answer. Until we have more data, I would like to continue my Intermittent ADT. I am fully convinced based on studies I have read that Intermittent ADT, in fact delays castration resistance besides reducing side effects of ADT.

6 months have passed since last lupron inj. and I have no problem. Watching markers frequently.

[Rkoma in reply to LearnAll]

In vitro and in vivo tests have shown that amount of PSA/gr of tumor was 24 in castrate case and 95 in case of castrate+Testosterone. That means that the high PSA after T Injection is not always caused by bigger tumor mass.

In the paper „Supplementary Materials for

Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: Results from a pilot clinical study“ DOI: 10.1126/scitranslmed.3010563 you can see PSA diagrams of people who did BAT. In some cases PSA was raising over three months but the decease was stable. In other cases PSA raise was sign for decease progression.

It seems there are 3 typical response diagram shapes There are also other shapes which finally were connected to positive or negative response without clear answer why..

Regards

Rkoma

[pjoshea13 in reply to LearnAll]

I would start with daily Androderm patches (4mg) - 2 would be needed to get much above 1,000 ng/dL. The T clears quickly. One can revert to continuous ADT rapidly.

I switched to T Cypionate because it was cheap & insurance was clamping down on expensive transdermals.

T Cypionate does not clear quickly. I had to go to a 2-month BAT cycle. In my view, Denmeade does not allow enough time in the castrate phase. Too much stimulation & not enough inhibition at the back end. I developed leg pain 3 months into BAT & it took a while before an S1 issue was identified. The 2 month cycle quickly reversed the problem.

I do believe that care is needed - essentially, a flexible schedule & initial monitoring.

I also think that the appropriate time to start BAT is at ADT initiation.

IMO

-Patrick

[Rkoma in reply to pjoshea13]

I agree with Patrick that Cypionate needs more than 1 month to clear. Giving it every 28 days is more like approach of another famous MO running therapy with constantly supra T level. I see two possible options to achieve high-low T switching.

1. just wait longer ( up to 2 months before starting next injection). Risk/danger of staying to long in the middle (200-600) T area

2. After certain time start taking antiandrogen with short half life time ( Flutamide or Darolutamide) and stop it after T achieves castration level. Next injection can be given after antiandrogen cleared.

This is not proposal to do it, just consideration of possible options.

Rkoma

[GDiane63]

My husband’s oncologist is going to start the testosterone injections tomorrow but he’s also scheduled for a Lupron shot which they’ve continued doing at 3 months since the chemo and ADT failed last year.

I know his dr has been researching this and consulting with another dr but i want to have good info to take with me tomorrow. Is that generally given at the same time that you start BAT?

[pjoshea13 in reply to GDiane63]

It is a matter of convenience. Lupron is continuous, since you can't stop/start it at short notice (as you can with oral ADT). Makes sense to align the shots. It will be counter-intuitive to some - a shot to inhibit T + a shot of T - both on the same day.

On the other hand, there is no reason why your husband (or you) should not administer the T injections into muscle. It isn't my favorite task, but I inject into the upper thigh.

Will there be monthly PSA tests? An upward trend isn't necessarily a sign of failure. If it were me in that scenario, I would consider extending the monthly cycle. I current need 2-month shots.

Best, -Patrick

[noahware]

Thanks for posting this!

The idea that testosterone at high levels can induce apoptosis in prostate cancer cells is consistent with the work of Huggins as far back as the 1940s. I read an article of his from the 1960s where he pointed out three potential ways to treat PC via hormonal therapy:

1) hormonal deprivation (castration)

2) hormonal interference

a) high-dose estrogen

b) high-dose testosterone

In addition to the idea that large amounts of either hormone might have a direct effect of "poisoning" cancer cells, there is Denmeade's idea that "changing the hormonal milieu" throws the PC off its game, so to speak. The PC is thriving under a particular hormonal environment, so a radical change to the environment forces the cancer to re-adapt to the new environment.

That is why, intuitively, the idea of ALTERNATING therapies seems to make more sense then doing one long, ongoing form of treatment (like ADT). Switching things up would seem to dampen the ability of some cancer to evolve into more lethal forms that resist ADT.

[LearnAll in reply to noahware]

This concept that strong and continuous suppression of testosterone eventually leads to androgen independent ,resistant cancer cells..has been gaining ground in last few years but the voices of Dr Laurece Klotz, Dr Denmeade ,Dr Leslie Castello and the likes .. have been drowned by standard of care loudmouths and their patrons in big pharma . But its not possible to block truth for a long time.

I foresee more and more doctors prescribing Intermittent ADT or Bipolar ADT in future.

[j-o-h-n]

youtube.com/watch?v=-prQ8AE...(Not working as expected?)

Good Luck, Good Health and Good Humor.

j-o-h-n Wednesday 06/03/2020 6:30 PM DST

[immunity1 in reply to j-o-h-n]

Bravo! and was Mario on BAT at the time?

[j-o-h-n in reply to immunity1]

Grazie, Now ya got me..... I do know he used to wear rubber suits (sweat to lose weight -he loved his pasta)....

Good Luck, Good Health and Good Humor.

j-o-h-n Wednesday 06/03/2020 8:05 PM DST

[pjoshea13 in reply to j-o-h-n]

He was 38 when he died. Perhaps from the "the twilight sleep treatment".

Sadly, he never made it to the PCa years.

& they say singing is good for you.

-Patrick