Walsh's Folly?

[VoxHope]

I posted earlier that I had to ask ChatGPt "who came up with the 'gasoline on a fire' characterization regarding the relationship of testosterone and prostate cancer" and that Chat GPT had answered -- Dr. Patrick Walsh -- (father of the radical prostatectomy.)

In that post, discussion turned to Walsh's book "Surviving Prostate Cancer" which I have found to still be a good discussion of the many complexities involved in understanding and treating PCa.

Walsh's book is the source of the scanned and attached Kaplan-Meier plots I want to share in this post because (if I am reading them correctly) they are so startling in their conclusions that they might still inform current patients whether locally advanced or metastatic.

(I was surprised that Walsh even included these plots in his book.)

The plots show the survival times and profiles for two groups:

* men who underwent orchiectomy and

* men who "delayed", got a placebo, and did nothing until some type of "progression" and then underwent ADT

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NB: This is the caption-text which got blurred in the scan.

I broke the text into a,b,c.-- I think I understand a) and b).

But c)? I have no idea what he is talking about, if you do, please post your interpretations.

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Page 408: Figure 12.2 Does Early ADT Prolong Life?

a) These two graphs show the results from the Veterans Administration Cooperative Urologic Research Study 1 of 954 men with prostate cancer. The men were randomly assigned either to immediate surgical castration or were given placebo therapy and followed closely until their cancer progressed, at which point they underwent definitive ADT.

b) The percentage of men left untreated is shown in the dark band below the x-axis.

c) With follow-up intervals up to nine years, there is no difference in survival in the men who received early versus later treatment. This study must be addressed by anyone who tries to argue that early ADT prolongs life - because if it does, then what's wrong with this carefully executed, long-term study of almost one thousand men?

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Here is the message of the plots as I see it.

The shape of the curves are almost identical for both groups-- so no advantage to orchiectomy.

The men who got the orchiectomy may have believed that their troubles were over. Not only had they eliminated the "gasoline", they had eliminated the entire "gas tank." But they did not survive any longer despite their sacrifice. Their curve "should have" plotted higher and longer than it did.

The men in the 2nd group delayed and did nothing, and so postponed the consequence of the complete castrate-level suppression of both testosterone and estrogen (at least until they started ADT.) In fact it was five years before even half of them needed or received any treatment at all.

And at the end points:

For the locally advanced- 35% never needed or had any treatment over the nine years.

For the metastatic: the delayed treatment group from four years onward still managed to out-survive their castrated brothers.

Have I interpreted the curves correctly or did I make some mistakes?

I see this plot as a metaphor for standard treatment, repeat this "experiment" with different participants and you will get similar results. The numbers will be different in each case but they will be roughly the same as well as the conclusion-- "sometimes nothing can be a real cool hand."

Now let's go out of the box... suppose we could substitute radical prostatectomy for the orchiectomy, would there be any change in the plotted outcomes or conclusion? What about any of the other "local" treatment that SOC forces you to endure before allowing the treatment that works best -- systemic hormone therapy?

And the reason for the superiority of hormone therapy?

Because prostate cancer is metastatic from its inception, way before it can be detected or show up on any scan or even DREs.

Doubt it? A series of men were on the operating table awaiting the start of their radical. Bone marrow biopsies were taken, and found that more that half of them already had prostate cancer in their marrow.

[Seasid]

You could wait until you develop bone pain and than you start treatment, or you could start treatment immediately after diagnosed as metastatic. The first one is an old approach. I started my treatment after I was diagnosed without waiting for a bone pain to develop.

I can't comment much as I don't know the inclusion and exclusion criterias of the trial.

The shape of the graph looks strange.

I would expect that people would be dying first slowly after the diagnosis and later it would speed up.

[MrG68]

I think that may be based on this study.... I think...

doi:10.1002/1097-0142(197311)32:53.0.co;2-c

It has this at the start of the article: (I assume that DES is diethylstilbestrol)

The results of these clinical trials over the past 12 years have revealed an unsuspected toxicity of DES used in treating patients with cancer of the 'prostate when given in a dose of 5.0 mg daily. The first VA study did not show that orchiectomy was superior to estrogen in treating cancer of the prostate or that the combination orchiectomy plus estrogen had much to offer beyond the benefits of estrogen alone when indicated. The preponderance of evidence from the second study shows that 1.0 mg of DES appears to be about as effective as the 5.0 mg dose in treating cancer of the prostate but does not carry the excess hazard of cardiovascular deaths. Our overall recommendation at present is that patients with prostatic cancer should not be treated until their symptoms require relief, and at that time we recommend starting treatment with 1.0 mg DES daily. These recommendations may change as we continue to analyze our data.

As for your point of c).... I believe its pointing out that its recommending that you use DES only when it's necessary later 'when it's required for relief' as opposed to earlier since it will not extend your life.

I assume that its suggesting, not only that, but also to use the reduced amount due to potential toxicity issues.

That's the way I read it anyway.

Hope that helps.

Edit: It should be noted that although ADT doesn't necessarily extend your life, you have to ask why you are taking it since it has potential toxicity. It offers an alternative path from the potential pain of bone metastasis. So basically you're swapping one issue for another that is more tolerable even with additional side effects . So I'm not really sure why the suggestion is to wait until 'required for relief'. Looks to me that that's the main point... I could be wrong though.

Maybe the book has some insight into that.

[VoxHope in reply to MrG68]

Thanks for digging this out.

You might be correct that Walsh is referring to the early or late DES treatments in that different? VA study.

In his caption Walsh says "there is no difference in survival in the men who received early versus later treatment." But I can't see that directly from his plots. You would need two separate curves- one for "early treatment" and another for "later treament". And if they were the same THEN you could see that there was "no difference in survival". But we are only given one line the delayed treatment line.

Don't want to beat this to death but do you see what I am getting at?

[MrG68 in reply to VoxHope]

I guess I'd have to read the book. It's hard to tell really what he's referring to otherwise. It could be that for each curve, both lines on each of the curves are literally on top of each other. If they diverged away from one another it each would have a difference in survival. The right curve does diverge slightly around the 9 years indicating a survival difference of around 10%. But really the two lines are practically in lockstep. Maybe...

[CaptainKrunch]

Seem like reasonable considerations for someone with prostate cancer in the 1970s (when it looks like these studies concluded). In the meantime... a handful of minor discoveries have been made... Hormone Therapy Advances: In the 1990s, newer and more effective hormone therapy drugs (like LHRH agonists and anti-androgens) came into wider use

Improved Radiation Techniques: Early 2000s saw advancements like Intensity-Modulated Radiation Therapy (IMRT), allowing for more precise targeting of tumors.

Targeted Therapies: Mid-2000s onward, drugs targeting specific cancer cell pathways (e.g., abiraterone, enzalutamide) became available for advanced prostate cancer.

Immunotherapy: More recently, immunotherapies like sipuleucel-T were approved, offering a new way to harness the immune system against prostate cancer.

[GeorgeGlass]

I’ve asked about this several times. Nobody can provide concrete answers about study results evidence.

[MrG68 in reply to GeorgeGlass]

Yep, it's all extremely complicated. Millions of confounding issues, chemical feedback loops everywhere, people doing different things, people have different epigenetic effects, livng in areas of differing sun exposures.. it's literally endless.Ever fixed an electronics board? A component can have a detrimental effect to the way the circuit works, but it's on the other side of the board and looks totally unrelated. Something just hasti be slightly out of tolerance.

I was working at a place where an engineer had an issue on a specific board - just this one board. If the board was replaced it fixed the issue. This guy was determined to find the cause. He literally tried everything. In the end he replaced every single component and still ended up with the issue.

Sometimes you can have the best engineer, with all the diagrams, all the right equipment, and all the resources but still not be able to fix the issue.

The body is infinitely more complex than a circuit board.

[GeorgeGlass in reply to MrG68]

Yes, I know what you mean about the circuit board analogy. Is like chemical reactions. Some elements change when confined with something else. I do think the wallah folly has some validity. It seems like one way to test that would be to see the records on when people nowadays never got treated But switched to an ultra, healthy diet, med, meditation, and exercise and then. compare. the people that did get treated. There’s a guy in this group that had Gleason eight or nine that had advanced. He decided to do no treatments at all and just eat healthy meditate exercise correctly and he ended up going 12 years before he felt any pain about three years ago to get treatments at this point, he allowed himself to have sex, normal testosterone and a high-quality life instead of eliminating sex and having a quality of life significant significantly Lower. I’m voice dictating and I don’t have my reading glasses on forgive any mistakes.

[chefjlu]

Always remember, studies can be difficult to assess when context is taken. Every year new treatments are developed, new medications, and changes in SOC. As well the ability to study the disease improves as new equipment is developed. I also find that too much study of information can develop a lot of questions. ---- All of us have our own unique parameters surrounding our diagnosis and progression. Genetic testing relating gene variants to PC are relatively new. This was a game changer for treatment for some. There has always been a debate about the role of testosterone in development of PC and in feeding PC.

[VoxHope in reply to chefjlu]

Thanks for the (3-part) article on BAT.

The interesting and new point mentioned in the article is that the cancer cell can express more of the "androgen receptor" when T levels are low and then shrink back to "normal" when T levels increase.

I wonder if this AR expansion works in any intermittent ADT regimen and whether it holds true for the other cancer cell receptors-- estrogen and progesterone.

I put that AR above in quotes because many do not know that there are two ARs an external membrane AR (formerly THE AR) and an internal intracellular AR which is where the DHT binds, I believe. Don't quote me on this... some say ONE AR in two different places.

[Professorgary]

I was diagnosed 3+3 Gleason July 13, 2000. My decision was to try to die before I needed treatment even though I was 50 at the time. I adjusted diet and worked on gut health and was on course until Covid hit and then Psa went through the roof. My urologist said since I refused radiation and surgery he recommended I wait until qol suffered. I had a completely normal sex life from 2000 when diagnosed until 2020 when Covid hit. 2022 when I had back pain and Mets in bones, nodes and lungs Doc says it’s now or never. Psa of 5664 went down to 6 over 10 month. Abi started 10,23 and Psa 1.02 and falling. Absolutely no pain and good energy but libido is zero. Gained a little weight but honestly I have more energy than before adt but doc says that is because I was a very sick man before adt. I also notice that some of the Covid symptoms are finally leaving so that could to me thinking my energy level improved. I know many think what I did is foolish but when I read all of the posts of folks giving up a normal sex life and the bowel or urinary incontinence caused by treatment I am good with my decision. The only thing that I would have done different would have been going on adt when Psa hit 900. After that point Psa rose quickly and so did pain. We each have to make our decisions and should never second guess ourselves. I am a man of faith yet I don’t asked to be cured. I simply ask for wisdom to help me choose the right path. I do find it interesting that my previous as well as my present urologist both told me that adt would not extend my life and that prolonging it wouldn’t shorten it. They both said it was to improve QOL. No way I am buying that. My Psa went from 900 in November to 5664 six months later. I just don’t think I’d be here without treatment. But then again, who knows? God bless!

[VoxHope in reply to Professorgary]

So your experience was similar to the "delayed treatment" arm of the VA study shown at the top. You skipped "local" treatment and waited until "progression", in your case PSA 900 and then when you should have started ADT your urologist discouraged you from starting and your PSA ultimately hit 5664?

They implied that postponing ADT would IMPROVE your QOL?

How did you get started with your ADT then... on oncologist?

I didn't follow the "prolonging it wouldn't shorten it." part of your post what did they mean?

You have still managed to survive 24 years even with REALLY "delayed treatment"!

[Professorgary in reply to VoxHope]

My urologist did not discourage starting adt. The one that retired asked me to consider adt in Apr 2021 with a Psa of 321 and metastatic spread shown on scans. Psa then went to 700 then down to 640 and down to 300 before spiking to 900. He retired and new urologist respected my wishes of not treating but ordered an mri to determine if my pain was due to stenosis or cancer. The mri revealed two compression fractures. He said he respects my right to forgo treatment but told me I was headed for a catastrophic spinal event without treatment. At that point he started 30 days of Casodex and after 15 days I had my first one month Lupron shot. My urologist asked if I’d like to consult with a MO, actually recommended it, but I declined but said I would probably agree in the future. After 9 months Psa hit 6 and started to climb along with alp. Alp went to 114 and Psa almost 20. At this point, Sept 23 MO started me on Abi. and 5mg prednisone once daily. I insisted on trying low dose with a low fat breakfast and he agreed. Psa now down near 1 and alp 72. As far as your questions they both said that the adt could improve quality but not prolong it, but as I said I feel it did both for me. I think they were both of the opinion that each patient has a window in which adt is effective. Basically, the sooner you start, the sooner it becomes ineffective. For one guy it may be 6 months and another 6 years. I had a urologist that wanted to start me on adt 5 years ago when I first hit stage 4 but I declined. If????? the window theory is true, I would have already used 5 years instead of 2. Hope this clears things up a bit. God bless.