Sorry I cannot recall who posted that great quote recently, but I thank you for it. It leverages off of another view from T_A pointing out that cancers are "complex adaptive systems" (inherently unpredictable, evolving and adaptive). This has broadened my own view of prostate cancer and how it responds to treatments. It evolves and it appears that treatments that do not cure it outright, killing every reproductively capable cancer stem cell, might be ultimately doomed to failure. Though how quickly or slowly, and just what way is, of course unpredictable.
But this theoretical framework makes sense of much that we can see happening. And it opens the door to at least considering strategies such as BAT and "Natural Adaptive Therapies" that use evolutionary dynamics of cancer genetics and cell regulatory mechanisms in ways that address the sub-populations of cells in a cancer along with the tumor micro-environment etc. It is a bit of an education but the overall concepts are straight-forward. Here are 3 articles for those who would like to explore this view and consider it further. It is not for making any specific treatment recommendations and it is a view on cancer altogether, including but not limited to prostate cancer. The first two are quite accessible to read. The last is much more detailed in the complexities of cell/cancer biology.
One thing I want to learn more about is how the body's micro-biome interacts with both healthy systems and with cancers in ways that can protect our health and longevity while we are fighting cancer. Any leads? - Paul
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MateoBeach
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Paul...Thank you for starting this very important topic. The good news is that many researchers are now working on models and concepts of Adaptive therapy. The concept of Intermittent ADT pioneered by Dr. Bruchowsky, Dr Morote, Dr Abrahamsson, Dr Laurence Klotz ,Dr Niraula and being propagated through conceptual models by Dr Zocita Hirata ,Dr Zhang (Mottet Center) is based on the same adaptive strategy. In simple terms....Do Not hit cancer cells so hard and keep hitting ..that they become desperate to change and stop being androgen dependent. So, Intermittently, hitting them hard and stopping and hitting them hard again after some time...keeps them androgen sensitive for a long time. I am using this principle myself and so far I am doing well.
Thank you. It is interesting in the 2nd article they point out a possible defect in the study comparing IADT to continuous: That all had an 8 month "induction period" of full androgen suppression and that may have already promoted or enabled androgen resistant populations to have become dominant. Thus the results not showing any advantage of IADT for castrate resistance emergence may not have been able to test a true adaptive strategy. Will be interesting to watch this be further clarified in expanded trials.
Induction period is variable in different research studies. They range from 3 months to 10 months in papers I have read.
I think the PSA response does vary from one man to another when they are subjected to ADT. There are about 35% men who are almost totally androgen sensitive ( I might be one of them) The next 45 % are Mixed type with Androgen sensitive and Androgen resistant cells in varying proportions. And the last 20 % are pre dominantly Androgen Resistant to begin with.
When these 3 subclasses are subjected to say 8 month long Induction period, the first group does the best as only a small part of their total androgen sensitive pool get converted to Androgen resistant. But. the last group does very bad as they have small pool of Androgen sensitive cells to begin with and those too end up becoming androgen resistant just like their other resistant cells..taking them into the kind which either do not respond to ADT or respond very little.
Dr Klotz 's studies do not talk about fixed lenghth of induction period...he determines end of " On period" when a Nadir PSA is reached irrespective of how long it takes.
Their is another problem with most of IADT studies...that is that they all choose high PSA values (anywhere from 10 to 20 ) in metastatic cases....to declare end of Off Period...and start of On period. I never understood Why ? Maha Hussain's SWOG trial was using set point of 20 . I think PSA 4.0 should be the set point for restrting a new on cycle and that is what I am doing in my own case. If a study is done with Nadir PSA 0.2 or less and upper set point of PSA 4.0, I guess it will show superiority of Intermittent ADT clearly over continuous ADT. There is no study yet with these parameters.
I am inclined to agree 4.0 makes more sense. But also perhaps not waiting for a true nadir “on” cycle but rather a % drop of PSA such as 50% to avoid overexposing/stressing the sensitivity population too much?
Yes...that's what Dr JingSong Zhang of Moffit Center thinks. Do you agree that if we make testosterone available to cancer cells long enough without them harming us...is the key as it takes them away from converting to aggressive variants. So how about using milder Anti Androgens like Bicalutamide which do not deprive cancer cells totally of testosterone. I am experimenting with this idea right now. My T is 310 but PSA still is 0.4.
Indeed. I used bicalutamide effectively for over 4 years with dutasteride. But unfortunately it can flip into being an AR agonist and stimulating PC growth. Then it must be stopped and not restarted. Not sure if mom cycling could have prolonged effectiveness but it’s possible.
4 years is a good amount of time with mild med with least side effects. I will love to get those 4 years with Bicalutamide and Finasteride. When my Biccky turns agonist, I will know by rise in PSA and will quickly stop and watch if I am lucky to get a long "bicalutamide withdrawal syndrome" . I will experiment when my PSA again touchesPSA 0.2 ....to stop Bicalutamide for 2 months and see effectiveness returns when I restart it back. I am curious to know if the effectiveness can be prolonged by this "Start-Stop-Start "watch closely tecnique . I don't know if any one has tried this before.
This is a great discussion. With no objective evidence other than what I have studied, this picture of cancer types and progression make perfect sense to me. I meet with my MO Tuesday October 20. I have been on Lupron / Zytiga / Prednisone since January of 2020. My latest PSA results from 10/8/2020: T-(<1), PSA-(0.1). This is the lowest PSA since ADT has been administered. Intermittent therapy shall be the topic for my 25 minutes.
It seems the PSA threshold progression is a critical point. Is it a mere value or velocity increase?
I met with my MO today. He is affiliated with the State hospital here in Connecticut. We discussed intermittent therapy and even the use of high testosterone. He cannot prescribe either of those approaches. But he did say that the MO at MSC in city can be reached to discuss through a zoom meeting. This shall be my next step.
Intermittent ADT in case of metastatic cancer is always a tricky thing because the risk is much higher. Not everyone is suitable candidate. However, it still is doable if the biomarkers and scan monitoring is done closely. Many doctors will not like to do that and would like to avoid the risk and extra work of surveillance.
Seems like you may be a suitable candidate as your Nadir PSA of 0.1 and Naditr T is less than 1.0. These Nadirs are excellent and my guess is you will do fine with intermittent but watch it closely.
Cycling of therapies for adaptive (Darwinian) stabilization between cell sub-populations would seem to me to need consideration of cell cycle rates. For example the work with LNCaP exografts in mice were used to develop the concept for BAT therapy. However, these PC cell lines are used for pre clinical research because they are fast growing and can demonstrate effects in a short timeframe.
But when this is applied to men with typically much slower growth rates in their cancers, then the cycling should take this into consideration with suitably longer on/off highT/lowT periods. It makes me wonder if the BAT clinical trial was sub optimal because of the monthly cycles. ADT cycling is much slower but criteria have been guesswork it appears.
I feel my left over PCa cells are soaked in testosterone these days as T is 250 now. Just the sight of T will stop them trying to change into cells who utilize something other than T. They may be jumping and dancing saying." "hey friends our real food is back here...Relax !" When PSA rose to 3.1 from 0.2 ..I got nervous and started Casodex and Finasteride...PSA dropped quickly back to 0.4. Sigh of relief ! I feel like I was feeling a few years ago. Energetic, happy, not tired much. Sexual desire and some performance returned and most importantly hot flashes and memory problems almost disappeared. Its very tempting to me to continue doing what I am doing . My Primary care doctor told me " keep taking what you are taking...your numbers are very good." Will update my oncologist about my adventures with Intermittent ADT, Casodex and Finasteride on Dec01.
Mateobeach..once T started rising, my PSA shot up sharply from 0.2 to 3.1 in 2 weeks and scared me into starting casodex+Finasteride. But its working good. PSA back to 0.4. Sharp rise...and sharp fall.
My biggest problem is how do I know that PSA rise was from normal prostate cells or PCa cells. I still have an untouched prostate100% intact so up to PSA 4.0 can be normal.
Tough nut to crack. My MO won’t prescribe me even Normal TRT without a Urologist signing off on it. I wonder how the bodybuilders access their meds?
Cancer is indeed very adaptive.
My analogy is weightlifting and endurance athletics. Your body adapts quickly to a certain stress. Continuing the same thing might cause little positive change or even a negative change. That said, some things (e.g. sound nutrition) don't seem to require any cycling. Not much negative adaptation to vitamins or minerals for example! No need to go to zero on B-12 and then to high levels
It is my opinion that cancer cells are similar to normal human cells and adapt to some stresses but not to others. For example, I haven't heard of adaptive surgeries or radiation. I'm certainly no expert on chemo but I think that the treatment pauses are dictated more by what the healthy cells can tolerate vs. an adaptation. Seems like the chemo drugs just keep killing cells. More chemo, more death.
So our job is to figure out when to cycle and when to remain constant. Similar to training. Some things you cycle. Some you don't.
Proper nutrition is likely a constant. And probably exercise. ADT can be cycled or it can be continuous. Depends on how long it takes for the PCa to adapt. SPT is a question. But like weightlifting certain markers can be monitored and logical decisions can be made. The micro-biome is probably a constant. That's my guess though and perhaps there are reasons to cycle certain bacteria in and out of the biome.
I don't do much in this area. My diet is mostly fruits, vegetables, and grains and I've read some medical doctors stating their opinions that fruit, vegetables, and grains are better than supplements to populate a healthy micro-biome (I've been a vegan off and on for 25 years - started in my early 30's when my athletic skills were waning and I was trying to delay the process).
By the way, TA, etc, I talked about radiation again with my onc yesterday and showed her some more studies. She was familiar with them but is really against radiation in my case. She didn't rule it out in the future but she said that she's very pleased with my progress and doesn't want me to entertain radiation or ADT (she assumed, as the Mayo docs assumed, that I would be in pain shortly after surgery). She's a strict SOC medical oncologist and it's amazing to me how she has watched what I am doing and how I am responding and now just tells me to keep doing what I am doing. She knows about the SPT. She knows my T levels are >3000 but she's 100% fine with it now.
However, the radiation oncologist was leaning towards early radiation. But after consulting with my main MO he became more neutral.
Thank you. Those are great links for me to study microbiome relationships. With regards to nutrition, would you consider certain supplements as nutriceuticals which perhaps should be cycled from time to time rather than kept continuous exposure? Especially those that seem to have some impact on PC or at least PSA (i.e. Curcumin), vs those that support overall health, protect from DNA and mitochondrial damage from ROS (i.e. metformin, l-carnitine, alpha-lipoic acid) and would more reasonably be kept constant.
You're spot on with my thoughts. I think that curcumin (I take mine with 1g of turmeric, 10mg of bioperine, some black pepper, some EGCG, a glass of green tea and some oil - or just a fatty meal). I cycle this. In general I cycle the things that might kill cancer. And the overall health foods/sups/drugs I take constantly. Only taking a couple of weeks off each quarter, on the advice of my doctor and some research from the NIH, to give my liver and kidneys a break.
Another bennie to cycling the suspected cancer killers, is that I don't have to destroy my liver or pick and choose which ones to take. I also don't kill my wallet
Ones I keep constant include metformin, a statin, vitamin D, red yeast rice (my experiments show that a verified brand of red yeast rice performs very well to reduce cholesterol and research from the NIH concludes that red yeast rice may be a better PCa deterrent than statins - I hedge my bets and use a low dose statin and some red yeast rice). I recently decided to constantly supplement vitamin D in a fairly moderate dose. But once a year I plan on doing a month of very high dose vitamin D. I'm going to start my first "high vitamin D cycle" in a couple of months and I'll monitor PSAs and blood markers to hopefully give me some kind of insight into what it might be doing.
With SPT I'm currently doing an experiment wherein I do 2-4 week cycles of lower dose T. By lower dose it should still be 1500+ (I'm taking a lab measurement Monday morning at the trough). Then 2-4 weeks of very high T. T should be 3000-4000+. Again, monitoring PSA. Interesting because I'm only two weeks into my first lower T cycle and I've gained a couple of percent of bodyfat. Not completely unexpected but surprising to me how much and how quickly.
Cat is ADT and finger is PSA.....Cat hits Finger...pauses...waits..as soon as Finger comes...hits it again. She is smart...She does not keep hitting when finger is "undetectable')
16 years ago, when I was 56, with PSA persistence following prostatectomy, I was about to begin salvage radiation - which, I was warned, was never performed with curative intent.
ADT (Lupron) was on the table, but I kept reading that it failed for the majority of men within 18-24 months. After that, there would be lackluster Taxotere & perhaps another year of life.
I had learned from PubMed that, at diagnosis, the androgen receptor [AR] was generally "wild-type" and that the alterations seen in advanced cases were always adaptations to ADT. What some now call "treatment-emergent".
The message was clear - put off ADT until needed. Treatment-emergent disease is difficult to manage.
A common term used back then was "hormone insensitive". ADT would fail when PCa no longer needed androgen. But this was incorrect - the AR remained in play for the majority of men, who were subsequently relabeled "castrate resistant". And so, the race was on to make us "more" castrate. A journey deeper down the Huggins rabbit hole, with perhaps even more unmanageable adaptations.
Johann de Bono, who was instrumental in bringing us Abiraterone and Enzalutamide, once fretted that there was no coherent plan B when Abi & Enza resistance set in.
Not that I am ungrateful. I will use palliative treatments when I need palliation.
I have sat on my typing hand when I have read advice given to hit the cancer early & hard. I posted a study in the past year or two that found that many men with metastatic disease feel that there is a possibility of a durable remission & even a cure with drugs that have been described to them as merely palliative. A surprisingly large percentage of men.
And even though other cancer types have been managed/cured with drugs that target multiple cancer cell survival pathways in concert, many men with PCa continue to be treated by drugs that only target the AR axis. There persists the idea that one should use a sequential approach. Good to have something in one's back pocket, etc. And maybe that's a good approach for older men with comorbidities.
LearnAll likes the kitten whack-a-finger analogy. Here's mine:
I share a room with a giant Norway rat. I would like to kill it but I lack the means. I have a newspaper which I can roll up to defend myself with. I can even attack him with it, but he would then become aggressive. And so I treat him gently.
My approach after salvage radiation failed to stall the cancer was to discover everything I could about the disease and to use supplements (unproven drugs), off-label drugs (unproven therapies) and testosterone (much frowned upon back then.)
The internet says that cancer hates oxygen. My rat loves oxygen. I use a nitroglycerine patch to keep him supplied. He likes it better than a tummy tickle.
He gets very irritable when deprived of testosterone, so I periodially revive him with a T boost.
Patrick..you made my day by this beautiful description of your "Giant Norway Rat" and how to keep it tame so he does not bite . When a friend told me that every morning I should talk to my cancer cells in loving manner and say " We are not enemies..we are part of each other...I want you to survive and please keep me alive. Dear friend, if one of us dies ..both of us die" I laughed and made fun of my friend...Now.I am understanding the symbolism of "peaceful coexistance" My wife says..In this Universe everything has its mind...cancer cells also have their own mind.. there is a micro cosmos in each of our cells.
Gandhi once said "Live and Let live"
I can't agree anymore about your concept of using all different means ..be it anticancer food, immunomodulators like Zinc and Vitamin D, lots of physical activity, and a a very logical, judicious use of medical treatments to prevent irreparably corrosion of our bodies .
Yes cancer has been my teacher too. Dreamed this night of a tiger sneaking up behind my wife in hunting mode. Moved her out of the way and then found the tiger some food. It seemed to be moving freely around the house. Reminds me of the tiger that must be dealt with in Life is Pi.
But we do have mine sniffing modern weapons like PSA, BALP, Albumin, Hb, NLR, PLR,LMR and of course high tech scans. We can know in advance where the mines are !
Maybe? APC is a most fickle and convoluted disease .
I think that this APC cornfield is like a maze for us all. Nobody has figured a way out yet. Being happily lost amongst the stalks .. is where it’s at . That’s really only possible when the APC isn’t actively chomping us down .
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