In the spirit of continuing cujoe's look at Adaptive Theory, I raise the question of whether early chemotherapy plays a role in creating resistance. Recently, posters/bloggers have been showing some of the early results reported from PEACE I trial, but the question remains as to what is good for the long haul.
Peace I looked at using radiation to the prostate, SOC, SOC plus abiraterone, SOC plus docetaxel, and SOC plus docetaxel and abiraterone. As many of you are aware, I am a fan of combination therapy. Was it a surprise that the combination of SOC plus docetaxel plus abiraterone resulted in the longest radiographic progression free survival?? Not really...
However, what is best for the long haul is the real question... What is best for OS, best for QOL, and best for not creating resistance to other treatments?? One of the concerns that I have with proponents of early chemo is the question as to whether this results in resistance to other treatments--Adaptive Theory??
In the CHECKMATE 650 trial (Immunotherapy), people that were chemo naive had a 25% response rate to Opdivo and Yervoy versus only a 10% response rate by those having previous chemo.
In the article below on using early Lu-177, those that had early chemotherapy had a poorer prognosis than those that used AR agents--abiraterone or enzalutamide--see below:
If radiopharmaceuticals and immunotherapy are the "treatments of the future", then does early docetaxel make sense for the long haul?? Would it be better to use SOC plus abiraterone first with prednisone, then change to SOC plus abiraterone with dexamethasone next using other options like SBRT for slowing down the adaptation of PCa cells??
Have I stormed the castle, created a hornets nest of controversy today?? Probably, but I think this is worthy of discussion.. Please note that every one is a case of n=1 and some have had amazing results using chemo-- gourd dancer being the poster child...
OK, unleash the dogs of discussion and let's have at it if you like...
Don Pescado
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1. Tall Allen mentioned something sort of related to this.
That FDG scans and PSMA scans each work best during different stages of the cancer.
2. There is some sort of recent statistical research that shows that when you are fighting an adaptive adversary (Covid, Cancer, whatever)
That it is best to hit it with everything at once as opposed to slowing escalating. This reduces its opportunity to mutate and adapt.
I believe this research is what generated the hypotheses that led to the research that has caused extensive use of "cocktail" treatments in recent years.
I think the question remains as to whether early chemo provides the initial resistance leading to decreased responsiveness to more modern therapies. I believe in the concept of cocktails, but finding the best cocktail is the key. Should early chemo be part of that key versus something else?? Each case is different, and so no two cases can ever be the same. PCa cells evolve differently. The science is evolving rapidly and new drugs are coming for that cocktail mix..Evaluating responsiveness to treatment based on genomics is evolving... Will we see chronic disease become the standard for most cases of PCa in the near future--say 5 years?? I think so...
"I think the question remains as to whether early chemo provides the initial resistance leading to decreased responsiveness to more modern therapies."
I think that is probably the wrong question.
I think the question is whether you can slow the natural mutation of the prostate cancer, to the point where you don't care about future responsiveness because you will be dead from other more natural causes.
And I think the growing consensus to slam any adaptive mutating adversary early and not give it opportunities to evolve.
If you follow the news, clearly countries that followed that approach got back to normal in weeks.
Those countries that didn't, are still losing people to the Covid-19 virus as I am typing this. And they are irresponsibly breeding new more deadly variants for the rest of us to deal with this coming fall.
Very interesting .This is a really tricky one. I am split both ways on this which is not helpful! Hammer it early or try and spin it out by slowing it down? I believe that some recent evidence may show some survival benefit for early chemo but is it only for a sub set. What do you think
I think researchers are looking at this genotypically to figure out who benefits from treatments and who does not benefit. By looking at germline and somatic mutations and treatments, they will find a higher level of success for patients in treating all cancers. Eventually, patients may have those tests and an AI will spit out your treatment plan, which may evolve based on new research and developments, and your reaction to treatment.. It will result in longer life spans for cancer patients and longer remissions/cures taking all factors into account... All IMHO...
I think each person must choose their path at this stage... As an oligometastatic patient, I chose to go IADT rather than continuous... I know of several others like me on these forums and almost all have had a vacation of more than 1 year... one beyond 2 years... Does a break in treatment prevent/ slow resistance?? According to game theory/adaptive theory--yes....
"The idea of treat to suppression, wait for recurrence, and treat again is the basis of gaming theory/adaptive theory. "
As intuitive as that is (it's what I used to intuitively think and it is what the insurers used to think), I believe that is now been proven to be an out-of-date approach.
You can argue about what are the best cocktails, to my knowledge no centers of excellence are arguing against them and they are all doing trials to get the right ingredient lists.
"Leaving out the fact that this was a manmade virus that has evolved faster than any other known virus may be playing a much larger role in the number of variants."
Man made or not is sort of irrelevant to the evidence. I am unaware of any logic that would make that point relevent. If I am overlooking anything, please explain.
It is perhaps a political talking point that many who desire to politicize Covid, might want to hear and repeat, but basically, all the evidence that counts is the difference between the response and results of different countries.
The science-denier countries killed their citizens, the science-compliant countries protected their economies.
At one point the US with 5% of the world population had 40% of the deaths. A loser response.
Australia, New Zealand, South Korea, Taiwan... Winner response, except when they temporarily lapsed.
Authoritarian science-denier countries Brazil and India, punching way above weight in generating needless deaths and needless economic self-harm.
And when the science-compliant countries lapsed and got complacent, they had unexpected flareups.
Those countries that didn't, are still losing people to the Covid-19 virus as I am typing this. And they are irresponsibly breeding new more deadly variants for the rest of us to deal with this coming fall.
I think the fact that this is a manmade virus and that it has evolved with more variants faster than other viruses does play a huge role in the fact that we face an up hill battle. Even more so than poor responsiveness. Each country has had various response rates to viral epidemics in the past, but has that resulted in large number of variants for each virus?? Answer--NO !!! This is different and the fact that it was created in a lab, possibly for biological warfare is a bigger factor in CoVid's ability to evolve than the poor response by some countries. We could continue arguing CoVid or stick with the PCa issue which is the reason for this forum, and the interest of all readers here..
Your other comment:
As intuitive as that is (it's what I used to intuitively think and it is what the insurers used to think), I believe that is now been proven to be an out-of-date approach.
Gaming theory is gaining attention, not losing it... The article from NCI that I posted to you earlier was in 2019. If Maha Hussain's study in 2013 that "your friend" loves to point out is so highly accepted, and one should do continuous ADT until death....hitting it with the kitchen sink..., then why are many MO's allowing their patients to take an ADT vacation?? Is it just QOL?? My MO has patients that followed a treatment strategy of SOC + Abi + SBRT for oligometastases and they are 4 years out off treatment. How do you explain that fact?? Do you believe they will be CR if they must have further treatment?? I do not....I believe they can repeat...
The new statistically based approach is based on pure math (though it is continually being validated in clinical trials) and assumes greater periods of respite, not less.
For illustrative purposes:
(a) repeated cycles of going in and brushing back 80% of the "infection" will breed new mutations and adaptations between each treatment.
(b) Going in with everything and killing 99% with each treatment not only gives longer periods of respite, but over the same amount of calendar time reduces the mutational evolution and adaptation of the "infectious" agent.
It's pure math backed up with clinical studies. Everyone is doing cocktails now. The leader in this approach was Dr. Myers. I remember people running around attempting to get Docs to do that, and the Docs just refusing to do so.
Before him, SOC was sequential escalation. And it was all the insurance companies would pay for.
2. Coronovirous
You are repeating misleading information about Coronavirous so I need to call you out on that. Sorry.
No one knows the source of the Covid virus, least of all you.
Maybe the Chinese government knows, maybe they don't, but they aren't talking.
The mutating nature of the coronavirus is well known, and probably predates the existence of humankind.
It is not some Chinese plot. It is the reason why we need annual flu shots instead of the once-in-a-lifetime measles shot. Measles doesn't mutate so much, Coronavirus, out in the wild, has evolved to do just that.
3. In my Opinion, You should refrain from Politicizing Science
Politicizing Science is not helpful to anyone's health.
As evidenced by the US representing 5% of world population quickly running up 20% of its deaths (and denialists refusing vaccines and getting violent over innocuous masking). The same with Brazil.
China, without any vaccine, snuffed out Covid-19, with indisputably less warning than the US, in about a month. They just shut down one city for a month and enforced mask-wearing. As a result, their economy grew during Covid, while that of the US and Brazil shrank.
There is no evil Asian conspiracy, just verifiably superior public health policy. Even if they accidentally released an engineered virus on themselves... it is irrelevant to what is a proper healthcare response.
And I wouldn't let your concerns about such a conspiracy interfere with the making of your health decisions.
Or in particular, encourage others here to do so.
This particular conspiracy is an especially dangerous one if you are Asian (even non-Chinese Asian).
Asians on the streets are running into enough problems without the spread of such uninformed conspiracies, don't you think?
The way the Science is evolving is mind boggling...they use Small Cell Lung Cancer drugs for NePCa now and with positive results... There are KRAS and EGFR inhibitors... what role will they play in developing a "cocktail" ?? I believe AI will play a larger role in treatment development in all cancers ... Keep them peepers on the Science....
We could not agree more on taking out the Mothership !!!! It is the source of initial cancer and evolves and speeds evolution by mRNA communication with CTC's. I took out the Mothership and the secondary Mothership using SBRT. Gene mapping is critical in knowing what mutations you face and finding a response to address them using other than SOC. Solid advice.
The fact that you took a second vacation longer than the first speaks volumes as to how effective your strategy has worked for you...
As time moves on, I believe that Adaptive Therapy will be the new standard resulting in slower progression to CRPC for all...
It does seem the treatment strategy, game, adaptive, or otherwise, may need to viewed differently for the very aggressive than for the more indolent. It also seems that since PCa tends to be a disease that gets diagnosed and treated in older adults, the long-term risks are partly hidden due to many patients dying of other causes. For one, I do not think that is the case, however, for the ever important QOL, which for many underpins their reason for wanting to live longer in the first place.
Like most cancers, the real risk is in the younger men, who will have a longer period for the cumulative effects of heavy upfront and continuous treatments to take their tolls on longevity and QOL. The tendency in most cancers is to treat more aggressively in younger individuals. I expect there is a large long-term ad-hoc clinical trial going on in that PCa population right now.
Thanks to all the commenters for expanding the discourse and thinking on these emerging treatment strategies. BS/SW - K9
I think you may be comparing apples (early chemo) and oranges (chemo in response to recurrence). In a brief look at the studies you linked, they just referred to chemotherapy naive versus prior chemotherapy without any mention of WHEN the chemotherapy occurred. Many of these patients could have come into these studies shortly after failing chemotherapy for recurrence. That could be significantly different than having early docetaxel and remaining progression free for a number of years.
Also of interest is that while the chemo-naive paitents fared better in the opdivo/yervoy study, they did note that there were two complete responses in each group, Also, I found the rate of side effects grade 3 (hospitalization) and 4 (life threatening) of 42-53% of patients to be astounding, not to mention the 4 treatment related deaths. So you're as likely to die from opdivo/yervoy as to get a complete response.
And also, a 25% response rate in chemotherapy naive patients is poor. The response rates for folfiri used as a second line treatment for NEPCa, IIRC, was about 1/3 had no response, 1/3 had stable disease, and 1/3 had reduction in tumor size. Opdivo/Yervoy has been mentioned as a potential treatment for me, but my genetic testing said I'm a poor candidate for PD-L1 directed therapy, so I'd probably go into a clinical trial for a new drug before trying that option, especially given my total of 27 cycles of chemo and counting.
I do not believe that they differentiated between early vs recurrence, but rather have you had chemo or not. I agree that the Opdivo/Yervoy study is not one that most people would sign up for unless desperate. None the less, the question remains what is it about chemo that leaves people less responsive to some other therapies , and is this the adaptive theory in action on responsiveness to those therapies?? Lu-177 is a choice that most people would make for treatment, and that is more concerning in this discussion on AT. Glad that Folfiri is working well for you. Wishing you the best of luck... Keep doing the 5K's and blogging...
Fish, you say, “what is it about chemo that leaves people less responsive to some other therapies??”
Isn’t it possible that in the case of Lu-177 patients that had chemo first had more disease than patients who didn’t, leaving Lu-177 with a much tougher job to do and therefore results weren’t as good as they were with patients who were chemo naive?
I do not think so... There were people that had abi and enza in the Lu-177 study and they had favorable treatment results. I have read other studies where people with prior chemo were less responsive to therapies than other treatments. I believe chemo is essentially poison, and what you do not kill with it, results in a tougher form of the cancer... For indolent cancers, AT makes sense. I think when you are a G9 or G10, attacking hard makes sense especially when more healthy, but I believe that poison and burn with the exception of SBRT will eventually become less prevalent in treatment. The new nanoparticle chemos may also be an exception.
Thanks Fish. Your statement, “I believe chemo is essentially poison, and what you do not kill with it, results in a tougher form of the cancer...” certainly gives me pause. Given the PEACE1 results I’m considering docetaxel, while I’m still relatively healthy and strong. This whole alternate way of thinking about indolent cancer certainly has its appeal. I do not relish starting chemo.
As I say, these are tough choices.... I believe you are in the "undetectables" and had SOC + abi+SBRT for oligometastatic disease... There is a friend here who is 2 years and 3 months out on ADT vacation, and JamesAtlanta is 16 months on his vacation. Both following SOC +abi+SBRT like me and you... My friend was G7 and JA and I are G8's... Hope you have a top MO to discuss the choices with and help you reach a decision. Did you have genetic testing?? The ORIOLE trial included genetic testing and SBRT for oligometastatic disease and that might help you in deciding as well...
I personally think adaption to treatment is not an active process, with the possible exception of Abiraterone, etc., which has been shown to actively cause changes that result in treatment emergent NEPCa in petri dishes.
Instead, I agree that the higher the tumor burden, the more likely it is for further mutations to occur that can result in treatment resistance. The evolutionary theory goes that the resistant cancer is kept in check by the cancer that isn't resistant by outcompeting it for resources. When you wipe out the non-resistant cancer with chemo or any treatment, then the resistant cancer is able to grow into the empty spaces left behind and without competition.
Given the YEARS of additional progression free survival reported by the PEACE-1 study, I expect people will live longer on average with the more aggressive upfront treatment, but yes, they may have a quicker decline once treatment fails because that cancer has survived so many treatments already, but that difference appears to be several MONTHS.
And of course, I had both early docetaxel and early abiraterone before the PEACE-1 results came out, reached undetectable PSA and had only minor fatigue as side effects, returned back to work full time (telecommuting 2 days a week) and ran a half marathon. The Stampede study said I had a 40% chance of being progression free for 5 years, but obviously I had to be a damn individual instead of a population
ps, my wife says I'm very talkative during the first few days of my chemo cycle, which just started yesterday. Apparently I'm also very type-ative too!
PEACE I is an incomplete study( partial results only). Thus, drawing a conclusion before all factors are considered may lead to an erroneous deduction. I'll wait for the final results before concluding anything from PEACE I...
I wrote this article to get people to look at AT and treatment options. It appears I have succeeded. For individuals with indolent disease, using AT as a treatment guide seems to make sense. How does one explain the results of cujoe, Nalakrats, pjoshea, Learnall, and others that decided not to go full SOC and took a different path ?? AT may be part of that explanation.
I used Covid to illustrated a point about infections and managing prostate cancer adaptative mutation.
Why would you politicize it?
3. "can you explain why people with prior chemo are less responsive to treatment with Lu-177 and immunotherapy ??"
Complex biological systems are complex.
I think you still never heard the original supplemental point I was making. LOL
4. Gaming Theory
It would seem to me "gaming theory/adaptive theory" is a nice shiny object, but...... I don't understand what you are saying about it. It's not making sense to me. But perhaps that is my personal deficiency.
5. My "Friend"
I don't use this forum to socialize. So I have no "friends" here.
I just give respect to where it is earned.
And I speak truth. Some people like that. Others don't. (see research from Royal Society B: Biological Sciences below)
And I call out foolishness when I see it, in order to limit the damage it does to the innocent onlookers.
Tall-Allen and Poshea have earned my respect. You actually have earned a fair amount of my respect, diminished a bit by your needless politicization of some black and white facts.
As best I can tell, neither Tall-Allen nor Poshea consider me to be a friend. And vice versa.
So that you may have animosity toward one or the other, probably shouldn't be the basis of any animosity toward me. Or Vice Versa.
6. The Real Problem
The real problem is mixing political ideology with healthcare decision-making.
According to the research, attempting to use reason is not effective in dampening this type of behavior:
"To steer people away from ideologically-motivated... we must focus on their psychological needs, such as meaning and belonging, and helping them attain richer, more satisfying, and better-balanced lives."
So my bad, I guess logic doesn't work so well.
Here is the research if you are interested in the mechanism by which politics seems to be corrupting healthcare decisions worldwide:
Leor Zmigrod et al. Computational and neurocognitive approaches to the political brain: key insights and future avenues for political neuroscience, Philosophical Transactions of the Royal Society B: Biological Sciences (2021). DOI: 10.1098/rstb.2020.0130
While having absolutely ZERO personal interest in political debates on a cancer forum, I would suggest in response (100% non-political) to your #4 above, that that "shiny object" you refer to has been at work since before terrestrial life climbed out of some slimy pond about 540 million years ago. Just sayin' . . . nothing new about it whatsoever, as in "What is old, is once again REdiscovered and called out as being "new".
"that that "shiny object" you refer to has been at work since before terrestrial life climbed out of some slimy pond about 540 million years ago"
Agreed
I was just attempting to supplement what I thought was an incomplete statement of the mechanisms at work.
Early and hard (vs long and sustained) reduces mutational adaptation. It just does. By the math.
How exactly to implement that requires clinical trials.
But the math doesn't change, and has been part of the "game" for billions of years before we discovered that.
Ritualized chanting of "game theory", "crypto", or "AI" doesn't make what one says right or wrong, does it? That is what I meant with the reference to "shiny object".
I think maybe you should take a look in depth at the AT models posted recently in AT Parts One & Two. I'm pretty sure the team at Moffitt is way ahead of you and me both on the concepts and the math involved. The math is way over my head, but the concepts that underpin the models are more easily understood. No doubt, AT has yet to be fully tested in the clinic, but Moffitt is doing that work now. A bit of their findings will be posted here in an AT Part Three that is in the works.
Again, Just Sayin'. (All in the spirit of learning from each other via civil discourse and shared information/experience.) Keep it Safe - K9
That's what happens when you follow certain people and never read the stuff in between. The filtering of info, either by the individual or by all the algorithms working in the background (for our benefit, of course) is why we live is such a polarized world. Clear out all the crap and you can almost be free to see both side of an issue again.
Parts One and Two are very easy to find just click on the "Posts" tab in the top menu.
It would seem that this AT model is based upon not dissimilar concepts from the concept of hitting the mutating cells hard and early from multiple directions. Killing as many as possible, then backing off to save your ammo.
But that mathematical modelling apparently indicated a different approach from this AT approach.
In both instances the goal is to reduce mutational adaptation.
On their face, it would seem only one of these approaches is right.
I guess the only way to determine that is clinical trials.
Dubious Question 1: 1) What country did the virus originate in? First cases??
Dubious Question 2: 2) Please give me a list of naturally occurring viruses that have been as deadly as CoVid and evolved into other variants so rapidly."
I am missing the logic of these questions unless and until I add a political context. Then all of the sudden they make sense. And then the anger also makes sense. The anger is the big tell by the way.
FitzGerald J. "Coronavirus: forgotten lessons of the Spanish flu pandemic". The Irish Times. Retrieved 14 June 2020. Yet the “Spanish” flu epidemic of 1918–19 resulted in about 25,000 extra deaths in Ireland, many of them young adults. This was almost as many deaths as occurred among the Irish fighting in the First World War.
But here is why none of that will satisfy you. Why no amount of facts or logic will satisfy you, ever:
Leor Zmigrod et al. Computational and neurocognitive approaches to the political brain: key insights and future avenues for political neuroscience, Philosophical Transactions of the Royal Society B: Biological Sciences (2021). DOI: 10.1098/rstb.2020.0130
Thank You
PS: Leading off with an ad hominem attack is another tell as is reliance on Straw Man Argument.
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