I'm full of good news today. My sixth and last Docetaxel infusion was two weeks ago and I should be feeling better in the weeks to come. My PSA was last seen at 0.02 and is probably even lower by now, though my MO decided it's not worth testing every three weeks at such low levels.
The plan has been to add Zytiga+Prednisone after recovering from the chemo. However, out of curiosity I asked for a T test to get an idea of how much benefit Zytiga might provide. My understanding is that 50 ng/dl is considered castration level, but with prostate cancer you really want to try to get it under 20. My test came back at "<7", which means I don't have enough T for the test to detect.
My question to the group is: If my testosterone is already too low to measure, and PSA seems to be following my T levels, does Zytiga+Prednisone provide any meaningful benefit? Or just hassle and side effects? As far as I'm aware, the studies that showed the benefit of early Zytiga didn't look at T levels.
All of us should have such a quandary
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Congratulations on the great response. It is the Lupron that determines your T level. Zytiga prevents other androgens from being synthesized by your adrenals and by your tumors. It improves survival to tackle it on both fronts.
That’s why I have been on Zytiga + P for three months, alongside eSRT after post-RRP PSA reached 0.12... kill every androgen receptor- sensitive PCa cell in sight for two years, and hope for a cure, or at least a long break.
But now, having read all this “game theory” stuff about letting the T-sensitive PCa come back ‘a bit’ so it can help control proliferation of truly receptor-negative PCa cells, I’m beginning to wonder if I might be better off just sticking with the underlying quarterly gosrelin shots....
Is anyone else doing ultra-early Zytiga andbeen having similar thoughts?
Sorry for the shorthand - I was referring to this paper (I can't seem to post the actual hyperlink) which says men can survive longer by taking Zytiga intermittently:
It proposes cutting Zytiga off once PSA falls below a pre-defined threshold, and only restarting it once PSA rises past a set threshold. The idea is to avoid entirely killing off androgen-sensitive PCa cells and thereby creating space for (untreatable) androgen-resistant cells to proliferate.
The on/off cycle may be able to be repeated numerous times, with the fraction of resistant cells increasing only slowly, lengthening the time to castrate resistance and reducing Zytiga exposure.
They include modelling based on a range of possible growth rates for androgen sensitive and insensitive cell populations, and show that real-life patient results span the outcomes their model predicts. There are some pretty compelling results from a matched-cohort trial - all in all, it looks like a credible piece of work.
The paper is from late 2017 but I have recently read of others going down a similar track so I assumed this 'game theory' approach was becoming widely known.
Intuitively, it makes sense to me to keep something in reserve, even though we hear a lot about multi-mode/hit-it-hard treatment.
Thanks for explaining. This isn't a new idea. I have long been fascinated by the use of mathematical modeling for personalized therapy with intermittent ADT (whether it be intermittent Lupron or intermittent Zytiga). In fact, I believe that for the men in whom BAT works, it is because the cancer is a complex adaptive system (CAS). Mathematical modeling may someday be used for personalized intermittent androgen therapy, but the barriers to translation into clinical practice are formidable. Peruse ( don't bother trying to understand the math, unless you want to) these random older papers (I have dozens more in my files) on the subject going back as far back as 2003:
The reason these ideas have not been translated into clinical practice is that they require the parameters be estimated continually for each individual, and those difficult partial differential equations be solved and re-solved as one goes along. This is not a "one size fits all" kind of thing.
As the researchers mention, we are just starting to get the tools for individualized parameter estimation. It involves knowing the relative ratios of hormone sensitive and insensitive cells as therapy proceeds. This involves some very expensive CTC analysis. It's not something you can do roughly on your own - the math comes from chaos theory, which means that very tiny differences in the initial state can make huge differences in the final state - i.e., it can easily cause the tumors to propagate out of control.
If you are interested in this sort of thing, Celestia Higano at University of Washington Seattle has been working on it for a number of years. Also, keep an eye out for clinical trials.
Just for clarification... the theory in the article (called here "game theory") is based on the predator/prey theory (mainly Lotz- Volterra equations).. dates back to 1999 but published around 2007. Of course, also in this case you can find "instabilities" that induce hyperbolic dynamics or Lorentz atractors but this is not the point AT ALL!
I think that your explanations are really limited by the classical concepts delivered since years by the pharma industry which is OK for most but not for me.
Without modelling all is nothing more than trial and error and WE are the guys being tested but NOT the latest discoveries ... the standard medicine uses just what they know that generally doesn't work (their protocols are made based on OLD results (trial and errors) (apart of this stupid 5 years survival...) is really embarrassing in my opinion!
We'll have to disagree. Chaos and complex adaptive systems of cancer is totally the point - read the references I provided. Here are a couple of more, if you're into this sort of thing.
Allen... I already read this stuff since a while. I'm not sure about your knowledge of mathematics but I think that you are not getting the point of what you are talking about. Could you please explain me your "view" about Chaotic theory and and your hypothesis? Perhaps with some math model?
I think I do understand better than you - I attended the Mandelbrot lectures on chaotic systems at Berkeley. The point is that every tumor is a collection of different interacting cell types - some hormone resistant, some hormone sensitive, some healthy tissue of various types. At any time, for example, a cancerous hormone-resistant cell can send a signal (vesicle) to a cancerous hormone-sensitive cell, and trigger it to become resistant also. (These signals are constantly occurring across the various cell types). Hormones and hormone depletion trigger changes as well. To maintain dynamic equilibrium, it is necessary that the effects roughly balance out. If it goes too far out of whack, the equilibrium is unrecoverable (chaotic). The hallmark of chaotic systems is that small changes in initial conditions can make vast changes in the results (the butterfly effect). I have no ability to write differential equations on HealthUnlocked, but if that interests you, read those papers.
Oh.. dear.... understand better than someone else... attended Berkeley... good for you... I've have a PhD in Mathematics and Physics if this matters (I don't think so because I've done research and teached at several universities and have seen that titles and places where people have attended their courses do not give any warranty (even less regarding UNDERSTANDING...). I'm, in my research, I think a step ahead of you... your mindset is still anchored in Active Principles (or "drugs" to "extend" "survival".... ) well... in a chaotic system, as you should have understood such "simple" systems like drug or limited combinations of such, DO NOT FIT in a complex system AT ALL! Just think about non-linear systems. Furthermore, the chemistry of what is happening to what you absorb in your body is far from being fully understood.
By the way, you haven't answered the question of Miriam Mole:
Where is your model? Can you share it? Or your "model" is already described in your "explanation" above? OK, I agree that most people can be "satisfied" by your "explanations" (Berkely wooowwww! ;)) but formally it was none just free statements based on what?
Just for your info, in chaotic systems, the equilibrium can be re-established also..... and please, don't use the "butterfly" effect to explain chaos... this was a real (un)fortunate analogy introduced by Lorentz (meteorologist) in 72 to "explain" some of the ideas of the chaotic theory to the general public and this was, largely misused (In my opinion like in your case... don't take me wrong please...).
You've gone to the heart of it - lack of effective feedback to drive the adjustment process in anything other than an R&D setting... and the distinct possibility that something done early on drives the whole system in a particular direction.
That's my concern with my early use of Zytiga - the intent has been to make sure we supercharge the eSRT and then mop up every last bit of remnant PCa… but as one of your references says:
"In summary, any therapy relying solely on tumour cytotoxic effects will be curative only if it is sufficiently effective to overcome the tumour phenotypic diversity such that it kills all proliferative cells in a time period sufficiently short to prevent evolution of resistance."
Maybe using Zytiga pushes you further towards overcoming that diversity and killing ALL proliferative cells sufficiently quickly, maybe not. But the flip side isn't necessarily just eSRT failure and subsequent recurrence, it's potentially an earlier trip to CRPC-land....
Sometimes I reckon it might be better not to delve into this stuff, since there seems to be many more questions than answers...
That said, do let me know if you come across anyone who's been looking at the cellular dynamics of potentially curative ADT alongside SRT - recent papers out of Italy and the US still point towards 24 months for high risk disease, but I find this kind of hard to reconcile with the notion of a "... time period sufficiently short to prevent evolution of resistance."
And yet again, thank you for your encyclopaedic knowledge of all things PCA...
There is just no good data yet on Zytiga adjuvant to eSRT. However, data do show that ADT of any kind seems to be overkill for eSRT. One wouldn't be taking it long enough to worry about resistance - that is not the issue. You are mixing up two different things - adjuvant ADT for "high risk" localized PC is not at all the same as adjuvant ADT for eSRT. (even 24 months of ADT for "high risk' is too short to worry about resistance in all but a small minority of men).
No, I do understand the difference - my focus is on the RRP + eSRT + ADT situation, where doi.org/10.1016/j.eururo.20... makes the case that ADT alongside eSRT can make a difference for high risk (including pT3b) disease, albeit they are clear that outcomes are uncertain. A high PSA (so not eSRT at all then!) is their best indicator for ADT, but they discuss the likelihood that short PSADT also likely warrants ADT.
Until the SPPORT, SALV-ENZA and FORMULA-509 trails report back on the impacts of PSADT, high Decipher score and use of second generation ADT agents, those of us making these decisions just have to take a punt... and with a PSADT of ca. 4 months and GC of 0.91, I have voted with my feet.
But the more I read about resistance developing, I'm not so sure that the ADT durations being suggested for pT3B plus another high risk factor (18 - 24 months) aren't significant in terms of developing resistance... that's what I need to dig into. I think the flip side question has to be "If abiterone does such a great job of starving any dispersed PCa cells, why would it need so long to wipe them all out?"
What's confusing you is vocabulary - "high risk" is usually reserved for localized cancer before any therapy. NCCN defines it as GS8-10 or T3/4 or PSA>20. What you're talking about is prostatectomy with high risk features (like pGS8-10, pT3/4, positive margins and/or persistently elevated PSA). eSRT - early SRT - usually means that PSA is still low - below 0.2. If SRT is done because of high risk pathology only, it is called adjuvant RT.
So focussing on SRT, which seems to be your concern here, the Fizazzi study suggests that longer term adjuvant ADT may be beneficial for men who have multiple high risk pathology features. There is no suggestion that resistance is even a small issue - you are fantasizing about that and creating your own anxiety. in fact in RTOG 9601, the men were given ADT (Casodex) for 3 years without any resistance issues. Hormone resistance during metastases is a completely different phenomenon from the case when the cancer is confined to the prostate bed.
Hey, hey. This is not a political site. But anyone whose platform is breaking up Amazon and Facebook should buy a TeePee quick. I understand they are on sale online at Amazon. She'll probably be able to see Russia out of her porthole. I think I spent enough on Amazon online just this week to finance Jeff Bezos's next divorce.
I agree. I had three different doctors tell me they would not prescribe "early" (before castrate resistance) Zytiga after early chemotherapy. They all said to wait on the Zytiga. One of their arguments was that early chemo and early zytiga has been proven, but not both together. That's what I did and I'm now on Zytiga after castrate resistance. Last PSA was undetectable.
I agree with Gregg and Nalakrats. I had early chemo and my MO said to wait until PSA reached 2.0 (up from undetectable) before starting Zytiga. That’s what we did. PSA went back to undetectable in a month and has been there for 15 months.
Good Dvice for those of us closing in on negligible PSA levels...I just cant imagine getting approval for 'pulling'..ie stopping ANY medication from my overprotective medoncs..
Thanks everybody for the thoughtful replies with a touch of humor thrown in. After considering the evidence and sleeping on things a bit, I'm inclined to give Zytiga a try. While "game theory" is an interesting concept, it's really about controlling the cancer instead of eliminating it. If I was to follow that approach, I probably shouldn't have had that second Lupron injection, never mind the Zytiga.
So given my great response to Lupron, not to mention chemo, I'm already well down the path of killing as much cancer as possible. Adding Zytiga just might help eradicate a number of my many metastases. If I should be so lucky as to get down to a few remaining metastases that you can count on one hand, that might open up some treatment options that are currently unavailable to me.
I still like the idea of taking a break from treatment sometime in the future, but more for quality of life and to give the bones and muscle a chance to recover.
I have a huge problem with current standards of care treating a disease that ostensibly doesn’t exist....it’s a unique feature of PC therapies...Personally I believe you’re making a good compromise in Zytiga. It’s supposed to block most of what else ails...keeping in mind Dr Liebovitz’ contraquip reminding us that so many non traditional illogical approach’s outlast standard logical.....but his results do come with a very important caveat....his successes rely on low metastatic outset’s....not my particular case..so I’ll stick somewhat reluctantly to the SOCs my Docs unrelentingly demand.....until, as I remind them the next big thing brandishes its steely cutting edge.
You are doing a great job in suppressing T. Keep it up. My guy wanted <5. I got it. While T is suppressed let the magic bullets do their thing. I don’t know much about these new drugs after 2004 as, although they were in the arsenal over the years, I never needed them. A six month Chemotherapy with ADT Trial with multiple agents did the trick for me.
Rejoice that T is suppressed. Forget about breaks until your guy can not find anymore cancer in your body.
Sounds like good advice. If I'm reading your profile correctly you were on ADT for about six years before the mets resolved? Wow. I expect I'll feel better about ongoing ADT after the body has had a chance to recover from chemo. Right now my attitude is best described as "stop kicking me!"
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AST and ALT levels higher a week after stopping Zytiga? 
Who got their T level done before ADT?
Fluctuating sugar levels on Zytiga and Prednisone
Problems with Zytiga?
Does Zytiga work or not?
