Risk Management (Taleb-style) meets Adaptive Theory (Moffitt-style)

[cujoe]

Those who know of the generational genius thinker, Nassim Taleb, should already be familiar with his concept of Antifragility, based on the notion of convex tinkering. And those who are aware of the concept of Adaptive Theory (as applied to human cancer) should also be well- acquainted with the pioneering work being done by the Integrated Mathematical Oncology Department at the Moffitt cancer Center in Tampa, FL. The following paper was done jointly by Taleb and Moffitt's Jeffrey West:

Working with Convex Responses: Antifragility from Finance to Oncology, by Nassim Nicholas Taleb and Jeffrey West, Entropy 2023, 25(2), 343, Submission received: 26 September 2022 / Revised: 23 January 2023 / Accepted: 25 January 2023 / Published: 13 February 2023.

mdpi.com/1099-4300/25/2/343

This closing excerpt from the paper summarizes the current treatment dilemma all patients with advanced/metastatic disease eventually face - and highlights the special debt we owe to those who continue to openly share their n=1 non-SOC protocols with our community:

* * *

There is active literature on “overdiagnosis”, see Kalager et al. (2012) [39] and Morell et al. (2012) [40]. The point is that treating a tumor that does not kill reduces life expectancy; hence the need to balance iatrogenics and risk of cancer. An application of nonlinearity can shed some light on the approach and clarify the public debate [1].

In a similar spirit of avoiding over-treatment, adaptive therapy in metastatic castrate-resistant prostate cancer (clinical trial NCT02415621) has illustrated the feasibility of irregular treatment protocols based on algorithms that react to tumor response. Adaptive treatment protocols maintain a stable population of sensitive cells in order to suppress the emergence of resistance [41,42]. Resistance, in some cases, is similar to the irreconcilable ruin of a financial “blowup” as patients may develop multi-drug resistance to structurally or functionally different drugs. The irreversibility of such clinical outcomes is similar to that of financial ruin, a tail fragility situation from which the agent cannot exit. Adaptive algorithms decrease the cumulative dose administered to a patient, lessening the selection for resistance [43]. While it is not an explicitly stated goal of adaptive therapy, these schedules increase both intra- and inter-patient dosing variance [44].

Last year (2022) saw the publication of calls from within the FDA to revamp the dose-finding protocols to be suitable for targeted therapies [45]. Traditional dose selection protocols invented for use with cytotoxic chemotherapies may not apply to targeted therapies that have exposure–response curves which plateau at low toxicities to the patient. Differences in convexity between chemotherapies and newly developed targeted therapies lead to differing outcomes in diminished returns of dose escalation and differing curvature of dose–response curves.

* * *

Here is a link to a short description about the paper by Jeffrey West in the online "LabPages" at the Evolutionary Dynamics, Interactions & Therapy Lab in the Integrated Mathematical Oncology Department with links to other resources there:

Antifragility & convexity in dose response, Written by Jeffrey West on 01 Sep 2022

labpages.moffitt.org/westj/...

And most importantly, here is a link to the many peer-reviewed and pre-print papers in which West was a participant:

labpages.moffitt.org/westj/...

And of special note to us PCa patients are the following Moffitt papers specific to PCa treatment protocols, i.e., single vs multi-drug agents at MTDs, lower dosages, or intermittent dosing combinations:

Multidrug Cancer Therapy in Metastatic Castrate-Resistant Prostate Cancer: An Evolution-Based Strategy, AACR - Translational Cancer Mechanisms and Therapy, July 15 2019.

aacrjournals.org/clincancer...

Range-Bounded Adaptive Therapy in Metastatic Prostate Cancer, Cancers 2022, 14(21), 5319; Submission received: 30 September 2022 / Revised: 25 October 2022 / Accepted: 27 October 2022 / Published: 28 October 2022

mdpi.com/2072-6694/14/21/5319

A Phase 1b Adaptive Androgen Deprivation Therapy Trial in Metastatic Castration Sensitive Prostate Cancer, Cancers (Basel). 2022 Nov; 14(21): 5225, Published online 2022 Oct 25.

ncbi.nlm.nih.gov/pmc/articl...

And finally this news release about their use of deep learning AI to better target precision treatment protocols:

Moffitt Cancer Center Uses AI to Develop More Personalized Cancer Treatment Strategies, May 28, 2024.

moffitt.org/newsroom/news-r...

* * *

Much going on at Moffitt that is worthy of watching. So, keep your dial on the Moffitt station and continue to be S&W,

Ciao - cujoe

[jdm3]

Brilliant!!

[MateoBeach]

This post is a tour de force, Cujoe. The very depth of the revolutionary concepts I am afraid will not land for too many here. I have not explored all of the pertinent references you have provided, but I intend to.

Let me offer my own simplified perspective on the “convex” model of anti-fragility. I believe it means that for low to moderate dose responses, that are less likely to lead to treatment resistance,there is an augmented overall response. (The first part of a convex curve). But the at higher dosages or persistence, there is a diminished responsiveness of benefit chiefly due to the emergence and increasing levels of resistance. This is the second portion of the convex function.

In other words, any treatment even if providing a favorable initial benefit will ultimately fail due to inevitable resistance. Adaptive therapy strategies is a particularly heat to overcome this inherent limitation. Pay attention ! Paul / MB

[MateoBeach in reply to MateoBeach]

Sorry about the spell check errors.

[Justfor_]

There is a paper regarding the half life of Bicalutamide as it varies with dosage. It covers values of 5 mg/day (my current one) up to 180 mg/day. In a graph depiction it has the shape of an inversed tilde (~). It starts with 7 days at 5mg/day then deeps to 5 days, resurfaces to 7 days again to finally get it's min at the 180 mg/day. To me this is an indication of how the human body reacts against this drug.

[cujoe in reply to Justfor_]

Thanks for the paper reference. As you know I'm currently using bical (+ 5ARi & low-dose tamox) and looking to either take a treatment break or do some dose reduction. My PSA has remained in the 0.2 to 0.4 range for the last 2 years - with a total-T in the 600-800+range and free-T at lowish 1%. (With multiple confirmed lymph node metastases, I'm no longer focused on getting to the somewhat arbitrary 0.1 "undetectable" level.)

Due to various treatment interruptions (to let PSA rise for PSMA scan and then a stop for RT treatment for gynecomastia) I've been on an irregular treatment program over that time, so there should be some adaptive diversity gained there. However, not wanting to stay too long with the current 3 drug treatment program, I will discuss some options with my MO at my upcoming appt next month. Currently, I'm just doing a full treatment break when I do a 3-day water fast, which I'm thinking of continuing @ 2 month intervals going forward.

I'm expecting you were already "on-top-of" this info from Moffitt and imagine that you are setting a bit of a standard for how to monitor dose reductions over time.

Μείνετε ασφαλείς και καλά, Ciao, Cujoe

[Justfor_ in reply to cujoe]

Please let us know if you make any changes in your current treatment regimen.

I am currently on a decision taking point. I was expecting a PSA of 0.012-0.013 and got 0.006 instead, but didn't change dosage as exactly one year back got another unexpectedly low PSA. If this running month will still be bellow 0.01 I will lower the dose. For quite few months I follow a 5+5+4 days (2 weeks - rinse and repeat) plan with split tablets i.e. 75 mg/14 days, or 5.36 mg/day on average. Dosage reduction will follow a 3 weeks plan in a 5+5+5+6 days sequence averaging 100 mg/21 days, or 4.76 mg/day.

From one of the references mentioned in the paper you posted I copy:

"Steering patient-specific evolution

This adaptive approach means that each patient’s treatment is truly personalized based on the tumor’s state and response rather than a one-size-fits-all fixed treatment regime (30). There remain several open challenges in designing adaptive therapies. First, treatments can aim to steer and control the eco-evolutionary dynamics to where the tumor finds itself in an evolutionary dead end (31), an evolutionary double-bind (32, 33, 34), or evolutionarily stable control (13, 35). Yet, for clinical practice, how to design such therapies remains difficult (36). ..."

This is exactly what makes the outmost sense to me. I read about "kitchen sinks" and "hit it hard" only to make me wonder how silly some can be.

[cujoe in reply to Justfor_]

Justfor_ - Similar to the Moffitt trial with mhsPCa, where they limited the initial ADT treatment period to a max of 12 weeks, through a strange set of circumstances at my 3-mo follow-up after my first round of ADT (following BCR#1), that was exactly how long I stayed on ADT. At my next appt 3 mos later, my PSA remained <0.1 and my T had amazingly recovered to 585 ng/dL, which was WAY higher than it had ever tested.

At that follow-up appointment, I chose to forego a second lupron injection and proceeded to stay "undetectable" for almost 4 years. Moffitt had 2 patients in their small hsPCa trial that also got over a year of undetectable PSA status after an initial ADT treatment. My experience later led me to wonder why ALL patients who get a good response from an initial ADT treatment (say, < 10 T and <0.05 PSA) are not "tested" for durability of that response by withholding treatment until PSA rises above some predetermined level.

As it turns out that is exactly the protocol that Moffitt employed in their trial. In their case they individualized their treatment programs based more-or-less on the criteria used in their crPCa trial of 50% reduction to stop and 2 x to start. To your point about the need for individualization of treatment protocols, the attached swimmer chart from the hsPCa trial shows the variations in treatment cycling that that criteria produced. The primary issue being that the universal treatment protocols that generations of PCa patient have been subjected to are summarized in the Taleb's quote from the posted paper:

"The point is that treating a tumor that does not kill reduces life expectancy . . ."

At my 3 mo appt with my MO after the stop of ADT (and with continued high-normal range T and <0.1 PSA), he said one of the docs on their treatment review panel recommended that I should consider "hitting it hard". Having been a bedside witness to 4 family members who died from cancer, I said I was not interested in a treatment program that was destined to have a heavy impact on my QOL and would instead continue to ride the treatment vacation horse until it threw me off.

When I think about all the people who are put on ADT long-term (heck, the "induction period" for IADT is usually 12 to 18 months), most would be at or near CR-status before they even start cycling. It has been speculated that that is exactly the reason the OS in the head-to-head trails of continuous vs intermittent ADT are nearly the same; i.e., after the induction period, most patients are on the verge of or have reached CR-status and, thus, derive no, or little benefit, from the cyclical effects in maintaining an ADT sensitive tumor population over time.

How many times have we seen people wander onto these forums who have been started on continuous ADT, only to find that they are in crPCa-desperate straits 2 years later and soon after that to be never heard from again. We know enough already for these antiquated SOC treatment protocols to change. Longevity + QOL would be the obvious benefits for all of us.

Swimmer's Plot

[Maxone73 in reply to cujoe]

I have been defined an “excellent responder” to triplet therapy. Not complete metastasis remission but quite good, and psa went from 70 at diagnosis to 0.03 few weeks ago. Now I am on adt (tryptorelin) plus daro. My MO is thinking about a new trial where they want to suspend and closely monitor patients like me that are below 0.2 and had a very fast 90% decline in PSA. I don’t know honestly…

[Justfor_ in reply to Maxone73]

I would drop the injectable ADT on grounds that it is not adjustable and find the Daro dosage that will keep your PSA at a low, but detectable, value. Proportional control is far better than ON-OFF control.

[cujoe in reply to Justfor_]

I assume this is the paper you are referring to?

Bicalutamide: Clinical Pharmacokinetics and Metabolism, by Ian D. Cockshott, AstraZeneca, Macclesfield, UK, Clinical Pharmacokinetics, 2004; 43 (13): 855-87

The link to the full article must be cut, patched and pasted to work:

sci-hub.st

/10.2165/00003088-200443130-00003

[Justfor_ in reply to cujoe]

Sorry Νo. It is the following one, but had to register to view it and there is a limit on the number of free viewings:

Levels of (R)-bicalutamide with a single 5, 10, 15, 20, 30, 50, or 80 mg oral dose of bicalutamide in men. Determinations were made using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). The mean elimination half-life of bicalutamide in this study was 5.6 to 7.5 days. Source of the values: (2006). "Pharmacokinetics of two novel bicalutamide formulations in healthy male volunteers". Pharmacology 77 (4): 171–8. DOI:10.1159/000094599. PMID 16847400.

Please also note that it extends up to 80 mg and not 180 that I wrote.

Saved values

[cujoe in reply to Justfor_]

I scanned the article I linked above when I found it about a year back., but never really got into the dosing details. I see that the link to the full article that I provided does not work, as for some reason HU keeps leaving off the "3" at the end of the hyperlink. (Maybe AstaZeneca/Springer is/are monitoring here? And are blocking Sci-Hub?; i.e., those damn Russkies are at it again!)

I tried several editing methods to no avail, so I've edited it by breaking the link into 2 pieces. Just copy and patch the two together (outside HU) and it should work fine in a new tab/window. The 21 page article (+2 of references) is quite detailed and I assume its author was a person affiliated with AstraZeneca, the developer of Casodex. I'm pretty sure you will find some additional useful info there.

If you can't get it to work and are interested in seeing the full paper, PM me via chat and I'll send you a PDF via email.

PS Thanks for the chart. The half-life variance being somewhat unrelated to dosage is a bit curious (to me). Attached is a chart from the Cockshott paper - which looks more like I would have expected for half-life ranges; i.e., mostly upward in relation to increased dosage.

Bical half-life via Cockshott paper

[Justfor_ in reply to cujoe]

Thanks for the table and your offer to send me the PDF file. I will pm you with my e-mail. At a first glance the 2 papers agree to the 30 mg dosage exhibiting the longest half life. But, this one goes further in detail to show that the inter-patient variance is of the order of x10, (2-20 days). This readily explains the varying per patient sensitivity to the drug and how silly the standard 50 mg dosage is.

[Maxone73]

+10 just for citing Taleb!

[cujoe in reply to Maxone73]

Max - I first found Taleb via his book the Black Swan, which basically predicted the financial crisis of 2008. I've since read his five-volume treatise on risk, Incerto. Along with Daniel Kahneman's Thnking Fast, and Slow, they are two of the most important books I have ever read. All of Talebs' books are very entertaining reads - and highly recommended. Skin in the Game, even in its title, reveals the nature of decisions where the risk is personal vs off-loaded to someone else. (Think Wall Street firms that used to be private companies where the risk was personal, vs the same now-public companies who take risk with other people's money - and unhedged risks are often 100% off-loaded to their customers and stock holders, i.e., CDOs, CDOs squared, etc. Also, something we cancer patients need to be fully aware of when our docs prescribe treatments or we signup for clinical trials.)

Michael Lewis's excellent book (The Undoing Project) about the collaborative relationship between Kahneman and co-researcher, Amos Tversky, is less of a slog than Kahneman's and contains the essence of their research into how our minds evolutionary structure interacts with the world in unexpected ways. ((After reading both books, I thought the Nobel Prize should have been jointly awarded to Kahneman and Tversy (posthumously). Michael Lewis' book explains why Kahneman would not have likely insisted on that - as, after reading of the very special creative dynamic between Kahneman and Tversy, one, IMO, would have expected he would have.)

PS - Max- as an AI expert, I don't know if you know of AI-researcher Lex Fridman @ MIT, but his podcasts with other researchers in AI and biology are pretty fascinating. He even has a recent very long one (@ 8+ hours) with Musk and the team that did the first human Neuralink Implant (incl the implant recipient).

Lex Fridman Podcast

lexfridman.com/podcast/

Here are just a few recent ones:

Elon Musk: War, AI, Aliens, Politics, Physics, Video Games, and Humanity | Lex Fridman Podcast #400

youtube.com/watch?v=Kbk9BiP...(Not working as expected?)

Aravind Srinivas: Perplexity CEO on Future of AI, Search & the Internet | Lex Fridman Podcast #434

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

Roman Yampolskiy: Dangers of Superintelligent AI | Lex Fridman Podcast #431

youtube.com/watch?v=NNr6gPe...(Not working as expected?)

Sam Altman: OpenAI, GPT-5, Sora, Board Saga, Elon Musk, Ilya, Power & AGI | Lex Fridman Podcast #419

youtube.com/watch?v=jvqFAi7...(Not working as expected?)

Yann Lecun: Meta AI, Open Source, Limits of LLMs, AGI & the Future of AI | Lex Fridman Podcast #416

youtube.com/watch?v=5t1vTLU...(Not working as expected?)

[Maxone73 in reply to cujoe]

yes! I find Lex Friedman the most informative in that field (basically, he lets them talk!). I know and read both Taleb and Khaneman but not the others you mentioned. I would add Harari and Mo Gawdat to the list…and the first book and author I read that talked indirectly about AI, the blind watchmaker by Dawkins. But Musk I cannot digest, he is brilliant but now he crossed that “I am the messiah” spot that he has been playing with for the past 5 years in my opinion 😂😂😂

[cujoe in reply to Maxone73]

No dissagrement Re: Elon. (And much of his sucess was financed directly or indirectly with tax-payer dollars - so how about just a tiny bit of humilty for our help!) However skip the Elon portion at the front of the Neuralink podcast and the rest is pretty good - and in some ways rather disturbing in the implications for the uncontrollable eventual merging of tech and biology. Dawkin's The Blind Watchmaker, captured me by title alone - and it challenges one to think about the nature of the origins of the universe. I maintain we are just part of a simulation. 👾

PS Lex also has a super-inqusitive mind and asks the sort of far-reaching questions that bring out the best in his guests.

[Maxone73 in reply to cujoe]

Yes, Lex does not talk much but he does it with purpose!

[cujoe in reply to Maxone73]

Always a quality of a good interviewer - and why there are so few of them. The best know about the person they are interviewing and are able "seed" the discussion and then let the response run - rather than trying to show how smart and knowledgeable they are. Many decades back in the history of TeeVee, Bill Moyers produced stand-out interviews for years at our Public Television Network (PBS) by displaying those characteristics. Most that came after him eventually were captured by their own "star-quality" and things went down-hill fast.

At first, I was sort of put off by Lex's dry monotone, but have now really come to like it. He also has a stealthy sense of humor that he usually uses with fine discretion. However, above all, his sincere interest in any and all topics gives him a depth that more narrow-focused people usually lack.

[Maxone73 in reply to cujoe]

I have been watching impact theory channel but I did not last long because the guy there cannot shut up, I was like “let them talk ffs!” (I cannot always switch immediately to something else because I listen to these channels while working out). Then I started with diary of a CEO, better, but once he was done with the best people he started hosting basically anybody controversial for the sake of it. Then I discovered Lex Friedman (when I have time) then Wes Roth (for technical hands on short info).

[marnieg46 in reply to Maxone73]

Yep. Agree with you about Impact Theory. It's tedious.

[Maxone73]

very interesting!

[cigafred]

No idea where you all find the time to listen to the long podcasts Lex does. I follow him on X, and maybe someday will find the time . . . . And great to see Taleb applied here, he is an exciting thinker.

[Maxone73 in reply to cigafred]

Personally I split Lex podcasts in 2-3 sessions, I can seldomly listen to something for 2-3 hours in a row!

[cigafred in reply to Maxone73]

You write "The free sharing of knowledge by two smart, big-brained experts in any field is, IMO, one of the great fulfilled promises of the Internet; i.e.,100% free education for anyone with a device that can connect to the net and the curiosity to use it." So true, in my macro field I wonder at the ability to watch experts discuss and debate, for example an X exchange just now between Mike Green and David Rosenburg--what an incredible window.

[cujoe in reply to cigafred]

I first really "discovered" podcasts during COVID, as I was doing 5 mile walks on a near-daily basis. I downloaded them as MP3 files (*) to listen to during those ~ 2 hour walks. I became a regular of the excellent Rich Roll podcasts and expanded from there. My curiosity is nearly unbounded, so I would much rather put on a 2-hour podcast than watch most anything on the TeeVee. I also used to listen to podcasts when I worked out at the gym, but now would rather interact with my fellow gym-rats than partition myself off with earbuds.

Of course, now many podcasts are running 4 hours or longer, so, like Max, I tend to break them up. The several Peter Attia podcasts with Dr. Ed Schaeffer are ones I still occasionally put on in the background while I cook dinner, etc. The free sharing of knowledge by two smart, big-brained experts in any field is, IMO, one of the great fulfilled promises of the Internet; i.e.,100% free education for anyone with a device that can connect to the net and the curiosity to use it. "Stay curious, my friends" . . . and be S&W,

Ciao - cujoe

(*) MediaHuman's "YouTube to MP3 Converter" freeware will covert any sound track heard on YouTube to MP3 format.

[j-o-h-n]

Never mind, I looked up Ciao on A i.

What does Ciao mean

ChatGPT said:

“Ciao” is an Italian word that’s used both to say “hello” and “goodbye.” It’s quite versatile and friendly, making it a popular choice in casual conversation. The term originally comes from the Venetian dialect, where “s-ciào” (short for “s-ciào vostro”) means “I am your slave,” a phrase used to express servitude or respect. Over time, it evolved into a more general greeting.

Ciao,

Good Luck, Good Health and Good Humor.

j-o-h-n

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

Any true NYC-based Yankee fan would never have needed AI's help with that word!?! 🙊

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

In the south Bronx and in the military we thought it meant food....

Good Luck, Good Health and Good Humor.

j-o-h-n

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

That's probably as close as one would expect for both.

[NanoMRI]

Very good discussion!

After the failure of my salvage RT and again after my successful salvage ePND, I was recommended for the STAMEPEDE trial; this being seven years ago.

Concerned for over-treatment I settled on taking one year only of bicalutamide, 150mg daily, after a deep discussion should I take a lower dose with a take-breaks strategy. Over six years later holding 0.03X (that pesky ultrasentive thing