Testosterone to TREAT prostate cancer - are they crazy? No - it just may work. (mCRPC)

"It's like throwing gasoline on a fire!" some say. Once again, similes and metaphors fail to help us understand biological systems. In real life, steroidal hormones (like testosterone, estrogen, progesterone, cortisol and Vitamin D) and other molecules called ligands, can both help and/or hinder depending on concentration, the state of the system, and the specific receptors they activate. It's beginning to look like testosterone is just such an agonist and antagonist with respect to prostate cancer.

Bipolar androgen therapy (BAT), where periods of androgen deprivation are alternated with injections of large amounts of testosterone, seems to slow down and temporarily reverse the cancer in some men who are metastatic and castration resistant. It also may restore lost sensitivity to second line hormonal agents like Xtandi and Zytiga. And all that comes with the added benefit of feeling darn good for a while. It's still early, but you may wish to learn more about it:

Testosterone to TREAT prostate cancer - are they crazy? No - it just may work. (mCRPC)

But you can hardly blame people for their "smiles and metaphors" because of their incomplete understanding of experimental "we thinks". In fact "incomplete" may be the operative word. Even in clinical trials "not everything turns out the way you think it should".

Well, yeah, but why use ADT if testosterone does not play a role in PCa...I think it is pretty well established that ADT has a negative effect on PCa. Is there some other mechanism that you know about other than suppressing testosterone ?

sheepguy, it's been known (as well as anything in science is known) for a long time that testosterone has a role to play in PC. 20 years ago, it was commonly understood that PC cells 'fed' on testosterone, and shutting down testosterone had the effect of shutting down the cancer.

Now, that understanding was incomplete--no one today would use the same language--but that is also the nature of scientific inquiry. Always remember that the most common result in science is "no, that didn't work".

As we've developed better tools, and better understanding of what is going on with PC, it makes sense to ask, "what is the optimum T level for cancer suppression" and even "what if we cycled T levels up and down...what would that do?"

I kind of like the "throwing fuel on the fire" metaphor: sometimes the best way to put out a forest fire is to start a back-fire. Fighting fire with fire DOES work...sometimes.

Of course, Halbert, "everyone knows that". and of course the language is different. But the insinuation, to many, is that testosterone is not a factor no matter what the "optimum level" or if it is "cycled up and down". I understand the notion that guys like to take T..because.."it's not you , it's a number" but they should realize it is still a factor. I'm not sure I agree that the most common result of scientific inquiry is failure..but that' beside the point.

sheepguy, you get to the real heart of the matter: "Joe Public" is remarkably ignorant on matters of science...and the popular press doesn't help any. Add to it the publish or perish mindset of researchers, and you have a perfect storm where incomplete or inconclusive information is published as FACT and NEW DISCOVERY and so on (remember cold fusion?).

Testosterone does seem to have a role to play in PC..which makes sense, by the way. The Prostate is one of the prime recipients of Testosterone in the body....and if the receptors get out of whack, something bad would likely happen.

Saying testosterone has no role in the development or growth or severity of prostate cancer would be irresponsible to a very high level. Hopefully nobody serious is saying that.

In the late 1980s, I was fortunate to attend a series a lectures at Berkeley by Benoit Mandelbrot, the father of chaos theory. I walked away stunned - this changes everything, I thought. At least everything since Aristotle and later Newton laid the groundwork of reductive science and linear cause and effect. Within ten years, the paradigm shift had worked its way through the higher level sciences (like biology and genetics), economics, sociology, ecology,politics, AI, the theory of consciousness, information theory, and almost every sufficiently complex discipline we consider to be meaningful. Unlike me, the new generation is being trained in the new way of seeing the world.

To those raised with the new paradigm, it will come as little surprise that testosterone moves the cancer system in one way, given one set of initial conditions, and another way, given a different set of initial conditions. And that such factors as rapid increase or decrease have an enormous effect. Unlike the previous paradigm, effects are never completely predictable. They can only sometimes move towards an average effect (called a "strange attractor.") They will also move far from that effect, in a completely unpredictable way (chaotic), if moved too far from a certain position. The effect is also a cause that can destabilize the system.That's inherent in the nature of all cancer cells, in cancerous tissues, and in the human host of those tissues.

The old way of reductive thinking about biology is becoming increasingly unproductive.

I have a whole folder on mathematical models of hormone sensitive and resistant prostate cancer based on chaos theory. The goal is to create a personalized hormone therapy based on each individual's circumstances. The systems of partial differential equations, and affine transformation matrixes are too much for my poor brain to comprehend. If I ever manage to wrap my head around it, I'll write it up.

Seeing life as a complex adaptive system is more useful to me in understanding cancer than any reductive explanation. The way I look at cancer is the variance or "noise" whereas healthy cells are the mean effect or "signal." The noise is always there in the background, because it is a necessary consequence of the signal being generated. The only way to eliminate the noise completely is to eliminate the signal completely - they are part of the same complex adaptive system. Normally, control systems, like negative feedback, assure that the signal predominates. Sometimes, through positive feedback, the noise overwhelms the signal.

sheepguy - T does play a role in PCa, as long as the patient's T level is above castrate level. If a patient's T level is below castration level (is that 20 or 50?), prostate cells and PC cells along with them, begin to slow or stop multiplication. If, however, the patient's T level is really low or normal, as long as it is above that castrate level, the cell division/multiplication of prostate and PC cells goes on at a normal level. If I understand saturation theory correctly, more T does not make more prostate cells. Enough T will allow them to replicate. Not enough T will stop that.

And I will apologize for airing my personal vent about PC, T and external T deprivation. I'm just still angry about having to stop the external T and probably have my T level drop to really low levels, but above castrate level, so I get all the side effects without the benefit. I'm hoping it doesn't drop that low, but really have no confidence that it won't.

Paxton -

50 is the "official" definition of castration, but a lot of doctors would like to see it go lower - below 20, if possible. This new data is raising questions about that.

- Allen

Hello all,

Last winter after failing Zytiga, I was offered the BAT trial for MCRPC though the University of Michigan. I met with Dr. Megan Caram. She described the trial as consisting of a "randomized phase II study comparing bipolar androgen therapy vs. Enzalutamide in asymptomatic men with mcrpc."

One of the less likely risks, (between 10-50% chance this will happen) as described in the information about risks and benefits of the testosterone injections scared me a bit. I felt that a 50% risk was too much of a chance that my mets would progress, so I decided to go with something that was more of a sure thing.

I decided to decline the BAT study and go on to Docetaxel chemo. One of the exclusionary criteria for eligibility was having chemo.

Fast forward to today, I just had my seventh chemo infusion this afternoon. I have been experiencing BRUTAL side effects from the chemo and I continue to kick myself for not joining the BAT study when I had a chance. My hope is that In the very near future there will be another study allowing patients that have had chemo be a part of the study.

There are several studies that I would really like to be a part of. In the mean time.....I sit here waiting for the chemo to fail. I am actulally hoping that it will fail fairly soon. I know that sounds crazy, but it is what it is.

C.G.

I'm afraid the math is way beyond me, having finished my math education with 2 semesters of Calculus. One could describe biology as the ultimate adaptive system, of which the evidence is all around us. What is a Darwinian 'environmental stressor', if it's not the very thing that pushes adaptation to the new environment (evolution).

Very interesting...and certainly an indication of where the research is taking us.

I'm a big fan of complex adaptive systems theory and have used it in my own work (in Jewish education!). I'm also, and probably more relevantly for this thread, a participant in the second of the two trials that Tall Allen cites: the one that is comparing BAT and enzaludamide. I became CR early in 2015, did a clinical trial with ipilimumab (progression after 2 months) and went on abiraterone in the fall of 2015. I had good results for two months, but then progression. The next step was the BAT trial. I was randomized to the enzalutamide arm and experienced an extremely rapid rise in PSA and ALP from 42 and 47 respectively in March 2016 to 256 and 533 respectively in June, when I was switched over to the BAT arm. Since then my results have been as follows: July: PSA 220, ALP 550; August PSA 123, ALP 358; September PSA 89, ALP 197. My scans do show extensive bone metasteses and a likely metastasis to the liver, as well as to various lymph nodes. But, the declining PSA and ALP numbers and the fact that my energy level has increased leads my oncologist to believe that it is worthwhile continuing the BAT. Obviously, it's too soon to know whether the BAT will produce a decisive change for the better and whether I will in fact be resensitized to abiraterone or enzalutamide when the time to try these again comes. But, it has certainly bought me a few months and the plus of feeling better as well. So, whatever the theoretical basis, I'm glad that someone decided to test it out.