BAT stumped, padding up for second innings

[kaptank]

G’day. This is another report on the saga of my BAT treatment. You will find previous reports in my profile but a very brief summary is: In late 2016 my zolodex ADT was failing, I started bicalutamide and a PSMA scan showed small lesions at paracaval and paraaortic nodes. After about a year the bicalutamide failed, I stopped taking it and commenced bipolar androgen therapy (BAT) against all advice.

I waited a month to allow the bicalutamide to wash through. My treatment then was to continue primary ADT (zolodex) and once per month an intra muscular injection of 400mg testosterone cypionate. PSA at start was 4.4, doubling at about 2 months. Two days after injection testosterone had gone from 0.3 to 54 nmol/L (normal range 9.5-28). T levels a month after injection were close to castrate again. PSA reduced over a couple of months to about 3.2 and was rising again at 8 months. I discontinued the T at a PSA of 3.9 and re-introduced the bicalutamide. In the first month PSA declined more than 50%. After 4 months it had declined to 0.5, about an 80% reduction. My latest PSA 2 months after that is a substantial rise to 1.4 and confirmation that bicalutamide resistance has re-commenced. At that point I stopped the bicalutamide (but continued ADT). The BAT lasted for 8 months, the rechallenge another 6 months. All in all, it more than doubled the time of effectiveness of bicalutamide and left me with a PSA about a third of the start. I had hoped for longer but we play the cards we are dealt.

I then discussed all this with my medical advisers plus my urologist suggested an additional oncologist. That extra point of view unearthed a possibility that had not previously occurred to me. I don’t think it is fully correct but it is worth considering. About 30% of PCa patients who suddenly withdraw their antiandrogen treatment (as I had when stopping bicalutamide preparatory to starting T injections) experience a significant drop in PSA and regression of disease for a period up to 8 months. It is called antiandrogen withdrawal syndrome (AAWS).

ncbi.nlm.nih.gov/pubmed/110...

Certainly the PSA behaviour during the T injection period mirrors that of a withdrawal episode. A classic case of the fallacy of post hoc ergo procter hoc? (after the fact therefore because of the fact). Possibly the T had little direct influence and it was a simple case of antiandrogen withdrawal syndrome –which in a few cases can result in a modest positive response to rechallenge by the antiandrogen. However the subsequent response in my case to rechallenge with bicalutamide was very significant and some kind of resetting, resensitising or reversal of resistance had occurred so there is something more involved than AAWS. However it could be a contributing factor.

I had not seen my usual onco since starting the BAT. She was cross at my folly and perhaps apprehensive of legal trends – here in Australia there have been high profile cases of oncologists being sued and struck off, essentially for applying judgement and varying the “standard of care”. Her remarks were interesting too. I am of course considering repeating the whole cycle to see what happens – I have stopped bicalutamide to let it wash through before restarting T injections. However I would not do it if there was significant evidence of progression since my last scan 2 years ago. After reviewing the PSA pattern since then, she said a new scan would be a waste of money and tell us little not already on the previous scan – good news if true. She suggested I continue with ADT, stay off bicalutamide for a little while and only reintroduce it when PSA gets to about 4, stop when PSA goes down more than 50% and cycle the treatment to try to keep PSA within limits. Of course she still does not approve of the BAT folly but I intend to mesh my repeat BAT with that cycle of on/off bicalutamide.

Here on HU there have recently been discussions on “adaptive, evolutionary management” and it seems to me that the approach suggested by my onco is an example of that. So is BAT itself – vary the tumour environment so it never gets to completely adapt to treatment. I think most good oncos do this anyway – when an agent is working, do not continue to failure (and adaptation) but stop when still working and re-expose the tumour to the original environment so the old unadapted cells flourish at the expense of the new adapted ones. When the unadapted cells start growing fast, hit them again with the agent. And so on.

healthunlocked.com/api/redi...

sci-hub.tw/10.1038/s41467-0...

So: conclusion. Yes I think it could be worthwhile in my case to repeat the BAT. I don’t recommend it. I am reporting my experiences and reasonings. We are all different and need make our own judgements. If we cannot cure then we should be thinking about managing it and finding tools for that.

Finally, the question of supplements. I take a varying range of the usual suspects. However I am thinking of changing that to supplements aimed at synergising with each of the phases of management: the BAT/no antiandrogen phase and the antiandrogen/rechallenge phase.

For the BAT phase, PARP inhibitors which stop the repair of the double strand DNA breaks produced by supra T. There are 2 known parp inhibitors over the counter(OTC). They are Quercitin and Bitter Melon extract.

Regarding the antiandrogen phase there are many targets.

1. AK1C3 inhibitors. AK1C3 is an enzyme that mediates the conversion of molecules like cholesterol into testosterone within the cancer cell. Implicated in the development of resistance. The best is indomethacin but I will need to ask my GP for a script. Then there is niclosamide (I have doubts about bioavailability), red reishi mushroom, green tea, black cohosh and Quercitin.

2. Broccoli sprouts, sulpuraphane and all things cruciferous

3. Anti inflammatories: curcumin, ginger, green tea, resveratrol, zyflamend, indomethacin.

4. 5 alpha reductase (5AR) inhibitors. 5AR is an enzyme that mediates the conversion of T into the far more potent androgen, dihydrotestosterone (DHT). Dutasteride and finasteride are pharmaceutical 5AR inhibitors. They have 2 disadvantages in my case: one is they mask PSA and make PSA results unreliable – and I need good PSA tests to determine as early as possible when resistance is starting. The second is that dutasteride, the best 5AR inhibitor has a biological half life of about 6 weeks which means I would need to wait for about 6 months after failure to let it wash through before starting BAT again. OTC agents include red reishi mushroom, saw palmetto (doubts about effectiveness) and green tea.

5. I have also noted some reports of synergy between Zyflamend and bicalutamide.

I have been wrassling this ugly beast for 17 years now and I am optimistic for the first time that it might just be manageable until I die something more pleasant (old age?).

[Hidden]

Congratulations! Yes, it seems that you are mimicking the adaptive therapy! and the target is to change PCa from a fatal disease to a chronic one, so that you die of something else.

[Hidden]

Please post you findings here, I'm doing research on BAT. Once I get a good foundation, will perform a "kaptank" like strategy based on my situation.

I'm a strong believer in not just sitting on SOC stage therapy, because it's working at the moment. And just wait when progression sets in - instead, take the Dr Myers approach of combination (probabilistic) therapies:

1/100 vs

1/100 * 1/100 = 1/10,000 vs

1/100 * 1/100 * 1/00 = 1/1,000,000

Obviously the risk is owned by the patient, with the likelihood of losing my Oncologist. The US is a litigious society, understand why the docs will not risk outside SOC, unless in clinical trials.

But, my PCa treatment is still based on 40 year old therapy...

[kaptank in reply to Hidden]

Yes. Nal, post your findings! There is a great deal of mythology and unsupported gobbledegook about T and prostate cancer. Its a flush that needs to be busted. Its still in textbooks and its still being uttered in lecture halls: "T is fuel for cancer." etc etc. Morgentaler comprehensively demolished it but its still "the paradigm". Even Huggins was clear: supra T may be as effective as ADT. The cases on which the myth was built had lousy case selection, questionable analysis (no PSA in those days) and numbers less than a handful. In case you haven't seen it this is Morgentaler's take on how the fantasy arose.

europeanurology.com/article...

[cujoe]

Kaptank, Thanks for taking the time to do such a comprehensive history of what can only be described as a "personal clinical trial" and for detailing what your logic was/is in its development . There are many others here who are in small or large ways challenging the SOC treatments and your information is of great value to us, as it provides first-person experience with "out of the box" thinking. The more we share, the more we learn. Keep that Optimism Going & Be Well - cujoe

[kaptank in reply to cujoe]

Thanks. I have found HU the greatest resource. I'm grateful you are all out there.

[cujoe in reply to kaptank]

Likewise!

[Jbooml]

Some have suggested that the desert T conditions of ADT promote Androgen Receptor (AR) avidity....consequently BAT somehow busts the cells by glut.

Following this reasoning supraphysiologic bioavailability is key to the knock up stage......perhaps upping the high T levels might create the desired response.

YOUR A VERY BRAVE THOUGHTFUL GUY.

[kaptank in reply to Jbooml]

There is some evidence that supra T turns off/knocks out the the ARV7 but there are about 8 different mechanisms (so far) by which supra T can possibly upset PCa - very complicated and my head hurt trying to read about it. Early on I tried upping the supra T by 50% and later a few weeks of continuous supra T but neither brought on any extra visible response (even a possible slight temporary increase in PSA) so I kept with the 400mg T cypionate that the Johns Hopkins people used - its the dosage we know most about but its choice was pretty arbitrary from the start. That gave me a bound T level of about twice the normal max and interestingly, a calculated free T level over three times the normal max. Free T should be what does the damage. There is great variability in individual responses to exogenous T.

[Jbooml in reply to kaptank]

Im using abiraterone..has anyone recommended it either monotherapeutically or con BAT.... There may be a valid thesis that by limiting evolving AR variants steroid supply you could direct the firehose at the wild T type receptors?????

[kaptank in reply to Jbooml]

The Johns Hopkins group have tested BAT against both Abi and Enza failure with encouraging results but small samples. I am starting to think that Abi, Enza and bicalutamide may have similar mechanisms of resistance despite their different modes of primary action as antiandrogens. There is certainly evidence that BAT may limit/turn off AR variants (among other things).There is so much we do not know. Its clear a major reassessment of the role of T is happening: eg T slows recurrence of low risk PCa:

practiceupdate.com/C/81090/...

See also Nalakrats latest post:

healthunlocked.com/advanced...

[Jbooml in reply to kaptank]

I can see i'm advising the professor...carry on, but please keep us posted on your very thorough treatment calculations...the one shining take away is that somethings likely to emerge head and shoulders above the current crop of contender meds that will drop a neutron bomb on our miscreant malignancies...looks like ill be in Oz this Christmas on our round the world adventures...I have a sissy in Melbourne.

Good hunting and stay well 🐨

[j-o-h-n]

"until I die something more pleasant (old age?)."

Like being smothered to death by four female naked Playboy centerfold models?

Good Luck, Good Health and Good Humor.

j-o-h-n Monday 04/01/2019 6:16 PM DST

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

Way to go!

[nobaday]

Very informative posts... thanks!

Why is it that there seem to be only a few trials with BAT when limited trials have shown BAT to be effective in a significant % of cases. Why are not more people using BAT? There seem to be a few small trials at John Hopkins but why not in other major centres around the world?

It looks as if after 14 months of Zytiga + prednisone along with Zoladex ADT I am becoming castrate resistant.

Any reason for me not to try the 28 day protocol of 400 mg testosterone... if I can source it and find someone to inject it?!

[kaptank in reply to nobaday]

Hi nobaday. There are a number of reasons why so few trials. Firstly there’s no money in it. T is a cheap chemical. The Johns Hopkins people are reportedly always looking for funds. Big pharma not interested. Secondly for the last 75 years T has had a curse put on it that it is dangerous with PCa, fuel for cancer. There has never been any evidence to support this. It rests on a simple fallacy of reasoning: low T good, therefore high T bad. That curse is still in place and institutions and researchers have to be very careful how they handle it. It takes a far sighted and very up to date doctor to even consider it. Judging from comments on HU, there are a few such doctors in the USA. Having said all that, there is a slowly expanding array of trials emerging. If in the US, have a look or ask your ONC what is available. Some of those trials go far beyond mere BAT, teaming it with the PARP inhibitors – a potential game changer.

Nalakrats has chiselled into his forehead the mirror image of the phrase “I am a reporter not an adviser”. It’s a delicate balance but in the end its you who has to make the decision and take the consequences. My conclusion, that the risks had systematically been over estimated was largely formed by Morgentaler’s demolition of the paradigm/myth although I was aware that some US doctors looked at and used T in a different way from the early 1990s and maybe earlier. Its important you do your own, serious risk analysis. I looked to the readily available community of body builders to try to figure what the risks of supra T were in the absence of PCa. With PCa, we do really only have the Johns Hopkins trials to go on. All other data relates either to non-supra T or T held supra continuously, not cycled as in BAT. So there are holes in my risk analysis.

I don’t know your history and that is important in any consideration of BAT. For example, a high tumour load, bone mets, pain symptoms are all cause for caution since such cases have so far been excluded from BAT trials so we just don’t know. My best guess is if you have bone mets or pain be wary. On the other hand, as I am finding out the more we are confronted with our mortality, the more we adjust our risk tolerance.

[nobaday in reply to kaptank]

Thanks for the speedy response.

My wife had asked me the same question on why high testosterone and BAT not more widely tried and I had given her the same answer that no money in it for the Big Pharma. So nice that u gave a similar answer.

My history is in my profile. I had a number of bone Mets on my bone scan. Recently I have had a tumour growing from 0.5cm to 2cm in my neck at C3 and my PSA has gone from undetectable in Oct 2018 to 0.025 in March 2019 doubling monthly. I have a bit of pain in my neck and am planning SBRT on a couple of weeks. I live in Vancouver Canada.

I see a few small trials as u mentioned with PARP and BAT but we will have to wait a year or so for any results from these. No trials in my area unfortunately.

From what I have read it appears that that I would find out quick if I get a response and I could resensitive to Zytiga which gives me no side effects.

[kaptank in reply to nobaday]

If I were you (and I'm not) I would do the SBRT first and see if it reduces pain. Zytiga has a short bio half life, so halt it a week before BATing. Your Onc may well recommend stopping anyway. If proceeding with BAT, have some pain killers handy. I regard cannabis + paracetemol + ibuprofen as good as the more problematic opiods. Get a baseline PSA before injection and testosterone and free T about 48 hours after injection. This will give an idea of how your body reacts and whether you need to increase or decrease dose. Do not take a PSA test in the first month. Take them at the end of the second and third month. If below baseline or declining, continue. If not, rechallenge with Zytiga. So you should know in 3-4 months from start.

There is another resensitizing agent that has been discussed in HU by some of our esteemed contributors. It is indomethacin, under trial in the US. Its a simple old NSAID with a well known risk profile. Worth considering.