End of STAMPEDE, what to do?

[lss65]

My guy has had success with no recurrence of CRPC on the STAMPEDE protocol - originally he was Stage IV, Gleason 9, had prostate removed, had 2 soft tissue mets found on PSMA, treated with radiation, and is BRCA2+. He had rapidly progressed to CRPC early in the cancer. He has been told he could possibly be cured of the cancer, and his mother who now is in her 90's was Stage IV breast cancer, BRCA2+ in her 50's and was cured. I know he hopes for that.

He has temporarily opted to continue with the abiraterone, prednisone and lupron, but the past 2 cycles of lupron have created significant mental health effects that it had not done before, significant enough that if they are not reversible as the lupron decreases in his system, it will be a problem.

I would hate for the lupron to effectively destroy his life through mental health side effects, after his getting this far with the cancer RX, and he has considered an orchiectomy, but is not thinking so well at the moment. I'd like to put together a list of options that he can consider and focus on as the lupron decreases in his system - the last go round, as the lupron level decreased his mental functioning improved and I am hoping for that same trajectory here.

I think whatever he does, he has to get off the lupron - he had a 4 month shot 3 weeks ago, and it is causing far worse problems than his former 3 month shot had caused.

Given this history, how is it best to think about what course to pursue?

And are there specific oncologists who are working at the forefront in this area, and will be accessible and have good judgment - any location is fine, preferably in the US, but not necessarily. We can travel. His current oncologist is inept from my perspective, but my guy was fine with her until now since he made sure he was on the STAMPEDE protocol, after consulting with Sartor at Tulane. Since he has done well on the protocol, he hasn't revisited his strategy regarding doctors. However, he is open to finding a better oncologist; again, I need to do the leg work for him.

Any thoughts appreciated.

[lss65]

He lives in Michigan; I am in DC. Either location, or somewhere close, would be best.

[Tall_Allen]

Consider orchiectomy. At U of Michigan, I think Joshi Alumkal is a good MO.

[lss65 in reply to Tall_Allen]

We were just beginning to discuss the orchiectomy when the bottom fell out emotionally, and I doubt we'll get much stable and productive conversation about it again for another few weeks, if the last go round on lupron is any indicator.

I think his big question is going to be - should I hope I am cured and explore that at some point, or should I do an orchiectomy to maximally protect myself, whether cured or not?

Is it productive to think about being cured given how aggressive and fast moving his cancer was at the start?

I guess this is the dialogue he needs to start having with an MO with good perspective, and now he needs to also take into account I am getting affected by the decisions he is making about his medical care - these past two cycles of lupron are the first time I have felt like I was getting pulled into his medical situation, and also have had to step up and research things because he is too chaotic inside to motivate and do what he had been doing pro-actively and aggressively in staying on top of things.

Thx for the referral.

[lss65 in reply to Tall_Allen]

We are seeing Joshi Alumkal today; or rather my guy is, and I'm being pulled in by Skype. Thx for the referral.

[Tall_Allen]

There have been good survival increases with PARP inhibitors among those with BRCA2 mutations. Their use cut the death rate by 31%, with 95% of patients reduced by half to none. Based on their data, cures did not happen.

nejm.org/doi/10.1056/NEJMoa...

[lss65 in reply to Tall_Allen]

thank you. that would be my gut feeling on this as well. cancer has been too aggressive and he had the two mets very early on. for two years he sat around waiting to die, and now that he hasn't and it is 3 years out since finding cancer, he is trying to gain his footing again. the first thing he needs, though, is to get off the lupron. for hm, it has become too toxic, putting more in his system, if there is any other option. this is not a good drug for people who have dissociative tendencies, and often those people are the most creative and driven. they should be steered in a different direction.

[Tall_Allen in reply to lss65]

If you dislike Lupron, you will hate PARP inhibitors. Side effects are very high.

[lss65 in reply to Tall_Allen]

thank you for the heads up. are the side effects also mental/emotional? if so, I think we need to consider getting my guy on psych meds if and when he progresses and needs a PARP inhibitor, because this came close to unmanageable on Thursday, and now isn't perfect but much more stable. sarcasm: he is going to love this suggestion from me.

this is the kind of information I need, btw, so thank you. I was taken by surprise by the sudden cognitive/mental changes from the lupron, as it hadn't had a noticeably detrimental effect before. and along with dissociative processes, he stops being able to manage his own care until he's better held together again. Hadn't been prepared for that either.

[Tall_Allen in reply to lss65]

Much of the mental health of cancer patients is geared to alleviating anxiety and depression. I've seen very little on dissociative illnesses from PC drugs, but since many cross the blood/brain barrier, it is probably underdiagnosed. There is one anti-androgen, Nubeqa, that was specifically designed to not cross the blood/barrier and it doesn't activate GABAA, so there may be less fatigue. It is only available right now for men with non-metastatic castration-resistant PC. But your husband's oncologist might be able to make the case for compassionate use of Nubeqa as a monotherapy (without Lupron). As for the PARP inhibitors, there is significant fatigue, but I could not say whether it exacerbates dissociative episodes.

[lss65 in reply to Tall_Allen]

You know, so many women have reported personality changes in their husbands on lupron, that I sure this is underreported. Most people don't know what dissociation is. But everybody is susceptible to it - the question is how strongly, and how fragmented will someone become. And then what state does the absence of testosterone and other issues trigger the person into. This may explain the fact that some men start affairs and leave spouses when they go on lupron. They literally have changed and can't imagine being anyone else.

A big question would be about the interaction between the lupron and some of the psych drugs that can help someone stay integrated, like risperdal or zyprexa. I am very curious what receptors the lupron is hitting in the brain to trigger the dissociation and when I have a moment will look into scientific papers and see if any work has been done on this front.

An anti-androgen that does not cross the BBB seems desirable, assuming there is nothing that needs to get hit in the brain.

The only reason I have had tools to deal with my situation is the fact my son had encephalitis and was recovering for many years and is just now coming out of it - I instinctively went into the "holding" mode I was in with my son to stabilize where we are now. It is helping.

In our case an orchiectomy seems like the best next step. Whether I can get past the mental health effects to someone who can make decisions again remains to be seen. When someone is fragmented they lose the core from which they make decisions, the "person" that holds them together. They only react from the state which they inhabit. Last go round with the lupron the lupron effect increasingly wore off as he came toward the end of the cycle. I'll cross my fingers that happens again.

ty so much for your thoughts and all the info.

[lss65 in reply to lss65]

just found this in the pdr:

Risperidone: (Major) Avoid coadministration of leuprolide with risperidone due to the risk of reduced efficacy of leuprolide; QT prolongation may also occur. Risperidone can cause hyperprolactinemia, which reduces the number of pituitary gonadotropin releasing hormone (GnRH) receptors; leuprolide is a GnRH analog. Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Androgen deprivation therapy (i.e., leuprolide) may also prolong the QT/QTc interval.

I expect that risperdal helps hold someone together, and lupron is having the exact opposite effect, causing someone to fragment. Zyprexa is also determined to have major interactive effects with lupron.

[Tall_Allen in reply to lss65]

Now that you mention it, I have a friend who has offered had bouts of "depersonalization," that seem to be more frequent now that he is on Lupron. He was always a little bit "on the spectrum," but he seems more autistic and more confused by other people than ever.

The FDA has a program called Medwatch:

accessdata.fda.gov/scripts/...

You can report or have his doctor report unexpected adverse events. If enough people report it, the FDA may issue an alert to patients, or drug companies may work on something to block those effects.

[lss65 in reply to Tall_Allen]

this makes sense. there is a theory that dissociation occurs when someone has a small autistic capsule, usually bc of some trauma, developmental or environmentally induced. and everyone has lots of micro traumas, its people who have more significant traumas that become obviously dissociative. You mentioned GABA, and too much glutamate contributes to autistic symptoms. If lupron is affecting GABA, then this would likely be where the problem lies. There are meds selective to the GABA system, even CBD oil, that can counteract this effect. In order to effectively treat my son's encephalitis, we discovered he had a glutathione deficiency, which led to too much glutamate. We've been able to counter this in working with a psychiatrist with a deep scientific understanding of pharmacology. Interestingly, my son is a bit on the spectrum, and is a math genius, which goes along with that. He is very social and has a lot of friends, so most people would not pick up on his slight spectrum qualities. But they have always been there.

I need to make a follow-up check in with my son's psychiatrist, so I am going to pull together some info on lupron, and then ask the doctor what he thinks about all of this. He's extremely creative and well-published.

[lss65 in reply to Tall_Allen]

found two papers when put together probably delineate what is going on - one is about the glutaminergic system dysfunction in autistic conditions, and the other is about that GABAA receptor. what is interesting in the second paper is that the change at the GABAA is assigned to hypogonadism, but they use lupron to cause it, so is the problem the lupron or the hypogonadism? I see the dissociation intensity paralleling the lupron dose in the system, or at least at times when the rate of testosterone change would be maximal. There is a lot that needs to be unpacked here. But this is the direction in which to understand this.

spectrumnews.org/news/drug-....

jamanetwork.com/journals/ja...

[Tall_Allen in reply to lss65]

I hope you are able to obtain Nubeqa under compassionate use.

[lss65 in reply to Tall_Allen]

that is what I am currently going to investigate. would it have to be compassionate use or could it be prescribed off-label? any idea?

[Tall_Allen in reply to lss65]

I'm thinking of the cost - insurance usually won't cover it unless you appeal and make a good case for it.

[lss65 in reply to Tall_Allen]

Good point. I'm hoping my son's psychiatrist will be intrigued by this situation and willing to put in some time to think through the various issues (of course, being paid for his time).

In the clinical oncologist/research community, do you have any idea who would be best versed in the relationship between lupron, orchiectomy and the other ADT drugs and the glutaminergic system?

Also, who would be most interested and/or willing to apply for compassionate use of a drug bc of significant, adverse psychiatric effects of the alternatives?

I feel like I am working in the dark here - it took me years to get up to speed on who would be relevant and willing/enthusiastic for what in my son's situation, with many false starts.

[Tall_Allen in reply to lss65]

I don't know a researcher on that topic. Perhaps start by contacting the mfr of Nubeqa, Bayer - (1-888-842-2937)

[lss65 in reply to Tall_Allen]

Thx. I found this which I find interesting as it mentions the withdrawal of estrogen being a potential cause of some of the psychiatric effects. When I went into peri-menopause and then menopause, I started developing more and more psychiatric type symptoms that became completely alleviated once I had a stable dose of estrogen re-introduced to my body.

My first cut at all of this is going to be getting a consult with my son's psychiatrist before looking into who in the oncological community would be the best fit for understanding and figuring out/be willing to implement a solution to our current problem.

psychiatrist.com/JCP/articl...

[Tall_Allen in reply to lss65]

Many men use estrogen patches to mitigate hot flashes from ADT. Since it is known to be necessary in men, for libido, it undoubtedly has some beneficial psychic effects. Drugs that eliminate estrogen entirely (like exemestane) are known to have negative mental effects. An estrogen patch with his Lupron seems like a pretty simple thing to try. There is a large clinical trial in the UK of using estrogen patches to replace Lupron entirely . Several men on this forum use it.

[lss65 in reply to Tall_Allen]

thank you - this is a good, easily implementable idea. a first step toward trying to sort this out and make the best decisions going forward. no one in mainstream medicine had ever mentioned to me that estrogen could have been the cause of my seriously worsening mental state as I entered menopause. At some point I started wondering about my loss of estrogen as a possible stimulus, and found a doctor very familiar with this effect in some women, who ably got me back up to my needed estrogen levels for emotional stability.

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

Ladies and Gentlemen.... a stand up round of applause for Mr. Tall_Allen, please take a bow.... Come on now put your hands togehter.... he certainly deserves it....

Good Luck, Good Health and Good Humor.

j-o-h-n Tuesday 02/02/2021 10:24 PM EST

[lss65 in reply to Tall_Allen]

Tall Allen, I thought I'd update you on an unexpected occurrence that has thrown new light on the situation involving the psychiatric effects from a lupron injection. While continuing to be emotionally unstable, my guy received a course of gabapentin for post-herpetic neuralgia. Amazingly, within a day or two on the gaba, he emotionally began to stabilize. Not perfect by a long shot, but far better than he was doing. I remembered putting my son on gabapentin at one point to help him sleep, and through that usage further discovered how to address processing problems my son was then having secondary to his recovery from encephalitis. I went back and looked at the scientific data, and it turns out that gabapentin blocks a voltage gated calcium channel in the glutaminergic system. See, eg.

bmjopen.bmj.com/content/7/3...

I then looked into information on Gnrh agonists, and discovered that Gnrh opens up these voltage channels, and one imagines that the agonist like lupron keeps this channel constantly open since the intended effect of the agonist is to create continuous firing of a system that in its natural state fires only intermittently. See, e.g.

pubmed.ncbi.nlm.nih.gov/242...

At any rate, this unexpected "experiment" does lend credence to the fact that lupron and gnrh agonists more generally have psychiatric/neurological effects that wouldn't be recreated by other methods of testosterone reducing methods. See, e.g.

nature.com/articles/nrd.201...

As of yet, I have no idea if an antagonist would be a better option in this dimension, nor how this pathway intersects with exogenous estrogen administration, if one still wanted to use a method other than an orchiectomy, but it seems for men having cognitive/mood/psychiatric effects severe enough to impact their lives and their families, the GABA system dysfunction aspect of gnrh agonist effect should be considered as a real possible cause and alternative explored.

On a separate note, I wonder about the very unusual emergence of the post-herpetic neuralgia 7 months after his shingles episode ended, and my instinct is to believe that the same toxicity his system is now facing in the psychological dimension has also been triggered with respect to this neurological aspect of the shingles virus, perhaps also through the same mechanisms since the gabapentin is having positive effects pain relief simultaneous with emotional stabilization.

Neither the pain situation or the emotional stability is where it was before the last lupron shot, but both are improved with the gabapentin. Having seen in the literature that getting shingles correlates with being on lupron, this may be another reason to opt for something other than a gnrh agonist, if one has concerns about potential shingles and additional later complications from that activation. This neuralgia pain has been quite severe.

[Tall_Allen in reply to lss65]

Thanks for that explanation. I think you are more expert about this than anyone.

[lss65 in reply to Tall_Allen]

unfortunately I had an intense education in figuring out how to treat my son's encephalitis, and related sequelae, and then finding like the one psychiatrist willing to do what was needed to get his cognitive processing restarted and ocd symptoms diminished. It was an act of desperation at that time, after 6 years of sickness.

But apparently I now have knowledge I can share in other venues.

Hope this can help someone additional to us.

[MateoBeach]

Glad your son is better. You sound very wise. He is so fortunate to have you at this time and always.