High ALP after tE2 failure

[noahware]

Interesting. After about 3 months of high-dose estradiol patches, I got my E2 up to 487. But my T only fell to 64. What gives?

I was pretty confident after the first month, when only got to T of 187 on 4 patches 2x weekly, that a 50% increase to 6 patches would do the trick... but on the elevated dose, T came in almost identical at 188 four week's later! (E2 level at that time was 190.) And PSA and ALP both rose, not surprisingly.

On a fool's errand, I wanted to see what going up to 8 patches would get me. Not castrate, that's what. T fell only to 64 with E2 at 487, which I think is up into the "red zone." My PSA did come back down to 75 after being at a high of 185, but alarmingly my ALP has doubled to about 1000 over these last few months. So the mets are obviously taking off. Probably loving the combination of low-but-not castrate T and very high E2?

I will be with the MO in a few days to start a different form of ADT. I believe chemo will be a few months down the road, but...

1) What else in addition to "standard" ADT could the MO consider as immediately beneficial to start right now, that I should be sure to discuss?

2) Will the MO (at DFCC) advise on best genetic testing to pursue now, or do I need to be specific in any request? If so, what am I asking for?

3) Given that the E2 feedback mechanism apparently failed to work as it does in most men, are there certain agents for ADT that are also likely to fail for me? If so, which types/formulations/brands might be LESS likely to fail?

I know that for a certain very small percentage of men, the normal Lupron dose fails to achieve castrate levels of T, and I know that in the PATCH trial there was not 100% success in getting all men castrate with estradiol, either. Is the best alternative for these men surgical castration? (As I am still free of pain and symptoms, I will probably avoid that for now.)

I would also love on this thread for any to share details of any experience of men (themselves or others) who failed to get T to castrate levels with any form of ADT, or explanations and theories on why and how this happens.

[GP24]

I would send an email to Dr. Langley and ask for her advice: [e-mail]

You can also add Dexamethasone 0.5 mg or 1.0 mg per day. This will stop the testosterone production of the adrenal gland and thus reduce T further.

[noahware in reply to GP24]

Email sent -- thanks!

[LearnAll]

noahware...your PCa is indicating that it is more aggressive than what we thought initially.Its time to knock down PSA with lupron and Abi or Enza. E2 treatment is not getting T below 20 which is what is required.

[Hidden in reply to LearnAll]

I think you need to go traditional and well understood approach...ADT + docetaxel followed by ADT + zytiga..Get that cancer under control with a more scorched earth approach.

[noahware in reply to Hidden]

We had already decided to add chemo, but MO thought waiting about 6 mos after ADT kicked in was the way to go. But that was before ADT attempt failed, so we'll see what he says now. I thought abi first, chemo after was the way to go, no?

[Hidden in reply to noahware]

Read TAs post...definitely chemo before abi because you don't have to wait...if you do abi before chemo I think you need to wait 6 months after you stop the abi before you can begin chemo

[noahware in reply to Hidden]

Thanks... I'll try to track that down.I have seen competing point-counterpoint cases being made, but haven't delved into them yet.

[Spyder54 in reply to noahware]

Noahware, TomTom is correct. I have been on Lupron + combo for 7 months. My Onco said to start Docetaxel now would accomplish nothing. Said ADT Combo puts PCa cells into sennescence. Once they wake up and we have ADT failure then stop for a few months and begin Docetaxel. I brought up ASCO 2021 and PEACE Trial. He said if Docetaxel first, then yes, but You are on ADT combo for 7 mos.. Also said once ADT Failure PROVENGE has proven to extend life significantly with lower PSA having more success.

[noahware in reply to Spyder54]

Thank you for the input!

[noahware in reply to LearnAll]

Yup, need some big guns now, it seems.

[LearnAll in reply to noahware]

Yes..Big Guns for now...but not necessarily forever...knock it real hard.. and leave it alone until it raises its ugly head again.

[pjoshea13]

Dr. Myers has said that DHT drives PCa - not T - & he wondered why it is rarely monitored. It would be interesting to know what your DHT was - & also what it might have been had you been taking Avodart.

Also, when monitoring T it is freeT that counts.

I have a feeling that supra-high E2 would induce extremely high levels of SHBG - which isn't the case with classic ADT. SHBG has a greater affinity for binding to T than to E2. So your freeT might have been in the castrate range.

Best, -Patrick

[noahware in reply to pjoshea13]

Didn't even think about adding a 5ari, even though we did add Proscar to the Casodex monotherapy.

If high E2 has that binding affinity and that effect you describe, wouldn't higher total T show up in men in the PATCH trial, in some statistical way? I assume that they measured total T only, at least I don't recall seeing any reference to free T in reading through PATCH stuff.

I'm a little confused by what your last paragraph means for me, sorry!

[pjoshea13 in reply to noahware]

Noah,

I wish I had something constructive to offer.

I got carried away with the significance of T when using transdermal E2 for castration. I found an old (2005) U.S. Phase II transdermal E2 study yesterday where the authors were apparently interested in freeT [1]:

"As a result of the increase in SHBG levels, free testosterone levels significantly decreased after 4 and 8 weeks" ...

"... any reduction in free testosterone levels may offer therapeutic benefits in subsets of patients who have resistant prostate carcinoma clones with androgen receptor amplifications."

I believe that Dr. Myers wanted DHT to be <5 pg/mL. (Maybe an old patient of Myers will correct me or confirm?).

I am using DES, a synthetic estrogen. My last freeT was 0.8 pg/mL. I don't know what the DHT was, but I suspect it was a lot lower than 5 pg/mL.. Of course, DHT can be produced via an alternative pathway.

There is a study that looked ar freeT & ADT [2]:

"... evidence is provided that free testosterone, the biologically active component, should be utilized to provide clinically relevant state of castration."

"The cutoffs established in this study for castrate levels were ... below 1.7 pg ml−1 ... for free testosterone."

Your post should be of interest to anyone considering transdermal E2 and I think that they should be aware that the total-T<20 ng/dL guideline does not apply. Best to monitor freeT.

Best, -Patrick

[1] acsjournals.onlinelibrary.w...

[2] ncbi.nlm.nih.gov/pmc/articl...

[noahware in reply to pjoshea13]

Thanks, that is interesting... I will mention that to RW next time I talk to him. He had some thoughts that estrogens in different forms and doses, and in steady-state patch delivery versus more pulsatile, may have different effects on relative densities and ratios of ER alpha and beta. Any thoughts on ER roles in tE2? Also wondering if BRCA mutations might be a factor.

[pjoshea13 in reply to noahware]

Noah,

I added to my last response. I cited a study that gives a castration limit for free T. I also made a correction: I had written "freeT" instead of "DHT" in reference to Dr. Myers DHT limit.

Typically in advanced PCa, ERbeta has disappeared in PCa cells. The growth-promoting ERalpha is powerless without T. I have no idea if ER expression is altered when using transdermal E2.

It's a pity that before the Lupron era began, when DES was commonly used, the tools were not available to determine how men became resistant. I imagine that DES & E2 resistance paths are similar - but are they similar to Lupron resistance?

One escape pathway is the synthesis of DHT via the alternative pathway, which is why I use Avodart.

I am using DES in the context of BAT, and those considering E2 have the option to periodically inject T cypionate to try to thwart resistance.

Best, -Patrick

[Justfor_ in reply to pjoshea13]

My hormone tests comprise the following triad: totalT, DHT and SHBG. There is an older formula by which and with the addition of Albumin estimates freeT and Bioavailable T.

issam.ch/freetesto.htm

There is also a newer empirical formula that leads to a freeT value very close to the above.

In my case, total T (1100-1300 ng/dl) and SHBG (12-17ng/dl) are both above normal range, BUT, free T (7-10 ng/dl) stays within (normal range 4.7-19 ng/dl).

FWI, after 11 data couples my (free T)/(total T) is 0.79%, SD 0.078%.

Lastly note that 1 ng/dl =10 pg/ml, so my freeT is 2 orders of magnitude greater than that of Patricks'.

[GP24]

Even if you get surgical castration your T may not get below 20. There are patients where surgical castration does not achive that.

The advantage of using patches is that you avoid the side effects caused by low E2 like hot flushes, bone loss etc. These side effects would occur with surgical castration as well.

[LearnAll in reply to GP24]

GP24, you are right that surgical castration may not cause T less than 20. But, Lupron plus Zytiga can certain take T below 20....In my case, in 2019, this regimen made my T go to 1.5. (Nadir T) Patrick's suggestion of monitoring DHT is very accurate because DHT is much more potent androgen and is mainly responsible for stimulating cancer cell growth.

[GP24 in reply to LearnAll]

I agree that Zytiga will achieve that, T should get below 10. But you get all the side effects of low T and low E2 and I think Noahware tries the patches to avoid some of these side effects. Therefore I think Dexamethasone may allow to continue with the patches by reducing T below 20 while leaving E2 high.

Here is a patient report of using patches plus Dexamethasone:

paact.help/a-prostate-cance...

Doug also mentions that Dexamethasone made DHT drop a lot.

[noahware in reply to GP24]

That may be, but I doubt my MO is going to want to keep with the E2 at this point, seeing as the dose was pretty high. Not sure I want to take the chance, either, after stretching the non-event out for an extra month!

Thanks for the link, I have read that account when linked before and find it very interesting. Note, though, when he added Dex it was when he was combining Lupron and E2... seems like to get an alreadt very low T even lower? In his early tE2 therapy, he got castrate pretty quickly, he actually abandoned patches and went with a cream. And I'm not sure keeping E2 above 700 is a good thing, even though it worked out for him.

I just spoke to a gentleman with good knowledge of tE2, and he thinks for some men the gel or cream may be important, because it allows for a more pulsatile delivery of the estradiol. Could the steady-state delivery of the patches be impacting the ratio and activity of ER alpha and ER beta in a way that's different from a cream or gel? These questions are way above my pay grade, but "alternating a big dab with a little dab, depending" is not something an MO will prescribe. Doug was doing his own thing but he is a braver (and more knowledgable) man than I.

[GP24 in reply to noahware]

ronronHU is using the gel, see this and his other posts:

healthunlocked.com/advanced...

[noahware in reply to GP24]

Oh yes, read 'em all. If I could have easily secured gel in the US, I would have started self-administering two years ago.

[noahware in reply to GP24]

Yes, I'm aware that T may not drop full with either castration, or Lupron, and I'd have the low-E SEs... that's why I went with tE2. (But I could always do some low dose E as add back with other ADT.) In the PATCH trial, I think the failure for E2 and Lupron at 3 months was about the same, at 7%. What do THOSE men then do?

What I'm really wonder is, does the E2 failure to get T low enough have a bearing on likelihood of getting low enough with other methods I might try? Is an agonist med going to be better than an antogonist, or vice versa?

[GP24 in reply to noahware]

Dr. Langley may be able to answer these questions. I would start with Rucaparib if you do not want to continue with the patches.

[maley2711]

Do you have an MO who is deeply versed in PCa treatment? Then, with all due respect, why don't you give more attention to what that MO advises, and less to what those on forums such as this suggest? if you are relying more on amateur opinions here, then maybe you need to seek out a new MO whom you believe to be more informed?

Do MDs with PCa look to forums such as this for guidance...or do they seek out and accept the advice of other professional experts in PCa treatment?

[noahware in reply to maley2711]

Why would you think I am "relying" only on opinions given here? How would you even presume to know what relative weight I give them? As well, many opinions given by men here reflect either opinions of their own MOs or are supported by cited research papers.

I am not afraid of "too much information" informing my decisions. There is plenty of weeding to be done, sure, but there is a lot of input that can be considered. Without this forum, many men would have no idea that many ADT serious SEs are estrogen-mediated and can be relieved with low-dose E2. How many MOs are going to tell patients that?

Frankly, the knowledge of Tall Allen probably exceeds that of many MOs. Being an amateur does not make one wrong, just as being a professional does not make one right. I do not value "appeal to authority" as a sufficient basis for gathering information.

[maley2711 in reply to noahware]

yes indeed, I cannot read your mind. It was just my impression, and apparently incorrect,but sincerely offered. I agree that there are probably many MOs whose responsibilities are too numerous and therefore not up to speed on all the research on evry type of cancer, includingPCa. The trick for each of us is to find the right MO......and not necessarily an easy thing to do. To supplant that, I will look to professional guidelines, and 3rd to forums such as this... I have assuredly spent too much time in such information gathering myself.

[noahware in reply to maley2711]

I do have to agree, there can be such thing as TOO much info, because filtering it and weighing its validity is not always easy. For me, the bigger trick is weighing potential costs with potential gains: the unknown severity of certain side effects to gain a decent likelihood of somewhat longer survival, but with little possibility of anything that could be called "cure." Neither an MO or anybody on a forum can do those calculations for me!

[maley2711 in reply to noahware]

sad but true i think. My Doc said at the beginning...." we have more questions than we have answwers? Grad Cornell med school...assume no dummy! he does work at Kaiser..much maligned Kaiser, fairly or not?

[E2-Guy]

noahware, I'm sorry to hear that the tE2 isn't giving you the numbers that you were hoping for! Just a layman's observation...it appears that most of us that are having positive results with tE2 therapy have had RPs. I have been supplying Oestrogel to a few of our comrades for some time now and this seems to be the case. You might try messaging Richard Wassersug (the tE2 guru) to get his professional opinion. Best, Ron

[noahware in reply to E2-Guy]

Thanks Ron... I have talked to Richard. That is an interesting observation about the RP factor, not sure what it means... I do know that many in the PATCH trial did not have RP but had success with E2 getting them castrate. But some (one?) are of the opinion that gels may work better for a subgroup of men, perhaps because they do not serve to deliver E2 at a steady absorbed dose, 24/7.

[Cooolone]

If you've already decided that Docetaxel is going to be used, why wouldn't you then follow the results of the PEACE-1 trial and also use ADT & Zytiga concurrent with the chemotherapy!? It almost 2x the time to progression for patients from 2+ to over 4+ years...

Just sayin...

Wishing you the best regards!

[noahware in reply to Cooolone]

Thanks, that's good info. I'm not up to speed yet on the latest thoughts on best efficacy of the various combos and sequencing options... was hoping to get a bit of mileage out of simple ADT first. I will check PEACE out. Until next time... peace out.

[Cooolone in reply to noahware]

With what I've read above, you are more in need of an anvil drop on your PCa than trying to brush it away with a feather! I do understand trying to use the feather, but only when it's appropriate for a given situation. Mono-therapy has already been shown to be less effective than multidisciplinary modalities applied at the same time. Combination of drugs given concurrently work better and for longer, than singular.

The real question is what you want as a result from your treatment? You already acknowledge possibly chasing a fool's errand! Why compound it?

The need for a systemic therapy that will have the greatest effect overall for metastatic disease seems appropriate in your description provided. The results (abstract) from PEACE-1 are very compelling, too much so to easily dismiss. And if the chemo is to be dismissed, the combination of ADT "with" other drugs has shown better results as well than just ADT in a metastatic condition. No?

Anyways, hope you can find what you're looking for and get the best results!

Best Regards

[noahware in reply to Cooolone]

Thanks... chemo was always in the plan to do relatively early. When we initiated ADT a few months ago, the MO suggested starting six month in to ADT... not sure why. But it seems that doing a two-prong combo and adding to that sequentially is still a common way to go? Personally, I always thought CAB w/ chemo made a lot of sense... putting it off made less sense, of course.

A few months later, the story has changed with a failure to reach a castrate state and a sharp rise in ALP. So yeah, anvil time. I believe the two different feathers I tried only served to tickle and annoy the PC, which comes as a disappointment but certainly not as a surprise. Less aggressive treatment yields odds of lesser response, for sure.

[MateoBeach]

Being severely intolerant (allergic) to leuprolide ADT, when I needed sometbong for adjuvant ADT with RT, I tried the PATCH protocol. After one month of 4 patches twice weekly (0.10 mg/24 her each) my T only went down to 63. So I immediately asked for a Firmagon shot. Half the normal starter dose at 120 mg. 24 hours later T was <20. I kept E2 patches, just one 2X weekly for side effects help and felt just fine on the combo. But yes you need to sort out high ALP. Abiraterone is another way to go. It might not even require Lupron to achieve castratrate T. It could do that on its own. Though few have tested and confirmed this as the trials all include Lupron for SOC ethical considerations.

[noahware in reply to MateoBeach]

Yeah, I thought "just a little more, just a little longer." However I go for ADT to get that T down, I hope to keep a little E2 added on. Given the failure of high-level E2 to get me to castrate, do you have thoughts on LHRH agonist vs antagonist? I was already leaning to Firmagon over Lupron, as I recall that it seems to get guys lower, faster, with greater efficacy (correct me if I'm wrong).

[MateoBeach in reply to noahware]

Firmagon is better. Antagonists work better. Recover faster when stopped better CV risk profile. No micro surges. Better. 👍🏼 Orgovix probably equally so if pills preferred.