The Perils and Pitfalls of "Treating ... - Advanced Prostate...

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The Perils and Pitfalls of "Treating PSA" in Advanced Prostate Cancer

Tall_Allen profile image
Tall_Allen

Sometimes we do things that interfere with our ability to use PSA to monitor success of our treatments: therapies that select for low PSA sub-types, supplements that interfere with PSA tests, and oligometastatic-directed SBRT. Here's what we know and don't know:

prostatecancer.news/2020/07...

80 Replies

Thank you. I really appreciate your clear summaries of information on a particular topic.

Thanks, TA. I read the article once but need to read it at least a few more times to get all the facts. As if it was written for my situation. I have been struggling to make a treatment decision for 2 years now. I am almost ready now but nervous to start treatments. Thanks again.

Tall_Allen profile image
Tall_Allen in reply to Ahk1

I usually avoid math, but because of Covid-19, most of us are familiar with exponential growth curves by now (sadly).

This is simply the best essay on ADT and PSA that I have ever read!

I hope it will somehow get republished in a journal like J. Urology or Nature Reviews Urology, where the MDs will see it.

Richard W.

cesanon profile image
cesanon in reply to Wassersug

Agreed

"Patients who use any complementary therapies are twice as likely to die of their cancer (see this link)."

Wow. I am going to have to digest that for a bit in order to figure out how to convert that into action.

By the way, thank you for the article. It is a work of art just packed with info.

I am going to have to read it multiple times just to absorb half of what's there.

Thanks

Don_1213 profile image
Don_1213 in reply to cesces

I read that paper late last night.. I didn't follow the "see this link"

That is one of those statements where more info might help clarify things. Is the complementary therapy causing the increased death rate, or is the severity of their disease making them seek out complementary therapies?

UPDATE: I went back and tracked down the paper where "complementary therapies are twice as likely to die of their cancer.." was stated..

Also stated in the paper was: "The differences in survival were attributable to refusal of conventional treatment."

So it may not be complementary therapies at blame here - at least not totally - it might be stupidity by the patients to blame.

The paper "The Danger of Complementary and Alternative Medicine" is worth a read - it's short and to the point. prostatecancer.news/2018/07...

cesanon profile image
cesanon in reply to Don_1213

"Is the complementary therapy causing the increased death rate, or is the severity of their disease making them seek out complementary therapies?"

I guessing that it is a pretty complex situation. Maybe no one knows exactly what is causing what.

Tall_Allen profile image
Tall_Allen in reply to cesanon

It is compared to people with similar disease characteristics.

Tall_Allen profile image
Tall_Allen in reply to Don_1213

I agree that it is foolish to think one can be less diligent about SOC therapies because one is lulled into complacency by the complementary therapies one is using. Yet, that is exactly what happens. You can see why if the complementary therapies mask PSA.

Thanks TA !

Thanks TA. Really appreciate and value your shared information and holistic approach. Thanks again.

Hugs from Micael

Thanks Allen, great information, thank you

Very informative, thanks for taking the time to post...

"the cancer is far from cured - the PSA has been treated, but the cancer is still micrometastatic and systemic."

Nice pen there Buckaroo👍

westof profile image
westof in reply to rust

Hmm... Nice catch Rust! I'll use the quote as a header, when I email my MO. (momentarily).

Along with the link to the report.

Thanks, TA!

Tall_Allen profile image
Tall_Allen in reply to westof

Let me know if your MO reads it and what his reaction is if he does. So far I've only shown it to ROs, and they like it because they believe OMDT has been oversold to patients.

westof profile image
westof in reply to Tall_Allen

OK, I sent the link to him and I also have a phone consult on Thursday.

Best

JRPnSD profile image
JRPnSD in reply to Tall_Allen

I have copied my MO, RO and URO. Thank you.

Don_1213 profile image
Don_1213 in reply to Tall_Allen

OMDT? I googled it - and found terms about education.

Tall_Allen profile image
Tall_Allen in reply to Don_1213

Oligometastatic-directed therapy

Thanks Allen,

That might be best explanation of what is going on with PCa progression and /or remission that I have seen. Still digesting it. I need to read through it more. Your writing is very reader friendly, understandable, with great technical references. I wish my Doctor could explain things like that. You were the first to tell me about micro-metastases, that my undetectable PSA might be hiding the real truth going on in my body. The detectable mets vs, years exponential curve is an eye opener. I believe I had 4 detectable, but that was about 6 years ago!!!

But then, there are the exceptions to all the studies, the ones on the "other" side of the life expectancy curve, I plan on continuing being in that scenario. I know I fortunately already am, getting extended benefits, as I did get Lupron and Zytiga early on.

Thank you. Great article.

Thank TA, for your digilants and preservence against this beast and keeping everyone informed on the latest.

My doctor has reminded me that we are treating the cancer and not the PSA. I see people here all the time getting stressed out about miniscule changes to PSA, trying to figure out what they mean.

I think PSA will always have a place as a "tumor marker" for prostate cancer, but it is only one indication and we have to make sure not to lose sight of the big picture. It becomes less important in advanced stages of prostate cancer. Definitely don't want to make treatment decisions based on PSA alone.

Thank you for taking the time to make all the information user friendly. It takes courage to look PC in the 👁 eye.

I dream of the day you post a study that proves cure. Faith love and hope to all you that live with aPC

Thanks again TA ❤️👍

An interesting research though. Especially on the effect or none of supplements plus the idea of using correct PSA markers.

And the concept of intermittent use of ADT is something worth pondering!

❤️

Haniff

Good work TA, thanks for posting this up, very informative, cheers 👍😎 DD.

In 2004, Dr Robert Amato, research medical oncologist, told me absolutely no supplements and if I was thinking about it to talk to him about it..... his direct words were that supplements affect PSA and will screw up my treatment as well as his research.

Excellent article, TA.

GD

Thank you for bringing clarity about PSA and ADT that eludes many patients of PCa. I enjoyed reading it as it brought together so many bits of study and research to come to a logical conclusion.

Thank you, very thorough and educative article! I appreciated the surrogate endpoints that was not PSA-based, I will make sure one way or another that this is the golden standard for my fathers!

Fascinating article. I have been taking biotin for my finger nails for years (it strengthens them and helps avoid splitting, etc.). Now, I wonder if I should stop taking it for a while and see what happens with my PSA levels.

Thank you for this valuable information!

Tall_Allen profile image
Tall_Allen in reply to dmt1121

You may be interested in the FDA warning:

fda.gov/medical-devices/saf...

dmt1121 profile image
dmt1121 in reply to Tall_Allen

The Mayo Clinic say not to take vitamins for twelve hours before. I think I have been following this but I will be sure I am following this protocol from now on.

Thanks again.

Thank You TA for the valuable information! I appreciate it!

Allen ...Everything you do is always well researched and extremely well written. Thank You Again. The only thing in your writings I quarrel with is this incongruity that I imagine may never be proven without a phase 3 trial, which I further imagine will never happen.

Two men whose age and prostate cancer is identical in all respects have a prostatectomy. The median time to detectable metastasis is 8 years. Year 2 both have identical PSA progression . One gets heavy ADT . The other waits to year 8 for the same ADT. If it is generally accepted that castration resistance occurs two to 3 years after heavy ADT , and it is further proven that 17 percent of the heavily treated men develop a more malignant form of cancer, how can we say with reasonable certainty that time to castration resistance is shorter for the man who starts treatment in year 8. Logically , by year 8 , the earlier treated man would have a more malignant form of cancer and/ or cycled through all medicines/ treatment designed to kill the castration resistant cells, by the time the untreated man even starts treatment. Granted, the untreated man , who starts treatment in year 8 , with a much higher tumor load , may become castration resistant in a shorter period of time than the earlier treated man did post treatment , but the absolute number of years would be substantially longer for the untreated man.

Tall_Allen profile image
Tall_Allen in reply to Dd7757

The longer time to CR in men getting heavier ADT is not based on logical inference, it's based on randomized clinical trials (evidence provided in the article). TOAD addressed exactly the situation you are talking about.

You are making the logical error called "Post hoc ergo propter hoc." That is, you are assuming that just because CR of virulent PC occurs after heavy ADT use, it is because of heavy ADT use. You are ignoring the overwhelming fact that the cancer itself is the key causative factor.

Dd7757 profile image
Dd7757 in reply to Tall_Allen

I can’t see where in the Toad Trial it answers my question.. . You evidently understand the Toad Trial to say that if a man starts treatment in 2020 and another in 2028 , and if the second becomes becomes castration resistant in 2010 the first will not become castration resistant until some time after 2010. Thus, castration resistance does not occur until at least 10 years after first treated. Is that what you are saying?

Tall_Allen profile image
Tall_Allen in reply to Dd7757

How can they become CR in 2010 if they began ADT in 2020 and 2028?

Dd7757 profile image
Dd7757 in reply to Dd7757

You know typos when you see them...2010...is 2030....

Tall_Allen profile image
Tall_Allen in reply to Dd7757

I have no idea what you are talking about. In the TOAD trial, recurrent patient who started ADT at the point of recurrence became castration resistant later than recurrent patients who delayed ADT.

"The HR [hazard ratio] of castration resistance for immediate vs delayed therapy calculated from the date of randomization was 0.76 and from the date of starting therapy was 0.30" (p.733)

I don't know how to make this any clearer.

Dd7757 profile image
Dd7757 in reply to Tall_Allen

I gave as an example two identical men who start ADT 8 years apart .

You ignore the fact that in the Toad Trial the men were generally two years apart. And then you say you have no idea what I am talking about when I say the Toad Trial did not speak to my hypothetical .

And that is because you think the Toad Trial stands for the proposition that no matter the interval between the start dates , two years, 5 years , 10 years, 15 years, the earlier start date group will always live longer.? And if, yes do you believe all Trials results can be extrapolated to identical conclusions based on totally different inputs?

“In this randomised, multicentre, phase 3, non-blinded trial, we recruited men through 29 oncology centres in Australia, New Zealand, and Canada. Men with prostate cancer were eligible if they had a PSA relapse after previous attempted curative therapy (radiotherapy or surgery, with or without postoperative radiotherapy) or if they were not considered suitable for curative treatment (because of age, comorbidity, or locally advanced disease). We used a database-embedded, dynamically balanced, randomisation algorithm, coordinated by the Cancer Council Victoria, to randomly assign participants (1:1) to immediate androgen-deprivation therapy (immediate therapy arm) or to delayed androgen-deprivation therapy (delayed therapy arm) with a recommended interval of at least 2 years unless clinically contraindicated. Randomisation for participants with PSA relapse was stratified by type of previous therapy, relapse-free interval, and PSA doubling time; randomisation for those with non-curative disease was stratified by metastatic status; and randomisation in both groups was stratified by planned treatment schedule (continuous or intermittent) and treatment centre. Clinicians could prescribe any form and schedule of androgen-deprivation therapy and group assignment was not masked. The primary outcome was overall survival in the intention-to-treat population. The trial closed to accrual in 2012 after review by the independent data monitoring committee, but data collection continued for 18 months until Feb 26, 2014. It is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12606000301561) and ClinicalTrials.gov ( NCT00110162).“

Tall_Allen profile image
Tall_Allen in reply to Dd7757

I did not understand your hypothetical. You apparently got the dates confused, and your hypothetical didn't reflect the protocol.

It doesn't matter what the dates were that they entered the trial (i.e., were randomized) - the trial looked at the duration that they were taking ADT before they became castration resistant (CR). So a hypothetical would be: two biochemically recurrent men enter the trial at the same time (Time T0), and are randomized to either immediate (Man I) or delayed (Man D) ADT. Man D didn't start ADT for, say, 3 years after T0. Man D became CR , say, 4 years after T0, which was 1 year after starting ADT. Man I became CR later, say, at 5 years after T0.

So you see, it didn't matter that the treatment was delayed for at least 2 years, they still became CR sooner (from the time of randomization), and ADT lasted much more briefly (from the time of starting ADT) in those who delayed.

This is a great summary of important info, something that doctors should be handing to their patients.

But I am still wondering about the Hussain study, and confused on how the two survival curves differ.

You say "it took 4-5 years for the survival curves to start separating - long follow-up is needed to detect survival differences." But when I look at the two individual curves (for men with minimal or extensive disease) I see the curves separate very quickly, in very different ways.

Men with extensive disease on cADT actually appear to to do worse right from year-one, and the curves come back together for years 5-7 before diverging again, with the benefit AFTER 7 years only then clearly going to the cADT group. The real survival benefit seems to appear around year-8 and beyond, after about 70% of men in both groups are already dead.

To the contrary, men with minimal disease on cADT appear to to do better after year-one, and the gap widens considerably between years 3-7. But after that, the curves converge and show no further benefit to cADT, once about 60% of men in both groups are dead.

So better overall survival for these men of "6.9 years for those on continuous therapy vs 5.4 years for those on intermittent therapy" exists as a benefit of statistical MEDIAN survival. If long follow-up is needed to detect survival differences, why does long follow-up show no real survival differences after year-eight (in men with minimal disease) for cADT versus iADT?

The longer follow up appears to show a long-term benefit of cADT over iADT for men with extensive disease but not for men with minimal disease. But oddly, for men with extensive disease, iADT actually appear to be superior in the very short term. This seems unlikely.

I understand that statistically, it appears that a random man within a larger aggregate can slightly improve his odds of living longer by choosing cADT over iADT. I am not disputing that. But the evidence that supports that ALSO gives the appearance that in men with extensive disease, those (over 50%) who die within five years can slightly improve the odds of living longer by choosing iADT over cADT, since the median survival for iADT is better by six months.

Should we suggest iADT to a man with extensive disease, since this study appears to show he is more likely than not to die within five years, and apparently more likely to have additional months of life with iADT over cADT?

Tall_Allen profile image
Tall_Allen in reply to noahware

That quote was from Maha Hussain herself. She is referring to Figure 1, which clearly shows the curves separating at about 4-5 years.

The reason curves can't be used the way you would like them to be is because the sample size deteriorates rapidly. The median survival in her trial was 5-6 years, and you can see on the bottom of the Kaplan-Meier curves that the sample size deteriorates rapidly. On Figure 2A - for men with minimal disease,, the curves separate rapidly and continuous therapy is always better than intermittent. You are trying to read too much into the small sample size later (only 39 men at 10 years). On Figure 2B- for men with extensive disease - the two curves are virtually on top of each other to well past the median. You are trying to draw conclusions at 10 years, when there were only 24/12 men left.

You are right that I should have written long follow-up and much larger sample size.

noahware profile image
noahware in reply to Tall_Allen

" On Figure 2B- for men with extensive disease - the two curves are virtually on top of each other to well past the median."

Yet the fact remains, in this study they report "The median survival after randomization among patients with extensive disease was 4.9 years in the intermittent-therapy group, as compared with 4.4 years in the continuous-therapy group."

So why do you say "the two curves are virtually on top of each other" instead of saying what the difference is, in terms of median survival? Why is that not worth mentioning, when you make a point to mention "for men with minimal disease, overall survival was 6.9 years for those on continuous therapy vs 5.4 years for those on intermittent therapy?"

I understand that there are reasons to not put as much weight on what the later stages of the study appear to show, because of the decrease in numbers of men. But as far as median survival, are you/they saying that the apparent advantage of 1.5 years (27% longer) in one group is "significant" but that the apparent advantage of only 0.5 years (12% longer) in the other group is not? If it is not, why not?

Tall_Allen profile image
Tall_Allen in reply to noahware

You were asking about the curves, so I talked about the curves and how you were misinterpreting them. If you want to talk about the numbers...The hazard ratio for difference in survival in the subgroup with extensive metastases was 1.02 (essentially no difference). With 95% confidence, that ranged from 0.85 (15% better with intermittent) to 1.22 (22% worse with intermittent).

noahware profile image
noahware in reply to Tall_Allen

My original comment asked, since the study "gives the appearance that in men with extensive disease, those (over 50%) who die within five years can slightly improve the odds of living longer by choosing iADT over cADT, since the median survival for iADT is better by six months... [then]... should we suggest iADT to a man with extensive disease, since this study appears to show he is more likely than not to die within five years, and apparently more likely to have additional months of life with iADT over cADT?"

And if not, why not? The curve for this group seems to only show clear survival benefit for cADT after over half the men have died, and when the sample size starts to deteriorate more rapidly.

Or to ask it another way, what would the statistics tell us about relative risks of iADT and cADT if the study had stopped at around 7 years, when the study group was less than a third of its original size and deemed less useful because of the smaller sample size?

It would seem the data from the first five years would be the most useful for these men to consider, simply by virtue of the fact that most of them are still alive earlier on. Since that is when most of the men are alive, and that is the period where median survival extension accrues to reach six months (a gain of 12%), why would we not suggest iADT to these men?

Tall_Allen profile image
Tall_Allen in reply to noahware

I think I answered that. The survival is not better by 6 months- the statistics show no difference in men with extensive metastases. This is based on the Kaplan-Meier curves which take into account the diminishing sample size over time.

Thanks, again, for the information and support you continue to offer to a growing group of patients and caregivers who seek some solid information to work with.

We are blessed to have such a great resource to help us manage our journey.

This is just superb - doctors need to read this. It deserves publication in a medical journal either as an article or letter. Many thanks, Tall Allen, again. I have a question about statins. I take 20mg of rosuvastatin daily (for cholesterol), and it works as it should, thankfully. Do you know how long it takes to clear my blood so a PSA test wouldn't be affected by it?

I don't take any of the supplements you listed, but I do take other supplements and medications that are said to attack cancer cells directly; I hope they don't also mask PSA: mebendazole, cimetidine, loratidine, and Gamma E (hopefully to counter the smaller amount of alpha E in my multi-vitamin, which also contains a very small dose of biotin - 25 mcg). I've been taking metformin (for pre-diabetes) along with the statin for years, and neither kept the PC from reactivating.

Tall_Allen profile image
Tall_Allen in reply to kapakahi

You can look up the serum half-life in the pharmacodynamics section of the physician prescribing information for prescription drugs you are taking. The rule of thumb is that after about 7 half-lives, the drug is effectively out of your serum. But some drugs are stored in fat and the liver, not just in serum. Also, cimetine is well-known to delay metabolism of many drugs. Then, there are drug-drug interactions.

kapakahi profile image
kapakahi in reply to Tall_Allen

Thanks for these leads. Turns out the half-life of rosuvastatin is 19 hours, so that would be about 140 hours to be effectively out of my system (it has only 20% bioavailability to start with). So I guess maybe 6-7 days without taking it before a PSA test. The cimetidine is possibly a way to enhance the absorption of mebendazole, which has very low bioavailability (2-10% I think), plus it may have its own anti-cancer properties; the same with loratidine (which helps with my allergies).

What does PSA mean again?

Good Luck, Good Health and Good Humor.

j-o-h-n Saturday 07/11/2020 12:30 PM DST

Tall_Allen profile image
Tall_Allen in reply to j-o-h-n

See first sentence.

Gotit thanks, now what's the prostate?

Prostate Specific Antigen (PSA) is a protein on the surface of all benign prostate cells and most malignant prostate cancer cells. In prostate cancer, expression of PSA is correlated with the size of the tumor.

Good Luck, Good Health and Good Humor.

j-o-h-n Saturday 07/11/2020 1:08 PM DST

Thank you TA, most informative.

You the man! Thanks for all your work!!

Thinking about the opposite effect, are there treatments and/or medications that would make the PSA artificially high for a bit? (I.e. Xofigo?) we heard one of the doctors at the Malecare conference in NYC last fall say once it’s spread trust the scans, not the PSA. It’s hard when the MO is very married to the standard of care, and monitoring the PSA. Thank you

Almost all therapies that are known to increase survival will raise serum PSA at first. This is because they initially kill lots of cancer cells, and their PSA is dumped into the serum. The serum half-life of PSA is about 2-3 days. So, it can take 2-3 weeks after radiation to a met for the extra PSA to get cleared away. I had my first PSA test after prostate radiation 3 months later for this reason.

Thank you!

Is this one of the reasons for givning ADT before a scan?

I'm not sure what you are referring to. They don't give ADT before a scan; they may give a scan after therapies to see if they are working.

Ah. One doctor suggested in May to my father to first go on Bicalutamide, then get a PSMA-scan (as the first scan). But now I’m wondering if the Bicalutamide should not have interfere with the scan. But I got some answers that it could be the other way around: Bicalutamide helping with PSMA expression.

Not bicalutamide, ADT.

The doctor suggested only bicalutamide, but you mean ADT in general makes the PSMA expression stronges...? (I have a video lecture about this that I will have to look at, thank you for explaining)

I haven't seen anything showing that Casodex causes much of an increase in PSMA expression - what have you seen that shows that?

Love all your info. Thanks so much for taking the time to help all of us.

TA, I can always count on you to inform, enlighten and teach, Your contributions toward understanding this maddening disease are of immense value.

Thanks, as always, for giving us more to consider.

It’s interesting that when you raised this topic previously, over a year ago, there was a fraction of the interest shown by the group now. This tome it really struck a chord.

Tall_Allen profile image
Tall_Allen in reply to 6357axbz

What do you attribute that to?

TA, thank you so very much for this article. The research and writing you put into it gave me more depth and clarity on the subject. My expertise is software engineering (non-medical).

In 2018, I entered into a very small clinical trial. Like many, mostly on faith. I knew a decision had to be made. It is only until later when time allowed me to better understand the disease.

In Jan, partial results were posted: clinicaltrials.gov/ct2/show.... I expect all results will then get posted this Fall, once the trial period completes. As for me, I am doing good. PSA testing all along has revealed no recurrence.

After the trial completes, I am thinking I should meet with the clinical trial MO to discuss. There were 22 participants in the trial, where I know he can't talk specifics (HIPPA, etc.) Yet he may be able to speak to broader insights gained from the trial. If you have any thoughts on this, please let me know. Thank you!

Tall_Allen profile image
Tall_Allen in reply to tkalaf

They won't know for some time whether it reduces the rate of salvage radiation required, and the study doesn't have long enough f/u to assess that.. I'm not sure what it is possible to learn from it at this early date, other that it shrinks tumors (which is unsurprising).

tkalaf profile image
tkalaf in reply to Tall_Allen

Thank you for the quick response. For the trial, I had to sign a release for biological matter removed during RP. This material went to cancer research labs. From what the MO said, they were interested to see how this mix of drugs worked together. He mentioned each had its' own mechanisms that worked against cancer. In particular, the Zytiga with the newer Apalutamide. Also, outcomes from RP pathology reports may be informative. If I read mine correct, mine revealed reduction (I presume by volume) from 0.7 to 0.07. At a post RP checkup, I remember the doctor mentioning one participant's pathology showed no signs of cancer left.

Take care good man, stay healthy, and thanks for all your research and contributions to this forum!

Tall_Allen profile image
Tall_Allen in reply to tkalaf

There is a trial of apalutamide for use in active surveillance patients - the hope is if it will delay or stop progression:

clinicaltrials.gov/ct2/show...

But for men with high risk PC, it doesn't really matter if there is no cancer in the prostate - the prostate has been removed. What matters is if there is still cancer outside of the prostate. They will only know that after years of PSA monitoring. That's why I said the only useful measure is the salvage radiation rate.

tkalaf profile image
tkalaf in reply to Tall_Allen

Guess I based my faith on assumptions. If this drug mix proved to work well in the removed prostate, it must of worked just as well in the rest of the body. So perhaps it would not be time well spent then, to follow up with the MO.

Tall_Allen profile image
Tall_Allen in reply to tkalaf

We know that hormone therapy alone is never curative, whereas RP or RT can be.

tkalaf profile image
tkalaf in reply to Tall_Allen

yes, understood. In my case, at biopsy I was Dx'd at T2d G9. (Dx fit window for trial). However pathology from RP downgraded my Dx to T3a (extra-capsular extension).

My biopsy revealed PNI in prostate, and my RP revealed PCa on surface (T3a). This is where concerns lie, there were escape routes. On the positive note, the removed prostate and surrounding 24 removed LNs all had negative margins.

I feel 'blessed' it was found just in time. I am 'hopeful' it was all removed. When I ask about recurrence, my urologist gave me the 5 year post RP timeframe. If PSA stays below (0.03) threshold I most likely will be fine. I am now at 25 months, and clear!

Thanks for all you do TA!

fluffyfur profile image
fluffyfur in reply to tkalaf

What exactly is the indomethacin supposed to do?

Tall_Allen profile image
Tall_Allen in reply to fluffyfur

ascopubs.org/doi/abs/10.120...

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