Advanced Prostate Cancer
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Alzheimer's Danger Seen in Prostate Drug 12/2015 article

Trying to organize old stacks of articles I came across one from December 2015 referencing a study that showed Alzheimer's danger seen in prostate drugs.

There are lots of you posting on here that seem brilliant to me but I was wondering if any of you have opinions regarding this study.

There is a graph showing the explosion of sales of androgen blocking drugs mainly to the US. The study was published in the Journal of Clinical Oncology by researchers at Stanford and U of Penn searching records from Stanford and Mount Sinai.

I remember asking the MO about the study and he poo poohed it.

Also asking as my husband complains of a failing memory at age 74 and is going in today for a brain scan and soon for in depth memory testing.

Thanks.

Mary

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Androgen Deprivation Therapy, ADT aka chemical castration, is definitely associated with increased risk of dementia, including Alzheimer's. It also increases risk of cardiac illnesses.

ADT often causes significant to severe cognitive decline as a direct consequence of castration testosterone levels. Not all men notice, not all men care, but it is real and in some cases extremely debilitating.

If you could post the URL to the study, or some more information about where it was published, it would help folks here respond to your question.

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I found the article

ascopubs.org/doi/full/10.12...

Patients Who Receive Androgen Deprivation Therapy Risk Adverse Cognitive Changes

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The articles describe a randomized, controlled trial of 82 men with nonlocalized PCa who were allocated to leuprorelin (Lucrin/Luprin), goserelin (Zoladex), cyproterone acetate (Androcur), or no treatment and who were reassessed at 6 and 12 months after baseline. There were controls from men without cancer in addition to the group that received no treatment.

They found significant cognitive decline after both 6 and 12 months of treatment; the decline was worse at 12 months.

They also discussed some similar studies. One of them, by Gonzalez et al, did not mention measurements of testosterone levels in their participants.

Think about that. A study of the effects of driving testosterone to castrate levels doesn't mention testosterone levels before, during, or after treatment!

I noted similar omissions in other studies of the long-term cognitive effects of castration. One study took all the cognitive scores of all men, added them up and averaged them, then compared the averages before and after.

This method is guaranteed to hide effects. If for example 10% of men report a very significant decline, but the rest do not, the averaging process will turn that into a negligible effect. Had the study compared the experience of individuals, and reported on how many men experienced major effects, that hypothetical 10% of men would have been obvious.

The people who design these studies aren't stupid. I tend to believe that they are aware of the effects of their study design, and aware of not measuring (or carefully avoiding any mention of) testosterone. It's only a small step from that belief to a reasonable suspicion that there was an agenda to the research.

Cancer is big business. ADT / castration is big business. Biopsies are big business. RP is big business. There is a consistent pattern of not informing men of well-established morbidities and risks associated with all of these treatments and procedures.

Informed consent is impossible if the patient is not informed. How many men here were informed that their ADT would have both immediate and long-term effects on their minds, and increase their risks of Alzheimer's, another fatal disease?

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I agree with all u say....the admit to hot flashes and thats it....not bone pain or the fn memory fog...id opt out but shit is working for now..

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If any man is experiencing irritating hot flashes and severe sweats like I have on Lupron I recommend that you consult with your doctor to see if venlafaxine is right for you. It worked the same day I started taking it (75-mg) and it stopped about 90% of the severe sweats and hot flashes. Plus, my wife said she likes my new attitude and wished I'd started it 30 years ago (it's also an anti-depressant).

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Two clues to help you as you read studies:

(1) association≠causation

(2) Level of Evidence is important in determining how much faith to put into a study

The association of dementia and ADT has been noticed for a while. But if you think about it, you'll see that the real cause is difficult to tease out. Older men are more likely to have dementia and they are more likely to have prostate cancer requiring ADT; smoking, diabetes, CV disease, lack of exercise, depression, drugs used to treat other cancers, BMI, poor eating habits, etc. all increase as we age and they are all risk factors for dementia.

In the latest study I've seen about this, by NIH of the Medicare database, they noticed a small association for both Alzheimer's and dementia; however, after adjusting for risk factors, the association disappeared entirely. In fact, there was a very small diminution of Alzheimer's risk. Furthermore, there was no dose effect - men on ADT for longer duration had no more dementia risk than men on ADT for shorter duration.

ascopubs.org/doi/full/10.12...

In the only randomized clinical trial (Level 1 evidence) I've seen related to this, they found that hypogonadal men treated with TRT had the same risk of dementia as those who did not receive TRT. So we can be certain that replacing testosterone does not prevent dementia.

ncbi.nlm.nih.gov/pmc/articl...

Several studies have suggested a positive association:

tandfonline.com/doi/abs/10....

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

Other studies have suggested no association:

ascopubs.org/doi/full/10.12...

ncbi.nlm.nih.gov/pmc/articl...

There will never be definitive evidence of causation or its lack. That would require a randomized clinical trial where one group got ADT and one group didn't. It would be unethical to withhold ADT from men with incurable PC. So each man has to decide whether the possibility of an increased risk is worth dying sooner.

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saw this yesterday, while STILL trying to decide on ANY treatment at all: ncbi.nlm.nih.gov/pmc/articl...

seems ADT+ DOCETAXEL (what used to be standard chemo for PCa) adds a whopping 13 months to PCa gone wild. i suppose if a dead-man-walking sees an extra year of life, that's a good thing. from where i'm sitting, this whole disgusting mess just blows chunks, period.

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Not sure of your diagnosis but SOC ADT + Docetaxel (or + Abiratrone / Zytiga) does add significantly to median OS. Better than an agonist ADT is an antagonist such as Firmagon / Degarelix. That's the treatment I'm on in OZ although it doesn't seem to be the SOC in USA. Not sure why given the results of clinical studies showing that it's better.

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A great reply. Your entries are always well worth reading. Thanks so much for your astute analyses. It helps us all be better informed.

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Thank you for this answer.

I think that we are always looking for explanations for things....I heard a woman, an investigative reporter, interviewed on NPR yesterday, who got breast cancer and because of her diagnosis she tried to figure out what her risk factors had been.....the discussion was mostly about alcohol......

Almost complete change of subject, but interesting.....a doctor who was an expert medical witness at a post-war trial at Dachau re: liver biopsies done on prisoners there has died.....he was Dr. Donald W. Seldin, and was involved in "(r)esearch that helped establish ethical guidelines, including informed consent, .."

utsouthwestern.edu/newsroom...

The Belmont Report - Dartmouth College

dartmouth.edu/~cphs/docs/be...

Donald W. Seldin, M.D., Professor and Chairman, Department of Internal .... This opportunity is provided when adequate standards for informed consent are .

Thanks for your meticulous analysis.

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That's a nice story, but the study referenced in the OP

"took into account comorbidities that, along with age, can influence cognitive performance,"

Dismiss the results if it pleases you, but don't pretend it's because of a flawed study.

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There are many risk factors for Alzheimers beyond age and comorbidities that were NOT accounted for. Unlike you, I look at all the studies, not just the ones that conform to pre-conceived beliefs.

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Tall Allen, On another subject.. You recently showed an article on Tamoxifen after a discussion on side effects of cosudex,lumps in breast. Well i showed it to my MO & after he scratched his head & did his own research i now have it but the side effects again are a problem as in blood clots& the possibility of it working against the cosudex.

Results of ultrasound soon will hopefully show no breast cancer just one of many side effects of cosudex so for now the Tamoxifen remains untried.

Thanks Again for your informed articles

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Very low risk of blood clots from tamoxifen, and why would it work against casodex? - it has no affinity for androgen receptors.

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Thank you,i was worried about that & hard to find such advice.MO seems to be learning from computor articles

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Does your MO specialize in urological cancers?

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Hello Tall Allen. The MO does specialize in prostate cancer but the doctor i see is one of his students that will visit him for advice. I might add they are not impressed with me because i will not take Luprin, but that is my choice.

On another note,i seem to be having teeth problems on this cosudex,im thinking i need vit c supplement.Does cosudex deplete or compete with vit c?The hair loss i was told about & the tiredness can be managed.

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I've never heard of teeth problems related to Casodex.

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That study was highly flawed in many ways and ADT does NOT cause dementia or AD. Read a real study on this subject here:

ascopubs.org/doi/full/10.12...

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Thank you for that.

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What about Xtandi, which doesn’t work in the standard ADT way? I am on Xtandi and my T went up and my PSA went down

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podsart,

I was thinking about trying to do Xtandi and Avadart without ADT as a first line treatment and avoid the ADT negative effects. Is that what you are doing?

What is your history and current state?

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George71

Gleason 4+3, RPP 2010 , started to go detectable a few months after surgery-didnt wait for it to really climb- added metformin & avodart, then started Xtandi 2/16, PSA went undetectable immediately, stayed there as of now. T climbed immediately to supra levels (max a bit over 1600), dropped Xtandi dose slowly until down to 3 pills per week now, T now at 1300-still supra high

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podsart,

That is really good. -- I am thinking of doing similar. They want me to start radiation of pelvic lymph nodes and adt -- but I am thinking that avadart and Xtandi may be less likely to make me crpc. I don't think avadart will make you castrate but do you know if Xtandi will? I was thinking I would do radiation / avadart / and Xtandi and then do only avadart and see what happens. What do you think?

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If they can accurately destroy Mets in lymph nodes (I assume surgical removal is not doable) , consider including that action , in addition to Xtandi, Metformin and avodart

My situation was a very low Pca burden when I started Xtandi and dr Myers was surprised how fast my PSA plummeted. He said I was extremely sensitive to Xtandi.

Ecach of us are unique cases. However, I do believe in attacking the pca aggressively while it is in a low volume state

I assume you have modified your diet to eliminate red meat, minimize cholesterol and follow a Mediterranean diet, take at least curcumin, resveratrol, pomegranate, etc. supplement. Take vitamin D3 and have blood tested regularly so that your vitamin d level appropriate I also take AHCC, it is expensive, but dr Myers said it was worth it.

Reducing internal inflammation is key, Nalakrats has a post focused on this issue, he’s very knowledgeable -there are others as well , such as Tall Allen

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Remember, however, I am not a dr but a fellow patient

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Yes, I am doing all those things -- including I take Inocell IP 6 with AHCC -- I guess that is the same. I haven't been tested lately for D3 but it was good a year ago -- I take 10000 daily. As far as the lymph nodes they don't know exactly which ones -- it didn't show on f-18 pet scan about 5 months ago. current psa is .4 and has been holding there for about 6 months -- while only on metformin and avadart. If I stay on metforim and avadart when do you think I should add Xtandi -- when psa reaches 1.0 or start it now and do radiation. I think surgery can make the cancer spread -- so i'm thinking radiation of pelvic area might get it all if it is only there and hasn't already spread. What do you think?

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George 71

If it were me, I would start Xtandi immediately, along with the other stuff

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2 questions -- in your opinion,

Xtandi and avadart with radiation and no adt?

Is Xtandi likely to make me become castrate resistant?

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podsart,

Apparently you went 5 years before adding Xtandi -- what was your PSA at the time you added Xtandi?

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My last reply seems to be missing from post

So I will restate -

1. I believe in max attack , especially when the Pca is at weak point, so I would do Xtandi, metformin and avodart (want DHT at 4 or below). I take 2 avodart per day with grapefruit juice to slow absorb of avodart to now reach that goal-DHT checked quarterly

2 if those lesions can be eliminated safely sounds like that should be done. Quality of radiologist and equipment is clearly important, as collateral radiation damage is problem. There are others that are knowledgeable about which ionizing particle, protons vs other types is best for this action

3 my Xtandi started via Dr. Myers at 2 pills per day, then I asked permission to ramp up to 4 pills per day. As PSA stayed undetectable, slowly ramped down to current 3 pills per week. My goal was to achieve max kill as fast as possible and then go down to minimal dose to keep remaining Pca in check, in the hope that Pca resistance is inversely correlated to dose level

4 my PSA a max I think was .078, so we are dealing in my case low volume but rather aggressive Pca-as my current dr says a “dangerous cancer”

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Thanks,

You never had radiation at all?

and never took lupron -- just Xtandi / Avadart / metformin plus supplements?

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No lupron or radiation

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thanks -- I will ask my Dr. about similar course of treatment

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Why did Dr. Myers go straight to Xtandi? With the numerous options and different mecahnisms, it's difficult to figure out which one, when, combinations, etc...

Thanks.

Josh

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If its lupron they are talking about ...yes ive heard stories about early onset dimentia and alz....stuff is poison my memeory sux and im on it forever....like they say if the cancer doesnt kill u the treatments will....its about quality of life...right bow mines ok..despite the fact i cant remember my name...but anymore than that ill choose a few good years over 10 bad ones.....

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What's the subject?

Good Luck and Good Health.

j-o-h-n Friday 05/11/2018 6:58 PM EDT

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We just got the brain scan results and nothing jumps out as alarming but I need to research some of the terminology to clearly understand. Nothing sounded like cancer in the brain at least.

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My reply is merely anecdotal, but I know my husband had no significant memory loss prior to submitting to two years of Firmagon/Lupron/Vantas. Now he still reads “The New Yorker” with understanding and listens to our library’s and Audible’s books. In our minimal time off the past couple of days, we’ve been listening to and discussing “Natural Causes” by Barbara Erhenreich which, btw, we recommend. So, Leswell is far from brain dead, but his short term memory loss is significant. How can I tell you how much it hurt to hear a neurologist diagnose him as demented.

When first informed of his Stage Four prostate cancer, we were in shock, of course, and grasping at straws. We hadn’t had time to become sufficiently informed by Google and Health Unlocked, and even if we had been, we probably would have still allowed those initial shots of Firmagon and all the life and death-dealing drugs that followed.

This week we have been informed by two physicians that unless my husband is treated with more powerful drugs, he isn’t likely to live more than a year. Our urologist/surgeon/prostate specialist has selected Zytiga, Prednisone, and Xgeva all of which have been approved by our insurance which means we will pay 28% of retail. Our insurance company today was happy to inform us that Zytiga has been approved which means that for us it will be $2000 per month unless and until it goes out of patent which,I have read somewhere, could be as early as October. Or perhaps the prior authorization expert at the clinic will come up with a miracle.

Our oncologist agrees with the urologist for the most part but not about the Xgeva schedule. The MO recommends an injection every three months over two years up to a maximum of eight; the other prefers monthly injections which, I guess is what we will begin with in three weeks. The biggest risk is ONJ which is somewhat less likely with the first doctor’s protocol and probably still less likely and far less expensive if we choose 15 minute infusions of zoledronic acid which Leswell tolerated well during chemotherapy.

Bone pain was the worst thus far today but better tonight. He took several ibuprofen but no narcotic although he has twenty-four of those left over from his hernia surgery. Sometimes it is difficult to ascertain which pain is which.

Mary, if you and your “young” husband keep reading all the exceedingly bright correspondents on this site, and we all know who they are, (lots of wonderfully encouraging others who make a big difference, too!) you two will make a more informed choice than we did. Nobody’s fault in our case, just live and learn and maybe die sooner, but the author mentioned above has much to say about our being the age to die and about random cellular warfare as causative which frees us all from the blame game. Tonight I enjoyed and profited from reading all of you! Best wishes with your memory, Mary’s husband, and the brain scan. Mrs. S

P.S. If Dan59 is handy please let him know that I did ask about Darolutamide and Proxalutamide. Dr. T knew that they were in trial and not yet approved but didn’t make a recommendation because he isn’t prescribing them. One of the good things will be no steroid, right? On the other hand, we were told the steroid might help with bone pain. Correct me anybody and everybody.

P.P.S. The Vantas will be left in until it expires at the end of October. It must be working because Leswell’s T just came in at 14 (oh goody); hot flashes are more frequent and stronger than ever. Remember that Nalakrats’s hot flashes stopped after the Vantas was removed and bicalutamide stopped. Mostly Leswell’s liver enzymes look okay, but the Alkaline Phosphatase has risen from 56 to 104 in the past six months. (No testing done during that time.) The PSA has gone up during the past couple of weeks from 166 to 181.2. I worry that maybe we should have chosen Xtandi. I was listening, Dan, just not aggressive when face to face with the pros.

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I probably should know this but about xtandi does that have to be taken with prednisone too?? The weight gain from prednisone is such a big problem for staying healthy.

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No, prednisone is not taken with Xtandi/enzalutamide, and, yes, weight gain is a big deal but not, perhaps, as much of one if the other option is a tumor in need of debulking. My brother was nearly double his normal weight on steroids when he died of a brain tumor and did go through debulking at Mayo. So sad. He looked like a Macy’s Thanksgiving Day Parade balloon on steroids. Btw, Dan59 mentioned Darolutamide’s advantage (in trials) of not requiring prednisone. I should look you up, but is your husband about to begin taking Zytiga or Xtandi? Mrs. S

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Thanks for the well wishes.

Because the cognitive decline has been slow, it's difficult to say just when it started but my husband delayed hormonal treatment for 14 years after Pca diagnosis.

He no longer reads books but continues to look at the WSJ daily. However, when I quiz him on an article he often doesn't recall it. He sleeps poorly due to all night peeing, hot flashes and ~medication side effects that make him groggy. He refuses to nap.

The neurologist offered to start him on a Parkinson's medication but we are doing a long road trip soon and it might interfere with driving.

Regarding the excellent advice received here, I am using it to get prepared for an upcoming appt with a different local MO, still not a prostate cancer specialist, but one who may be more open to Avodart and/or Metformin and my question about taking Xtandi with Casodex before we see the specialist at Mayo in late summer.

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Just wrote a reply and lost it. Let’s see how my memory is. I’m probably in denial about the in-depth nature of our book discussions. What I CAN do is try to be more patient in repetition and association. Groggy I don’t like, but naps are essential for us both due to the nightly interruptions. Tell your husband our lymphedema specialist recommends naps.

I must look up Parkinson’s medications for dementia. Les is still taking Avodart, Proscar, and metformin but isn’t allowed Casodex while on Zytiga. I want him to increase the metformin since we aren’t exercising enough. The MO asked me with a straight face if we are still running together. Those were the days.

Have a safe road trip and great summer. We’ll be thinking of you at what must be “our” Mayo in Rochester. (My brother left his body to Mayo.) He was married to my husband’s sister who lives in Northfield and sometimes travels with another widow on Professor-led trips from St. Olaf.

Go well. We will check to see how you are doing on this site. Mrs. S

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Forgot to say, I will ask again about why we’re starting with Zytiga vs Xtandi. It may be because our insurance (UCare Value Plus for Seniors) more readily approves of it as a first choice leaving Xtandi “in the wings”.

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Husband diagnosed with dementia could be Alzheimer’s and started on Aricept. His memory has been worsening over the past six years or so but seems to be more rapidly declining since ADT. I know it’s not proven.

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