You guys have empowered me to ask the right questions...
I met with my MO today and he agreed to start measuring DHT , Estradiol and free Testosterone as well and PSA and T going forward.
PSA was stable at 0.03 only blood # out of ordinary was ALT = 99 normal range 16-61. Dr. says "liver enzymes were elevated and your potassium levels were low."
We had a discussion about Avodart and he said he would consider a prescription if I could show him persuasive studies.
The following 5 are the best I could find. Does anyone have a favorite study that helped them convince their MD to prescribe Avodart?
Dutasteride is known to be effective in preventing prostate cancer and treating low-risk prostate cancer. However, the role of SRD5A inhibitors in the progression of prostate cancer to CRPC has not been well studied (18). The development of CRPC is still dependent on DHT, and some next-generation drugs targeting the androgen signaling pathway were reportedly effective (11-13). We therefore assessed the effects of dutasteride in patients with CRPC by assessing changes in PSA levels. The present study showed that 41% of patients with progressive CRPC showed a decrease in their PSA level, with 17% showing a decrease greater than 50%.
In a paper published in June of 2018, a team led by Nima Sharifi from the Cleveland Clinic identified that certain metabolites of abiraterone are AR agonists. As such, abiraterone metabolism creates its own competitor, in a manner of speaking... [by producing] 3-keto-5-beta abira abiraterone [which] ends up as an androgen agonist, thus potentially mitigating the antitumor potency.
The enzyme that catalyzes the conversion of D4 abiraterone to 3-keto-5-alpha abiraterone is 5 alpha reductase, the very enzyme that could be catabolized by the addition of a 5 alpha-reductase inhibitor such as finasteride or dutasteride. Although such treatments have not resulted in substantial antitumor activity, they have not been studied in this context.
One possibility is that we could combine abiraterone with 5 alpha reductase inhibitors. This has been done on a small scale but not based on the genetics of polymorphisms."
Do you take many supplements/drugs? I used to take too many and my liver enzymes started going up and my kidney function deteriorated. I stopped them for a couple of weeks, retested, and everything was going back to normal. So I reduced them other than the ones that my MO suggested and the ones that have some RCT backing.
If you aren't doing high T or BAT I think that dutasteride is a great option. It's going to take whatever DHT you have lower. I haven't noticed many sides so I take some finasteride (short half-life) during the low T phase of BAT.
In general, I'm not sure if the drug sides are worth it for the small decrease in DHT if you are on ADT (particularly if you are concurrently using a cyp17 inhibitor such as Zytiga). But that probably depends on the individual and how they react. If the sides are palatable, I would opt for it. I did both fina and duta when I did ADT.
As long as you look at lab studies and retrospective analyses, you will never convince a doctor who knows anything about research methods. You are trying to confirm your bias, which is not what anyone interested in the truth should be doing.
This is not what you want to see, but it is what you should see... There was a randomised clinical trial that looked at whether a 5ARi was beneficial in men on iADT. They found the opposite was true:
Interesting. Exactly the opposite of what my MO thinks. Likely depends on individuals, therapies both past and present as well as future plans, and the phenotype of the cancer.
This observation helps further cement the heterogeneous nature of the cancer and individuals.
This is what occurs in most men. Research never predicts for individuals, but what are the odds that you are different from the average? It's not a bet I'd ever want to make.
Amazed at how you misunderstood what I wrote. It is not statistically significant and I pointed that out. But given there is no benefit, and you have no indication that you are anything but average, there are no data on which to base a treatment decision.
Yes, the time on "vacation" was shorter by over a month if they took the 5ari, so it is indeed true that it had the "opposite of a benefit". Not s.s. on this sample size, as I've repeatedly stated, but it was an underpowered Phase 2 study. They were only looking for a signal of a benefit. If they had found one, they might have conducted a larger, Phase 3 trial. But finding no benefit, we all moved on.
I am saying that you do not have any reason to believe that you are any different than the average man in the AVIAS trial. That's the power of randomization.
But you seem to be suffering from confirmation bias instead of looking at it scientifically. In fact, that is the main characteristic of pseudoscience (see #1,3,6,7,9 below). You may as well hire a witch doctor to guide you.
I remember when the trial was published. Everyone was excited about Scholz' retrospective analysis, and "combined androgen blockade (CAB)" was the big buzzword. When we finally got Klotz's trial results it was sobering to many, but most of us accepted it and moved on. Some get stuck in the past and get left behind.
Mark Scholz and Snuffy were proponents of 5ARIs. Mark has moderated his opinion but still prescribes it.
My opinion is that if part of your individual therapy calls for DHT reduction and the rewards outweigh the risk of sides, 5ARIs should be considered. Per discussions with my MO I used dutasteride during my short ADT stint and also for a very short Casodex/dutasteride stint (1 month). But now I will only use finasteride during the low testosterone portion of the program I am following. I need something with a short half-life so dutasteride is not a viable option for me.
I am planning on testing out the addition of finasteride. But unless the effect size appears to be large in magnitude I'm not certain how actionable the results will be. I don't make much endogenous testosterone given the cyp17 inhibitor and LH/FSH suppression drugs that I am using (plus I use Casodex for about a week every couple of months to interfere with the exogenous androgens while they clear my system). So I don't think the use of a 5ARI makes a huge difference given my active therapies. My MO thinks I should continue with the program and that's the primary reason that I'll test it out.
Yes-Scholz was an early advocate of Total Androgen Blockade for intermittent therapy. There was enough interest at the time to do a prospective randomized trial, which is why Klotz did AVIAS. Unfortunately, it did not prolong the vacations as hoped. Klotz believes the poor results were because the intermittent 5ari use created resistance (similar to how antibiotics create resistance if used intermittently), or because "5ARIs exert a deleterious effect on prostate cancer in this situation, promoting more rapid recovery of PSA than expected."
I think it still has a place in recurrent patients with no metastases who are using Casodex as their only therapy. Casodex-only causes a build-up of testosterone, which metabolizes to estrogen and DHT. The 5ari prevents DHT build-up, and tamoxifen can prevent gynecomastia from estrogen build-up. If PSADT is rapid., there is more interest in temporary use of an advanced hormonal agent for such men.
Hi Allen, if you can comment the following, please.
PMC5330377 (Early dutasteride monotherapy in men with detectable serum prostate-specific antigen levels following radical prostatectomy: A prospective trial)
Presented to my MO two years ago (BCR status).
He passed over it very quickly and was adamant not to do Avodart/Finasteride.
1. He asked if I had noticed the following statement: "Patients undergoing adjuvant EBRT or androgen deprivation therapy were excluded from the study".
(My adjuvant EBRT (2016) had knocked PSA from post RP 0.06 to 0.03).
"EBRT had changed your androgen receptors" he said. No detailed explanation given.
2. "Just small number of patients had benefitted according to trial" was his second argument.
PG04 - guidance for BPH treatments(in my country):
For medications related to BPH (Avodart/Finasteride) there is statement: "Can't be prescribed after prostatectomy".
So, prescribing it would be a significant risk for MO.
1. I don't know that adjuvant EBRT changes androgen receptors - never heard that before. And if it does, it only changes them in the treated area. Most recurrences occur in the untreated areas due to occult micrometastases. But it is true that that trial did not include men in your situation (RP+aRT)
2. Of the 80 patients in that study, 56 (70%) had at least temporary declining PSA, and 44 (55%) had PSA declines lasting through the end of the follow-up (median 52 months). Whether such early treatment provides a long-term benefit remains controversial.
5aris can't be prescribed post-rp for BPH because there is no prostate in which a man might have BPH.
Small scale study, with men going on and off ADT depending on PSA. I’ll stick with the Snuffy Myers approach and continue to use dutasteride as part of a multidimensional approach. This approach has worked for 8+ years. If I based my treatment on every trial result out there I probably wouldn’t be here right now.
In fairness, TA has a valid point. If I was the average 70+ year old with Gleason 6 PCa I could afford to sit around and only entertain approved SOC treatments. That would most likely be good enough. I'm not in this bin though so my MO and I need to be proactive rather than reactive.
No ADT now for18 months. PSA <0.4 Taking Dutasteride and finasteride daily. Should I stop? At age 81 now seriously considering High T since my T is still below >10. Will I awaken the devil ? Another doctor suggests I do the high T. He claims to have helped six men with it and it worked fine. He did so by saying that no guarantees.
I would hesitate before stopping duta and fina. Something has worked (could be the 5ARIs, could be luck, could be orange juice )How high does your doctor want your tT? (tT > 1500 ng/dl or? Or does he look at free T instead?)
If it were me I would do the T (in fact, that is what I did for 2 years - my serum T was well over 2000 on average, my free went over 40 and my bioavailable went above 1000).
Also, have you asked this doctor about what he thinks of using 5ARIs during high T? Conflicting thoughts on this one. I have opted not to use them during high T. And duta has a long half-life. So I never use duta anymore.
What does your doctor think about using a lower dose of T?
I'm not sure why most MOs let guys coming off of ADT suffer with low T. My T recovered really fast (a few weeks). But for many guys it takes months or years. Why suffer the variability when it is as easy to control as clicking the channel-change button on the TV remote? Maybe there are reasons that most doctors seem to prefer endogenous T instead of exogenous but since we are messing with the hormones anyway, what is the logic?
The high T seemed to work well for me (according to my MO and my labs). Regardless of that, I do not regret it. My 2 high T years were the best of my life.
Whatever you decide to do, as always, monitor, monitor, and monitor some more.
Exactly 1 year ago, I completed full pelvic SBRT. Ever since, I've been on Avodart and Metformin only. I suggested Casodex instead of Avodart but MO, preferred Avodart. She said something like .... "when off treatment she prefers off treatment to allow the body to recover"...Evidently, based on that remark, she doesn't consider Avodart as being ADT. I was thinking and hoping in a way, that My Testosterone level would rise...never did, 2 days ago, the T value remained at 21, with PSA rising slightly to 1.40. Scheduled a Pet Ct scan, searching for psa, my friend of 17 years.
She sounds something like my MO. My MO talks me out of many therapies because of the sides. She wants me to be healthy enough to enjoy the life that I have. I like her outlook and think that waiting makes sense for another reason: new and improved therapies come out all the time. The landscape has changed considerably just in the 4 years since my diagnosis.
Did you do straight T or what is described as BAT?Also, what caused you to stop T. This is my concern as to what is done it T allows the demon to raise its ugly head. Just going on ADT and ? I have two doctors ( an onco and family MD ) that are willing to do this.
To address possible sub-optimal issues with the standard BAT therapy I designed ABAT (adaptive BAT). It is more complicated than a standard BAT program. There aren’t any trials on ABAT so feel free to modify it or add a couple of the ABAT components to your standard BAT program. If I were going to make one change in standard BAT, I would apply Androgel for 1 week instead of using testosterone cypionate. The other change that would be important for me is to add a low dose estrogen patch replacement to the LT phase of BAT. People react differently to a low testosterone/low estrogen environment and I do not fare well mentally.
The maximum allowed PSA (X) is up to the individual. Based on my status I choose X = 0.05.
The maximum allowed PSA to determine termination (Y) during ABAT is up to the individual. Because my PSA during the lead-in phase was zero, I choose Y = 4.
• Step 1. Lead-in ADT
1. Lead-in ADT drugs/therapies
1. Lupron or another ADT therapy (e.g., Relugolix or Orgovyx or an orchiectomy). Another possibility is to use 1000 mg/day of Zytiga on an empty stomach for the ADT. Prednisone should be used at 5 mg 1-2x/day with food.
2. Estrogen patches (0.05 mg/day). This is a low dose estrogen replacement.
3. Cabergoline to reduce prolactin (0.25 mg twice weekly).
4. Optional: Zytiga (either 1000 mg on an empty stomach or 250 mg with a low-fat meal). Zytiga is used to prevent testes, adrenal, and cancer cells from manufacturing testosterone by interfering with an enzyme required for testosterone production (cyp17).
5. Optional: Prednisone (10 mg/day split into two doses). Zytiga depletes steroid production so 10 mg of prednisone a day is used to supplement.
2. Start a lead-in ADT phase and continue until PSA is less than X. If it has not dropped below X within 6 months, consult your MO or move on to a different therapy.
• Step 2. ABAT
1. ABAT Cycle drugs (example 8-week cycle)
1. We need some way to reduce the body’s internally produced testosterone to zero or close to it. Some options are Firmagon, Relugolix, and Lupron. Another possibility is to use 1000 mg/day of Zytiga on an empty stomach for the ADT, or possibly 250 mg of Zytiga with a small meal. If the Zytiga route is preferred, then Zytiga should probably be started one week prior to the LT phase of BAT. Note that when Zytiga is taken, prednisone should be used at 5 mg 1-2x/day with food.
2. Estrogen will be replaced during the HT portion of ABAT via aromatase activity and during the LT portion of ABAT via the estrogen patch. Estrogen replacement negates many of the harmful side effects of ADT.
3. HT:
1. Starts day 1 and ends day 28
2. Day 1-56: 0.25 mg twice weekly cabergoline to reduce prolactin.
3. Day 1-28: Apply 8 pumps a day of 1.82% Androgel. Each pump is 1.25 g of gel). Note that you could also use three or four 5 g packets of 1% Cernos gel a day.
4. Day 1-28: Take an AI. I take a 2.5 mg tablet of letrozole (weekly so day 1, 8, 15, 22). Anastrozole or exemestane might be preferable but they give me insomnia and bloating.
5. Optional: Day 1: Inject 200-400 mg nandrolone phenylpropionate (NPP)1.
6. Optional: Day 7-20: 10 mg/day of Tuinabol1.
4. LT:
1. Starts day 29 and ends day 56
2. Optional: Day 22-49: 250 mg Zytiga with a low-fat meal (approximately 300 calories with less than 2 grams from fat – 12 ounces of pomegranate juice with an ounce of soy or whey protein satisfies this). When taking Zytiga, corticosteroid replacement is necessary and typically this is done by taking 10 mg of prednisone each day split into two doses. Zytiga takes about 2 days to reduce testosterone. This is optional. Zytiga reduces the small amount of testosterone made by the adrenals and cancer cells. Note that you could also take 1000 mg of Zytiga on an empty stomach.
3. Optional:
• Day 29: take 100 mg bicalutamide. Bicalutamide will inactivate most of your residual testosterone from the Androgel. Without using bicalutamide, the testosterone gel will still be cleared within 4 or 5 days; bicalutamide slightly reduces the effective clearance time.
• Day 30-35: take 50 mg/day bicalutamide.
4. Optional: Day 29-56: A moderate to high dose statin. Statins reduce the small amount of testosterone made by the adrenals. I would take Atorvastatin. Atorvastatin gives me insomnia, so I take Lovastatin. They are both lipophilic and might be more therapeutic than hydrophilic statins. This is optional. Some research indicates that a statin might help control cancer during the LT phase. Note that I also take 500 mg of metformin per day as well as 300 mg of EGCG, 300 mg of curcumin, 60 mg of melatonin before bed, and 81 mg of aspirin before bed.
5. Optional: Day 29-49: 5 mg/day Rad-140.
6. Day 36-49: Apply estrogen patches (delivering 0.05 mg/day). I use Climara.
7. Optional: Day 36-49: take 1-5 mg/day finasteride. This is optional. It lowers DHT but DHT should be close to zero in the LT phase. Note that finasteride should not be used during the HT phase.
2. The first ABAT cycle length is a minimum of 6 weeks but no longer than 12 weeks.
3. Continue the cycle until PSA is undetectable or is less than (X).
4. If greater than X at the lowest point, discontinue ABAT and determine next therapy. It might be desired to do 6 cycles of a static BAT (BAT with 4-week cycle lengths). This might re-sensitize cancer to Xtandi. If already Xtandi sensitive perhaps a 6-month stint of Xtandi, 6 cycles of static BAT, another 6 months of Xtandi, etc. Other options might be ADT or radiation, or an adaptive Zytiga or Xtandi approach. Adaptive approach: if PSA > 10 then start Zytiga (or Xtandi). When PSA drops below 4, discontinue AR drug. When PSA recovers and exceeds 10 restart AR drug. Continue until PSA will not go below (Y) within 4 months (Gattenby?). Or RBAT which is explained below.
• Example:
1. Lead-in phase, PSA target 0.05 (X).
2. Hypothetical result: PSA dropped to 0.0 so start cycle #1.
3. Start Cycle#1 (minimum cycle length – 8 weeks, maximum = 12 weeks). Increase X to 1.15*.05 = .058 to allow for slow cancer growth.
a. Start HT phase. Continue for 4 weeks.
b. Enter LT phase. Continue until PSA is less than 0.058 (X) or 12 weeks whichever comes first.
c. Hypothetical result: PSA dropped to 0.02 during week 8. Note that if PSA had not dropped below 0.058 (X) by the end of the 12th week I would have ended ABAT and sought another therapy instead.
4. Start Cycle#2 (minimum cycle length – 8 weeks, maximum = 12 weeks). Increase X to 1.15*.058 = 0.067 to allow for slow cancer growth.
a. Start HT phase. Continue for 4 weeks.
b. Start LT phase.
c. Hypothetical result: PSA dropped to 0.02 during week 9.
5. Start Cycle#3 (minimum cycle length – 8 weeks, maximum = 12 weeks). Increase X to 1.15*.067 = 0.077 to allow for slow cancer growth.
a. Start HT phase. Continue for 4 weeks.
b. Start LT phase.
c. Hypothetical result: PSA dropped to 0.07 during week 8.
6. Start Cycle#4 (minimum cycle length – 8 weeks, maximum = 12 weeks). Increase X to 1.15*.077 = 0.089 to allow for slow cancer growth
a. Start HT phase. Continue for 4 weeks.
b. Start LT phase.
c. Hypothetical result: PSA dropped to 0.08 during week 8.
7. Start Cycle#4 (minimum cycle length – 8 weeks, maximum = 12 weeks). Increase X to 1.15*.089 = 0.102 to allow for slow cancer growth
a. Start HT phase. Continue for 4 weeks.
b. Start LT phase.
c. Hypothetical result: PSA dropped to 0.07 by the end of week 10.
2. Start Cycle#5 (minimum cycle length – 8 weeks, maximum = 12 weeks). Increase X to 1.15*.102 = 0.117 to allow for slow cancer growth
a. Start HT phase. Continue for 4 weeks.
b. Start LT phase.
c. Hypothetical result: PSA only dropped to 0.15 by the end of week 12.
d. This is greater than X so end ABAT and go to the next therapy.
Notes:
1. These are optional and are included only for muscle building/bone loss mitigation.
2. A standard blood test is not capable of distinguishing Nandrolone from testosterone so your blood test values might appear skewed (common forms of Nandrolone are Deca Durabolin and NPP). However, the Liquid Chromatography tandem Mass Spectrometry (LC/MS-MS) Total Testosterone test can distinguish real testosterone from Nandrolone.
3. Nandrolone is produced in small amounts in the body.
4. SARMs and AAS might reduce HDL cholesterol, increase LDL cholesterol, and negatively affect liver enzymes. This needs to be monitored. In my experience, HDL cholesterol is the only one that is severely affected.
References
1. How To Test If Your Deca Is Real | Nandrolone Registers as Testosterone
The most important mod is the use of Androgel instead of cypionate. Danmeade recently said that he wants to use a testosterone gel because cypionate is not optimal for BAT.
Another important mod is the use of a low-dose estrogen patch during the LT phase. Its function is to reduce cardiac issues, improve bone health, and improve mental health. My DEXA scans show that my bone mass went up in some places. And I have seen firsthand the mental detriment in me when I don't have any T or E (yes, John, close to T&A but I'm not a teenager and I can get by without daily T&A).
Making LT length PSA-driven instead of static makes sense to me so I would put this as the third most important change.
I fully understand that I have a bias based on the anecdotal results of some of the more aggressive guys on this site. I see little downside unless I have a reaction to Avodart and I know some have, in which case I will stop using it.
If you could point me to a cure or permanent remission in the SOC stable I would go in that direction. Until that happens my choice is to use every weapon available to possibly slow this baby down. My goal is to remain Hormone Sensitive as long as possible.
I intend to be an experiment of One. Looking for the best QOL for as long as I can make it last.
If you see no downside, you haven't read the AVIAS trial that I linked. "The median time off treatment was shorter for dutasteride-treated patients (19.8 vs. 21.3 months)." While that difference was not statistically significant on n=80, it may be a deleterious effect on a larger study. Klotz proposes mechanisms for it.
You can't be "an experiment of one." because you have no clue as to what would have otherwise occurred. It is better for your health if you stick with what is known than if you simply imagine things.
If you look at the conclusion you will perhaps learn something.
I find this extremely entertaining. I once attempted to pull statistical significance from a relationship with a p-value > 0.05 and you tried hard to convince me that I was doing something stupid. How exactly is this different? And now you cite a hypothetical mechanism as part of your argument? Really? No need to answer unless you feel the need.
Sometimes you seem intelligent and sometimes you leave me shaking my head. Today is a shake my head day. Gleason 6.7 vs Gleason 9? 71 vs 58? How are these the same? If you can give me a good argument perhaps I can convince the IRS that my income taxes should be the same as someone who makes 20k a year.
We're all individuals. I know that you are going to take calculated risks and won't be emotionally attached to a given study or therapy. I suspect that most of the guys who have shown some success with advanced prostate cancer follow the same guidelines.
My mom was studying to be a physicist when she was waylaid with housewife duty. My point is that she was brilliant. She would sometimes say, "statistics are statistics but if something happens to you it's 100%".
Whatever you do, test, test, and test some more. And since PSA can be misleading in some cases (although the directional behavior is rarely misleading unless you have graduated to NEPC or small cell) take into account your liver enzymes and eventual PSMA or choline scans.
The opposite of benefit is "This small-scale Phase II randomized controlled trial showed no benefit to the addition of dutasteride to an IAD regimen."
I usually think of the opposite of benefit as detrimental. It is interesting, and nothing more, the emotional tilts and what they say about individuals. I have been accused many times in my life (almost daily) of looking at the positives and have actually had people tell me that I am "too happy". Simply a random observation and has no connection to the study.
Why take the risk of trying to infer statistical outcomes from a small underpowered study instead of looking at a larger study that had government oversight? Why try to read into a tiny study instead of listening to my MO? Why rely on a tiny, underpowered, inconclusive study that, even if it was larger, would apply to men much older than I am with much more benign cancer? Is it your thought that we should start reviewing small trials for BPH because Gleason 9 PCa is in some way similar?
In my unscientific reading, the vacation was two months longer for those using drug as opposed to the placebo group, so small benefit. "The median time off treatment for patients reaching ≥5 ng/mL was 18.6 and 16.7 months for dutasteride and placebo, respectively"
The results for the total men who went the at least 2 yrs off-treatment orreached PSA of 5.0 during the off-treatment period: "The median time off treatment was shorter for dutasteride-treated patients (19.8 vs. 21.3 months)"
You are quoting the results just for the subgroup of men who reached PSA of 5.0. That suggests that the difference was even more extreme in the small sub-group (favoring placebo) who was able to go at least 2 years off-treatment without reaching PSA of 5.0.
Again, non-science person here, but helped people with more aggressive PC a little but worse outcome for those with less aggressive? So net draw? Or basically a crap shoot on whether it hurt or helps.
Don't try to make too much of these low sample-size subsets. The only group worth drawing a conclusion about is the total - no significant difference. All the direction of the total and the subsets do are suggest hypotheses for further testing. I don't think any top oncologist advocates using a 5ari for iADT anymore.
There are much larger RCTs that show benefits. Look at the balance of evidence. Look at all studies, both good and bad. Cancer doesn't care how we cherry-pick to confirm our internal biases.
And discuss with your MO. We are not all identical. My MO said that dutasteride is usually something she uses towards the end of cancer therapies but because of my particular therapies she wanted to add it earlier and in a different fashion.
My MO is open-minded and quite progressive for a SOC doctor. So, I just asked her and she was willing to prescribe. For simplicity I had my NMD prescribe instead. And you can also get the stuff on the black market. There are some fairly reputable manufacturers and distributors. So I frequently call it the grey market.
If I had an MO who was not able to review studies and RCTs and was not able to grasp the conversion from T to DHT, I would be very suspicious of them. But at least he is open to learning and some of them aren't able to admit that they don't know everything.
The first 4 MOs I talked to did not seem to understand the T -> E regulation and actually told me that you could increase E as high as you wanted and still not affect T. Wow! 4 of 4. My current MO was the first to say that it would decrease T but she didn't think it would be enough. That told me that she actually had some level of understanding of High School biology. She has not failed to disappoint me. Smart and thoughtful.
1. I have a lot of respect for your quickly acquired domain knowledge and rapidly developing intuition.
2. What would I do?
o You are locked and loaded and ready to go on with what appears to be a really good plan, Nothing wrong about it that I can see.
o Personally, I would slow down now and get a bunch of second opinions from different major medical centers. You have collected more lab data on yourself than you had at the start. You will soon have more.
o You have bought yourself some thinking and recalibration time. I would now make use of it. It can only result in smarter decisions.
Excellent summation showing judgement and clarity in this jungle. Bravo! I too admire Scout’s dogged pursuit of knowledge and rapid learning curve about PC. Time for reflection and consolidation are also needed to get a clear perspective above the weeds. 🙏 Happy Easter and Spring to all 💐
Consulted with ROs at U of Chicago, UCLA and 2 at the largest independent practice of cancer only ROs in Chicagoland, one who only does only Proton, the other recommended by TA.All have had similar proposals based on my cancers individual characteristics.Not sure what would be gained by consulting more.
Coco has asked me the same question, why radiation now?I don’t have any answer other than that is SOC and has shown the best results when combined with Lupron and Zytiga.
I do not want to stay on ADT any longer than I have to because of the toll it is taking on my body. (Accelerated aging)Since ADT does not kill cancer cells, once I exit ADT I expect PCa will re-emerge if I do not kill most of it with radiation.
What benefits would I get by waiting to do radiation?
The stats say that hit it hard is best for PCa mortality and that is why I sometimes come back to therapy addition when I talk to my MO. Her point is really good though: Russ, how do you prioritize QoL? She knows darn well that this is my kryptonite. She wins the discussion every single time.
There are three very valid arguments in this situation.
1. Do it now. Kill as much as you can right now and maybe that will be good enough.
2. Wait. New technologies are coming out rapidly. If you wait a few years perhaps there will be more effective RT treatments. (in 2018 I was adamant that I would NEVER do RT. Too many side effects. Tech changed and my opinion changed with it.)
3. Wait. You do not know if it will benefit you to do it now. But you do know that you will have side effects (my MO is in this camp and constantly talks me out of ramping up my therapies).
It would be nice if we knew which one was the best course of action for both QoL and mortality. I tend to want to do #1 but my MO goes for #3. I rely on her when it comes to SOC so I wait.
The statistics say hit it with everything you have for a short time to kill it off.
I think the trials basically back this up.
But question. Does the ADT kill it or does it just stunt its growth? If it is just suspending its growth, then the statistics about fighting an adaptive disease aren't applicable.
It would be nice to get a confirmation from Tall Allen about whether or not ADT actually kills off prostate cancer cells, or merely slows their growth?
ADT kills some cells. It weakens others. These are the androgen-sensitive cells (a dominant cell line). Some cells still eke out a living and then upregulate ARs (or mutate them) so that they can survive even in a very low androgen environment. For this reason, it is called castrate-resistant prostate cancer (CRPC). Not a digital thing though. It's really analog and not some ridiculous step function from 0 to 100. Very misleading and I would guess that some doctors can fall into the trap as well as patients.
"For this reason, it is called castrate-resistant prostate cancer (CRPC). Not a digital thing though. It's really analog and not some ridiculous step function from 0 to 100. Very misleading and I would guess that some doctors can fall into the trap as well as patients."
Androgen-sensitive prostate cancer cells do not suddenly become completely androgen insensitive. This is a somewhat common misconception.
What really happens is an analog change. Cells start to upregulate and mutate ARs in order to survive a low T environment.
They don't go from needing lots of T to only needing a tiny bit of T in the blink of an eye. In reality, the change takes place over some period of time. I don't know what it is - weeks, months, years? I'm guessing that it starts almost immediately after ADT is started and then continues for years until it is efficient enough to survive ADT.
Anyway, at first, ADT works great and controls/kills lots of androgen-sensitive cells. As the remaining cells upregulate/mutate ARs the ADT environment doesn't work as well but still works to some degree. As the cells continue upregulating/mutating ARs the ADT environment doesn't work at all. So we can continue decreasing T and it will continue to work. Until we aren't able to further decrease T and then...
But, imagine, if you will, an environment with absolute zero T (say that with a Rod Serling voice). We don't have the tech to create such an environment in the human body. And I do not know what would happen if we had zero T. Absolute zero mind you. Not just undetectable (which does not mean zero but for practical purposes we sometimes call zero).
In this environment, it does not matter how many ARs a cancer cell has. Actually, the increased ARs are just a burden on the cancer cell. Even if they capture 100% of nothing it is still nothing.
You are correct. Technically there aren't many analog processes in the universe outside of maybe quantum mechanics. Even the path of a photon with sextillion different options for a directional change is obviously discrete.
This one is even more discrete. If you have a billion ARs, and if one is added you now have 1 billion and 1. I think that this is what you are getting at. A discrete change, even if it changes the total by millionths or trillionths of a percent, is discrete. But the general definition doesn't encompass this. I guess that is a question for the philosophers (I enjoyed philosophy in school but I didn't see a future in it).
I'm actually guessing that there are not more than a dozen or fewer of such mutations. Though if you factor that out, it probably comes close to being analog.
Oh. You meant the number of types of mutations. I thought you meant the number of mutated ARs. Most of us probably have a few trillion ARs in cancerous cells.
The following papers are related to post RP BCR slowing-down.
Not related to your personal case, I know, but none the less may prove useful to making a case.
1)2009 - European countries (9):"Can dutasteride delay or prevent the progression of prostate cancer in patients with biochemical failure after radical therapy? Rationale and design of the Avodart after Radical Therapy for Prostate Cancer Study",
also: "Dutasteride Treatment Over 2 Years Delays Prostate-specific Antigen Progression in Patients with Biochemical Failure After Radical Therapy for Prostate Cancer: Results from the Randomised, Placebo-controlled Avodart After Radical Therapy for Prostate Cancer Study (ARTS)".
2) 2010 - USA: "Effect of Dutasteride on the Risk of Prostate Cancer".
3) 2017 - Korea: "Early dutasteride monotherapy in men with detectable serum prostate-specific antigen levels following radical prostatectomy: A prospective trial".
4) 2019 - Taiwan: "Early Dutasteride Monotherapy in Patients With Elevated Serum Prostate-Specific Antigen Levels Following Robot-Assisted Radical Prostatectomy".
Use Google to get the links.
On further inspection, the average participant age for the guys in TA's posted "inconclusive" study is 71 and the average Gleason is 6.7. Doesn't fit me. I'm over a decade younger and more than 2 levels higher. Art, you are in a different category also.
With many of these things, I have found in my medical career that the way to pursue them is not to be emotionally attached to a given tool, but rather to unemotionally research, discuss, and then test. I have already discussed this with my MO and have plans to do the third step when I get into my next ADT phase. We don't think that it is beneficial for me, at this time, to use 5ARIs during the high T phase of BAT.
I was a medical engineer. Bread and butter. But the gravy was from a hedge fund. Yup, get out and try again. Lots of losers but every once in a while there was the home run. Fun times!
Actually many things. Research, design, testing, data analysis, FDA presentations. Some of them work closely with Doctors (I did not interface very often with Doctors). Some of them work on drug development. My particular company was mostly involved in implantable medical devices and was the largest implantable medical device company in the world. Diabetes, neuro devices, cardiac monitors, defibs, pacemakers, etc etc. They even worked on space programs, glucometers, heads-up displays for fighter pilots, and hearing aids in the 90s. For about 5 years I worked on various defense-related military devices. That's how I got in at the company. I worked on some (at the time 30+ years ago) state-of-the-art, military programs for the government.
The company I worked for has a giant engineering campus in another state. It's larger than most universities. Really cool research facility. Kind of like a huge library with labs, billions of dollars of scientific equipment, daycares, gyms, and restaurants. Alas, I worked in a much smaller facility. No daycare but we did have a restaurant and a nicely outfitted gym!
I was a quality screen design engineer for a Fortune 500 medical company. But they were not involved in cancer research. It did set me up with some understanding of quality, testing, verification, and the FDA.
Just wondered obviously. This post and the replies /debate among a small number of HU members leave some others, like yours truly, dazed and confused with the biological terms.....especially when a discussion enters into the speculation about mechanisms. I'm simplistic......given proposed treatment x, are there studies that with a high level of confidence show y efficacy with acceptable z side effects. If I'm going to consider some treatment for which the benefit is actually not well established, then there should at least be good confidence that side effects do not result in significant harm.
With those as treatment guidelines, what can we say about Avodart...whatever that substance specifically does biologically?
maley2711 wrote --- " ...If I'm going to consider some treatment for which the benefit is actually not well established, then there should at least be good confidence that side effects do not result in significant harm... "
Or you could do as I did and *take a leap of faith* and go where no man had gone before with an unproven, untested, non FDA Approved treatment that could result in my demise earlier than the various SOC Protocols postulate.
GL10 right half so immediate castration, Dr. prescribes Avodart (dutasteride + 1,700mg Metformin), hemi-cryoablation of right side then the still not currently FDA Approved 3drug combo immuno injection and completely counterintuitive began bi-weekly Testosterone injections.
7 YEAR ANIVERSARY of diagnosis last month and had a PSMA Pet PYLARIFY Scan this past Tuesday with nothing showing.
As you know, I am also outside the SOC box and I have trashed the SOC predictions of 3 months max before being in a hospital by over 3 years and counting. My current MO thinks I have decades and don't need to do chemo, RT, ADT, or scans ("there is nothing to find").
SOC is great to get SOC results and for many scenarios, the average SOC result is more than good enough. But I do not have the average scenario. So I take SOC and modify it. Even if I wind up in the hospital tomorrow, I've gone 13 times the average.
Congrats on that of course! with your results, are there any current trials using that protocol ? Did you have any detected metastases when you began your treatment?
Dr. has advanced the protocol and is treating men around the World with Mets, unlike me. My trial is to prevent advancement since I also receive Testosterone injections even though a GL 10, so only time will tell
I again hate to preach but the reality is we are all very sick guys with a very limited future and there is point in hiding this fact from anyone, including yourself. In my view it helps to deal with this up front, then plan, make your bucket list and live large, as long as you can. Spending too much time on bits and pieces does little to enhance one's life as it will NOT change things very much, no matter what treatment you end up taking, or not. Your best days are those right in front of you, not some dream that all will be good, when that is not the case for the vast majority of us. I am now in year 19 so think I have some basis to make these statements. My pals who spent the remaining days jumping from doc to doc, etc.lost that valuable time of perhaps living and getting the most out of life that remained to them. If you have money, spend it on doing things that make you and your family happy, DO IT TODAY, do not wait or linger.
Lastly, do not blame docs, none of them have the magic cure because there is NONE, some are certainly better than others, have better resources etc. as well, but please respect the sad fact that any medical practitioner in this field, has a very very tough time in watching all of their patients die before their eyes-try that for an extended period. So, hug them, thank them and take it upon yourself to get up to speed, make the call on your treatment and again, get out of the house and rock on!!!!!
If you are seeing Dr. S, let me know if you can get an Avodart script from him. The last time I tried, and I thought I made a compelling argument, his prompt reply was, “Although DHT is more potent androgen to be sure, lowering DHT levels will not slow progression. Studies have been done that have been negative, including one that we did many years ago. It may lower PSA nominally, but will not impact your longer term clinical outcome. ”
Which Dr. S? The Dr. S I see prescribed finasteride and dutasteride after I explained what I wanted to do and showed him some clinical trials and research. He understood the T->DHT conversion so it wasn't hard to convince him (as I recall pretty much zero convincing was required). My MO will also write the scripts for these. She thinks that 5ARIs are beneficial for me (we combined them with bicalutamide). As TA pointed out, there is at least one study showing that they may or may be efficacious as monotherapy for older men with less advanced cancer. I have never asked her what her opinion is about the use of 5ARIs for other people.
A doctor who understands basic physiology of conversion of T to DHT...will not hesitate to add Finasteride or Dutasteride. This physiological principle is enough evidence to use 5 ARI drugs and that is why I use them.
I did not move to Dr. S. As he did not offer anything different then current MO, but after talking with him for an hour, my impression is that he is a very bright guy .
No study here but a little horror flick. My urologist had me on Avadart for years, problem was it hid the real PSA. By the time my PSA started rising I already had stage 4 cancer. Just saying 😡😡😡😡
Larry...you need to thank your Doctor for not putting you on Lupron ..15 years ago. If he did by this time, you probably would have developed NeuroEndocrine variant and may not be writing . Never forget that Continuous ADT for a long time converts regular Prostate Cancer to a very aggressive type called NeuroEndocrine Variant...In 20 % of men.
Were your DREs normal? Mine didn't show anything. My doctor was fond of saying "your prostate is as smooth as a baby's butt". My PSA was rising but didn't indicate anything close to the T3b/c Gleason 9 PCa that I had. I had an MRI-guided biopsy and the grading doctor graded it a Gleason 3+4, localized, no big deal. After surgery, Johns Hopkins reviewed the biopsy sample and graded it a Gleason 4+5.
I look at my situation and history in two ways:
1. I am in the state I am today. No use crying over spilled milk.
2. If the tech hadn't changed for 100 years I'd likely be dead today. But here I am with a chance to fight.
No had a hard spot on it for 30 plus years. As my doctor says. No one wants cancer but there has never been a better time to have it with all the new stuff coming Dailey.
4. External validation of Memorial Sloan Kettering Cancer Center nomogram and prediction of optimal candidate for lymph node dissection in clinically localized prostate cancer – PMC ncbi.nlm.nih.gov/labs/pmc/a...
Just a quick note here. Measure your DHT levels with a blood test. I was on Dutasterid for and year and measured my DHT levels before starting and every 3 months. My levels did NOT go down but actually increased a bit by the end of the year so I stopped taking it. So Dutasteride did not work for me.Bill
Did you also measure your testosterone, SHBG, and/or estradiol? By any chance did your hormonal therapies change during that timeframe (for example, perhaps a change to cyp17 inhibitor use)?
My DHT tanked when I used 5ARIs. I started using them somewhere between points 2 and 3 on this chart. The chart covers a year and a half.
It's not great data though. I was using a high testosterone therapy but discontinued it around point 7. So the last two very low data points could probably be ignored.
My testosterone levels did not change. I was not on any other treatments other than Metformin. My PSA was slowly rising after surgery but was still under 0.1. I tried Dutasteride on Snuffy Myers advice.
2. Dutasteride treatment over 2 years delays prostate-specific antigen progression in patients with biochemical failure after radical therapy for prostate cancer: results from the randomised, placebo-controlled Avodart After Radical Therapy for Prostate Cancer Study (ARTS) - PubMed
5. Assessment Of Dutasteride (AVODART) In Extending the Time to Progression of Low-Risk, Localized Prostate Cancer In Men - Study Results - ClinicalTrials.gov
6. Early dutasteride monotherapy in men with detectable serum prostate-specific antigen levels following radical prostatectomy: A prospective trial - PMC
9. "REDUCE" - A Clinical Research Study To Reduce The Incidence Of Prostate Cancer In Men Who Are At Increased Risk - Study Results - ClinicalTrials.gov
11. Possible PSA masking: Association of Treatment With 5α-Reductase Inhibitors with Time to Diagnosis and Mortality in Prostate Cancer | Oncology | JAMA Internal Medicine | JAMA Network
12. Study was underpowered but has a neutral conclusion: Effect of dutasteride in men receiving intermittent androgen ablation therapy: The AVIAS trial - PMC
13. A metanalysis that had neutral conclusions: Prostate cancer specific mortality after 5α-reductase inhibitors medication in benign prostatic hyperplasia patients: systematic review and meta-analysis - PubMed
This is one of the more fascinating threads I've just discovered here. Correct me if I'm wrong but it seems the "common sense" take on all this to me seems to be:
1) 5α-Reductase Inhibitors are not as effective as ADT in slowing/stopping cancer progression at least mid-term (as we know ADT isn't a long-term solution since PCa becomes castration resistant.)
2) There is evidence 5α-Reductase Inhibitors may allow patients to delay initiation of ADT when used in the early stages where PSA has rised above undetectable levels (> 0.04, probably confirmed by two consecutive rises?) This would be in the absence of concurrent salvage radiotherapy treatment (as I believe ADT has been shown to increase the effectiveness of radiation?)
The question to me becomes, in the long-run would initially using a 5α-Reductase Inhibitors instead of ADT early on (to delay that negative hit to QOL due to ADT side effects) really make any difference as far as time to Prostate Cancer Specific Mortality? My hunch would be no significant difference.
I'm thinking a cutting edge strategy to delay ADT and CRPC as long as possible might be, upon exceeding undetectable threshold (two PSA readings > 0.04), initiate Dutasteride. Upon biochemical failure (two readings above 0.2) initiate salvage radiation (for RP patients) with simultaneous short-course ADT (6 months). It sounds like from studies, ADT beyond 6 months has permanent lasting negative effects on sexual health. Obviously many have understandably chosen to prioritize potential for longer survival over sexual health but it remains a bit foggy to me how much long-term ADT REALLY makes a difference in the long-term when also factoring in negative Quality of Life impact or versus intermittent short-course ADT. Not sure about timing of Cabergoline in all this to keep Prolactin low?
From what I have gathered both from studies and many anecdotal reports in several forums, the typical SOC of long-term ADT is common due to its proven effectiveness but it's only a mid-term solution. So it leaves one wondering if CRPC can be delayed in the long-term by thinking outside of the box of SOC Long-Term ADT, or at least a better balance can be achieved between slowing/delaying progression and maintaining a higher quality of life through more novel approaches that involve less long-term use of ADT.
Of course now I'm reading Dutasteide may have sexual side effects. Seems like there's pretty much no way around sexual health issues no matter what treatment path you take after recurrence be it Dutasteride, Salvage Radiation, ADT or combination? Or is the sexual side effect potential the least of the three for Dutasteride?
The problem as I see it is, all the studies with results on 5α-Reductase Inhibitors have an average follow-up time of about 3 years (including Dr. Snuffy's which was only 2 years), unless I overlooked a long-term study. That doesn't tell someone if the slowing/reversal of PSA kinetics by Avodart to delay initiating (or taking a vacation from) ADT versus following the current SOC involving ADT is going to make a big difference as to where you will ultimately end up in 10 or 15+ years.
I found a recent post by PBnative with interesting anecdotal evidence by examining his post and his profile info. He started Advodart 13 years ago in 2009 with PSA 8 (Gleason 6 and appears to have foregone any radical primary treatment at that time) which cut his PSA initially from 8 to 4 and "kept it down for 10 years." At 10 years, June 2019, his PSA jumped from 12 to 24 in a month after stopping Advodart. So obviously as he neared the end of 10 years on Advodart his PSA had climbed over the original 8 to 12 so he stopped it as it wasn't keeping his PSA down anymore. (Look, we have our first long-term study with a cohort of n=1 !! LOL) Fast forward 2 years to August 2021 and his PSA is 61 - BUT, with a clean PSMA PET scan mind you! He started ADT October 2021. As of 5/22 his PSA was 0.2.
Obviously it is basically impossible to predict the difference in ultimate outcome as far as Prostate Cancer Specific Mortality in his case (or any case due to lack of long term studies involving Avodart.) But what are people's gut feelings, disregarding the delay until radiation, as far as of right now, assuming all other factors being equal, is he likely worse off, better off, or no different than if he had started ADT much longer ago more in line with the SOC? That's the Million Dollar question for me. If he's better off or about the same, then he sure enjoyed quite a few more years void of ADT side effects along the way to end up 13 years later at a place no worse than had he taken combinations of other systemic drugs with worse side effects most of those years!
With lack of longer term studies, I'd like to find more anecdotal evidence from patients with similar long-term use of Avodart (10+ years) without ADT that had a more typical initial primary treatment path (RP or RT). These differences in these studies so far when they use the word "significant" (difference) or "significantly" (affected) I sort of roll my eyes wondering really how "significant" does it end up being in the end-game of delaying PSCM over a 10, 15 or 20 year period when the study follow up was only typically 2-7 years?
For sort of my case in point this is a graph from one of my favorite studies that was at least 10 years follow up by Amar Kishan at UCLA released in 2021. Note that "Optimal" RT/BT groups were defined as also having long-term ADT. Look at the difference in the graphs for 10 year PCSM rates between the groups using long term ADT and not using long-term ADT. Not that big. This begs the bigger question, are the side effects from long-term ADT really worth it in the long run? (Probably a highly personal decision?)
Jaz, you got my story right except for the reason I stopped Avodart with PSA 12 . In hindsight I may have been deluded because I wasn’t worried by the rise in PSA . I stopped Avodart because my uro said I should stop occasionally because the cancer could adapt and make an end run around it ( kind of like CRPC .) I guess I was afraid to take a break earlier .To be honest I was over confident that I was “ out of the woods “ ten years from diagnosis and biopsy . My theory is that a month long dose of DHT woke up the sleeping beast.
Avodart cut PSA from 8 to 4 initially in 2009 . . It rose to 12 on Avodart in ten years . Where would it be now 3 years later if I hadn’t taken that break from Avodart ?
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ADT + Abi + Docetaxel for metastatic prostate cancer?
After Xtandi, 177Lu-PSMA-617 or BAT?
