“our aim is to make you die of someth... - Advanced Prostate...
“our aim is to make you die of something else”
"In the simulations, the typical administration of the drug led to drug-resistant cancer cells rapidly running rampant. The treatment would ultimately fail each time. That bleak outcome matched up with the results seen in hospital records. In contrast, the computer simulations suggested that if Zytiga were administered only when the tumor seemed to be growing, then the drug-resistant cells would take much longer to gain enough advantage to overrun the cancer.
In 2014 the Moffitt team managed to get the first small study to test this adaptive therapy approach off the ground, recruiting Robert Butler and a small group of other men with advanced prostate cancer. Butler’s oncologist explained to him how it would work. He would remain on the Lupron he’d taken for years, and each month he would go to the hospital to get his PSA level tested, to judge whether his prostate tumor was growing. Every three months, he would get a CT scan and a full-body bone scan to watch for disease spread. Whenever his PSA level edged above where it stood when he entered the trial, he would start taking the more powerful Zytiga. But when his PSA level fell to under half of the baseline, he could go without Zytiga. This is appealing because Zytiga and drugs like it can cause side effects like hot flashes, muscle pain, and hypertension.
The Moffitt approach also promised to be far cheaper than taking Zytiga continuously. When purchased wholesale, a one-month supply costs almost $11,000. Butler had health insurance, but even so, his first month’s supply each year would set him back $2,700 in out-of-pocket copayments, and $400 a month thereafter. Going off the drug whenever his PSA level was low would translate to huge cost savings."
It’s a shame that Dr Huggins found a way to slow down prostate cancer with hormone therapy in 1940 and almost 80 years later we still don’t have a cure. I’m happy about Zytiga and Lu177 but these treatments only came out recently. In 80 years one would hope/think for a lot more lines of defense in order to prolong the disease
We need a longer runway !!!!
Rather than on and off strategy, what about high to low strategy? Initial max attack, followed by maintenance/ containment ,once initial target achieved-say undetectable. Iterate to lowest dose for containment.
What the simulations show is that if you first knock down the cancer cells that depend on exogenous testosterone, plus the ones that make their own, many of the remaining cells are just not responsive to Zytiga.
But they are the ones growing the fastest at that point, because the Zytiga has killed or stunned most of the rest. Without competition, the non-responsive cells grow quickly.
So now, rather than just drop the dose, which would keep the selective pressure on the Zytiga-sensitive cells and do nothing for the cells that don't respond, switch to a conventional chemo agent that kills the fastest growing cells.
Like docetaxel, a tubulin inhibitor. Or fenben, another tubulin inhibitor.
Their simulations predict a 4-fold increase in the duration where this cycling approach will remain effective.
This strategy is discussed in the Moffitt group's May 2019 paper:
Multidrug cancer therapy in metastatic castrate-resistant prostate cancer: An evolution-based strategy.
You can download the full paper at
sci-hub.tw/10.1158/1078-043...
Thanks for the reference to the Moffitt Cancer Centre study. It continues a Game Theory reference in an earlier post by Metungboy. I was unaware that the Moffitt Cancer Centre has a clinical trial underway (NCT02415621) due to be completed by 20 December 2020. This will never cure anything but impresses me as promising pathway to extend control. Unfortunately the statistical modelling is way beyond my maths.
Moffitt has 67 trials related to prostate cancer in clinicaltrials.gov.
Two of them relevant to this discussion are
Adaptive Abiraterone Therapy for Metastatic Castration Resistant Prostate Cancer NCT02415621
and
Intermittent Androgen Deprivation Therapy for Stage IV Castration Sensitive Prostate Cancer NCT03511196
In the trial for hormone sensitive PCa, they will start with 4 weeks of GnRH therapy (Lupron or similar) then add abiraterone (Zytiga) for 8 weeks. 14 men who experience PSA drops of over 75% will be enrolled, where they stop treatment and wait for PSA to double from the baseline, then restart treatment.
Thanks. I'm 12 months in and I see myself as being in the cancer breeding business. So research that might help me select the types of cancer I have is of great interest. I'm not sure the timeframe for the research is going to match the timeframe of my PCa progression though. Time will tell.
The link doesn’t seem to work
Are you talking about the link to the Multidrug cancer therapy... paper?
I just checked and that link works fine for me.
sci-hub.tw/10.1158/1078-043...
Anyone else having trouble with that link?
Did not work for me.
that works -- I read the evolutionary approach, interesting, but mine is a bit different, design by Dr Myers
My understanding of the Myers protocol is that he hits the cancer with multiple agents that have different paths of action. It's another way to try to kill the cells that are resistant to one agent.
Thank you for the link, it is very interesting. I am assuming that the researchers have done genetic testing on their patients and it would be very interesting to see which mutations appear to respond to this, and which do not. It seems to work great for some, and not so well for others, but the nonresponders might be fewer in number than in continuous therapy. So the median time to progression is too imprecise a measure of how well it works with just 11 subjects.
There is actually something buried in the article about fast mutating cancers vs slower mutating cancers. And how they believe this works better with one than the other.
But this approach is essentially independent of what the initial mutation is. I believe is assumes a constant state of ever mutating cancer.
Yes I think I saw that. My husband had a genetic test of his 5 year old surgery sample before his PSMA-pet scan recently and so I have been trying to find everything relevant to his particular mutations. I have not found that many definitive articles, just a few which identified certain clusters of mutated genes usually in castration resistant samples. None of these were able to measure mutation rate because they mostly did not have samples from different time points for the same patient.
I don’t won’t pretend to know if “microsatellite instability” is someone relevant to this discussion but it does get into genetic/DNA stuff and prostate cancer. So I’ll post it here for the more PCa literate to tell us in layman’s terms just what the relevancy might be. Looks to be immunotherapy related.
They don't do genetic testing, at least not in the initial models and small clinical trial.
What matters is the relative populations of the different kinds of cancer cells. In a man with many cells responsive to Zytiga and relatively few non-responding cells, a target reduction of 50% or 75% in PSA might produce the longest lifetime before treatment failure. In a man who already has many non-responding cells, they found that setting the target to just a 20% reduction would give the best results. The second man probably had been on continuous ADT for longer, and was closer to complete treatment failure. Or perhaps there was some genetics involved, but that doesn't directly matter. What matters for treatment decisions is knowing the relative populations of each cancer cell type.
The problem is that there is no practical way to measure the populations of each kind of cell. CTC tests don't necessarily reflect what is going on inside the tumor, only what escapes into the blood. If a good test was available, they could rapidly fine-tune the dosing schedule and targets for each individual patient.
youtube.com/watch?v=HwELajF...
odds or even?
Good Luck, Good Health and Good Humor.
j-o-h-n Tuesday 07/02/2019 6:05 PM DST
Unfortunately, the odds seem way too even. I happen to think that the environmental toxins that have been developed (especially plastics) that are ingested, breathed, absorbed through our skin, etc. may have a strong link to many of the hormone based diseases, including PCA. We only learn from mounds of reports and have to prove something is unsafe, rather than safe to begin with.
The truth is that big money talks and the rest of us can suffer the consequences.
youtube.com/watch?v=PSxihhB...
Good Luck, Good Health and Good Humor.
j-o-h-n Wednesday 07/03/2019 5:49 PM DST
Although I can't get access to the paper referred to I must say how grateful I am to be able to access many other scientific articles through the sites shared with us: booksc and sci-hub. Thanks.
Re outliving the clones, I intuitively believe this approach, being an immunologist and microbiologist. And whilst there is so much less known about mutation events and how they relate to tumour therapy, as compared to the rationale of antibiotic or anthelmintic treatment I think the same principles apply.
So in the absence of this molecular knowledge what do you do? I think just mix and match treatments in the most logical way; not an easy plan. For me, given an aggressive, low PSA, tumour T3bM0N0 in 2010, it has been Rad Prostatectomy, adjuvant EBRT, ADT (combined and later only GNRH agonist) for 6y, with CRPC came Lu177 (x4) a couple of years ago. All treatments have been effective in the short term but 1 bone met and with PSA rising what now? Probably docetaxel or even more radiotherapy before or after, depending on PSMA avidity.
Yes, keeping your nose in front is a challenge. Rob.
Where were u treated with Lu177?
What is your current psa?
Lu177 treatment in Australia at Genesiscare Theranostics for oligometastatic PC- that were all soft tissue. My PSA is 13 (PSADT of 1.8 months) but I don't regard the absolute value as important. PSA was 4.7ng/ml at diagnosis in 2010 (Gleeson Score 5+4=9). I have attempted to change treatments whenever It has been over 1ng/ml following my primary treatment (RP). Cheers and all the best. Rob.
I'm just beginning this journey. At dx, (Gleason 8-PIRAD5- 2 mets) my PSA was only 2.4. Also, Testosterone only 350 - I'm 79. (I'm wondering if I already have a castration - resistant cancer at diagnoses)
These Adaptive Therapy use as a biomarker PSA doubled or halved.
Without PSA, what biomarker would give these benchmarks?
Maybe something as simple as an ultrasound?
I think, like me, your PSA was unimportant re diagnosis. Assuming it is an adenocarcinoma you are one of the 5% with high(er) grade PC with low PSA at Dx. I don't think your Test levels are low (borderline) so given the lack of other knowledge castration resistant PC can only be diagnosed by trial and error (suck it and see), if your MO or advisor recommends ADT.
I would definitely use imaging of some sort to look at distribution of lesions (PSMA PET preferably).
Cheers, Rob.
Fritz1, I just finished the Wired article. Great article! It helped me understand It helped me better understand some of what I see in posts.
Their approach is to stop treatment after the PSA drops a given amount, with the target value based on their models. In each cycle, first they knock the cancer down with Zytiga, perhaps adding another drug like docetaxel. Then they stop all drugs and wait. Resume drug treatment only when the PSA climbs back to the baseline level or some similar mark.
If the cancer is dormant, the man gets to wait a long time. In the study they did with men far along with mCRPC, they had cycle times from 4 months to over 1 year.
Different objectives but related techniques. From Stanford University.
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