Different sensitivity to ADT depending on Gleason

[TheTopBanana]

Hello!

My father send this to me as an argument for him (Gleason 9) to start early Chemo. pubmed.ncbi.nlm.nih.gov/305...

Any thoughts on the article?

[Tall_Allen]

I hope you understand that this has nothing to do with your father's situation - he is metastatic and recurrent. That article is about men with localized PC being treated with prostate radiation and adjuvant ADT. It only means that the presence of pattern 5 confers more radioresistance.

[TheTopBanana in reply to Tall_Allen]

Aha!! What is radioresistance?

[Tall_Allen in reply to TheTopBanana]

It means the extent to which the cancer resists being killed by radiation.

[TheTopBanana in reply to Tall_Allen]

If the 5 is less radiosensitive, does that not mean that ADT works less well?

[Tall_Allen in reply to TheTopBanana]

It means that higher doses of radiation to the prostate and more hormone therapy and possibly even chemotherapy may be necessary to have the same effect. Again, this applies only to the prostate, and not to metastases (which do not have Gleason scores, of course). When metastases are zapped, much higher biologically effective doses are used because toxicity to surrounding organs is not an issue.

[TheTopBanana in reply to Tall_Allen]

I’m a little confused with the mets not being Gleason. I thought the mets of a Gleason 8 was different than the mets of a Gleason 9?

[timotur in reply to TheTopBanana]

I believe the Gleason score only refers to original staging of PC cells in the prostate, not local or distant PC cells in the mets, and Gleason is an indicator of aggressiveness, and subsequently potential to metastasize to LN's or bone.

[Tall_Allen in reply to TheTopBanana]

No. Gleason score is just what the architecture of cells within the prostate looks like. Once cells have gained the ability to live and travel outside of the prostate, there is no Gleason pattern.

[TheTopBanana in reply to Tall_Allen]

So the mets could be more or less aggressive, not depending on the original gleason?

[Tall_Allen in reply to TheTopBanana]

It depends only on their phenotype and genomics.

[TheTopBanana in reply to Tall_Allen]

And phenotype and genomics is something completely different from gleason? (Sorry for understanding slowly)

[Tall_Allen in reply to TheTopBanana]

Yes, they are different. To repeat, Gleason score is a metric about the architecture of cells in the prostate. That architecture is no longer visible in metastases. Pattern 5 has greater risk of metastasizing than pattern 3, but after metastases have occurred, the Gleason score in the prostate no longer matters .

[Dett in reply to Tall_Allen]

Does this mean that once the cancer has metasticized, then the aggressiveness of the cancer in the prostate (Gleason score) has no bearing on overall survival, all else being equal (in other words, men with pattern 3 have the same odds as met with pattern 5 once there are mets)? Or are pattern 5 people still at higher risk for additional mets or quicker met recurrence? Or worse ‘phenotype and genomics’ (although I don’t really know what that means)?

[Tall_Allen in reply to Dett]

You are confusing different things. Gleason score, PSA, and T stage (as well as prostate cell phenotype and genotype) are prognostic for recurrence and metastases . But the Gleason score has no prognostic value after metastases are discovered. The phenotype (the kind of cells, e.g., undifferentiated, low AR, stemness) and genotype (e.g..mutations in BRCA, p53, or PTEN loss) determine the aggressiveness of the metastases.

[TheTopBanana in reply to Tall_Allen]

How much of these is it possible to test for? We have only tested for BRCA (negative).

[Tall_Allen in reply to TheTopBanana]

There is no point in testing for things for which there are no specific therapies.

[Patrick-Turner in reply to Tall_Allen]

What you've said about Gleason score is about right. But the higher the Gleason score is at diagnosis, the worse is the time for overall survival and it seems a Gleason score of 9 indicates high chance of spread that has occurred before diagnosis. It seems also independent of Psa.

In y case, diagnosis in 2009 was Gleason 9, T3, and 9/9 biopsy samples were positive, and Psa was only 8. This led me to believe there was a high chance I would not live another 2 years, because some other blokes with similar diagnosis had Pca which did not slow down with ADT. Mine did, and I had minimum nadir Psa of 0.08 after 70 Grey of initial EBRT to PG. Mets did not show up in any CT scan but did in first PsMa Ga68 scan I had in 2016, so I had what was considered a very bad dose of inoperable Pca in my PG, and which had spread, but QOL didn't change a bit, although with low Testosterone from ADT my average cycling speed went lower, so I cycled longer each week and am still doing 200km + now at 73yo.

The PsMa Ga68 scans showed that the initial EBRT in 2010 and a following 31Grey of salvation IMRT to PG didn't do much to reduce Pca in PG, so my Pca I seemed to be resistant to a high level of Xrays, 101Grey inn total. Sometimes 160Grey is needed to kill Pca cells in PG but unless that's delivered by Brachy Therapy or with some EBRT as well, Pca cells at PG just won't die in some men. And damage to healthy parts of PG such as nerves and prostatic urethra is likely.

The reason why chemo is not given early after diagnosis for many men is that it lowers QOL so much, and chemo is thus best delayed until ADT fails to work as it often does within an average of about 4 years.

Men differ in their Pca response to ADT, and EBRT, and some have their Pca completely eliminated by ADT+EBRT, but it seems many of these men have low Gleason scores, but had a high enough Psa to get a doctor to fully examine a patient and do a biopsy, which was once the gold standard for Pca diagnosis. Well, I had quite a low Psa of only 6 at biopsy, but had Gleason 9, and during attempt at open RP the doc could not remove my PG -too much cancer out and around PG to be able to remove PG.

I had no other option than that offered by the hospital, an initial 2 years of ADT + 70Grey EBRT at 8 months after start of ADT when PG would have shrunk from its swollen size to be an small target of the EBRT, thus less damage to bowels would occur because width of beam size can be reduced. I met me where what I had initially worked very well, and these men told me I had nothing to worry about. They had my treatment 10 years before, and Psa was < 0.01. No more ADT was needed.

But my Pca was deemed to be "aggressive, young man's type of cells", and sure enough that seemed to be true. Cosadex then Zytiga +ADT + salvation RT didn't eliminate my Pca; it kept growing. Chemo failed, But Lu177 became available and it was only 300km away in Sydney from where I live in Canberra, and doc running the clinic said in late 2018 he'd treated 700 cases of Pca since he started business in 2015 and had 70% get a benefit, defined as having a mean 14 months of added time to life, which means some got no benefit and some got near remissions. I figured I might do OK because I had a low Psa to begin with and the biggest bone met was size of a pea.

But if mets have spread to organs and bone mets are size of golf ball and Psa is 500, then I would say Lu177 may not bring back a lasting QOL.

So the trend has been to have Lu177 sooner rather than later, when Psa is low, and mets are not big, and Melbourne PeterMac cancer hospital offer a "Lutectomy" aka initial form of targeted nuclide radiation which allows surgery or additional EBRT later and ADT if or when Pca keeps on growing. Lu177 is often 4 doses, but 2 doses is sometimes enough to kill soft tissue mets and begin to work on bone mets.

My PsMa scans have so far shown my countless mets in lymph nodes have vanished but I have some stubborn bone mets after 4 shots finishing in May 2019.

I am having more Lu177 now, and initial response is going well. I really don't want more chemo which has The Worst side effects. I may get PARP inhibitor if DNA analysis now underway indicates it might work if I am Brca1+2 positive. I lost a sister to Oa, and another surviving sister got Brca, Dad died of melanoma, and his mum died of UTca. So lots of cancer in my family tree. My mum died at 98 from old age, and never got cancer, so I may have inherited some protection not none. All mum's many friends died before she did, except a few whom she met when she was maybe 30 years older than they were. I'm still cycling 200km a week.

Patrick Turner.

[Tall_Allen in reply to Patrick-Turner]

What you say is only true until mets have been detected - Gleason score, PSA, and Tstage determines the odds of metastases being detected. The point I was making is that Gleason score is no longer prognostic after metastases have been detected. A man who originally had a GS 4+3 and now has visceral metastases has a worse prognosis than a man who originally had GS 5+4 and has only pelvic lymph node metastases.

[Patrick-Turner in reply to Tall_Allen]

Well, I am not able to gain anything by proving you right or wrong about how Gleason scores are interpreted by medicos or the patients. I do know I had a Gleason 9 T3 at diagnosis, and during failed attempt to remove my PG the uro removed some lymph nodes, seminal vesicles and some other tissue samples to have them looked at by a man with microscope to search for Pca cells. None were found. CT scans showed no mets. But I bet I had mets that were there, but so small they could not be seen.

A Gleason 9 meant I was much more likely to die from Pca than if I had a Gleason 4.

Gleason 9 meant much more Pca was found than in is the case with Gleason 4.

And from the moment the first Pca cell forms in a PG, then it would seem possible to give the Pca status a Gleason score. I had a low Psa, so I missed out being diagnosed early enough to get a successful RP, and avoid the spread that had probably begun before I was diagnosed. My first 2 mets were not seen until 2016 when I had my first PsMa Ga68 PET/CT scan in 2016 when ADT failed, some 6.5 years after diagnosis. When found, the 2 mets were thought to be 2mm dia, and were two small blue spots on scan, and doc said these would not have appeared in any CT scan for another couple of years, ie, maybe not until 2018. How long had the mets been there? I can guess a long time, and that they remained suppressed by ADT like the main tumor in PG, which showed up as big bright blue blob on scan in 2016.

St Vincent's Hospital in Sydney had a website page with forecasts about longevity and Gleason scores, and effectiveness of EBRT + ADT as initial treatment, and the web page said that men having Gleason score of over 8 had a 10% probability of surviving more than 5 years. Unfortunately, that web page has been removed, maybe due to someone somewhere thinking such info was "unhelpful" if read by patients smart enough to find that page. Those with Gleason 5 or less had far higher probability of living longer than 5 years.

Basically, the earlier a man gets his PG removed, the more likely he might live to 90 without any PG trouble, but PG removal by surgery isn't always successful because surgeon skills are involved, and some PG tissue can be left behind after surgery, and if that small amount of PG tissue has no Pca at time of operation, it may develop Pca maybe years later, and then the man has the Long Fight like I have.

So whether a man has Pca mets or not is a bit of a difficult thing to establish. If mets are there, and cannot be seen by anyone at diagnosis, and the man has RP but no ADT, then man may think he's lucky, but then Psa rises. Oops! Pca has appeared, so how did that happen? Well, happen it does.

I am sure my Pca was fairly resistant to to X-ray EBRT, and to the added salvation IMRT. Doc giving me salvation IMRT said "this will definitely kill all Pca remaining in your PG" But following PsMa scans showed he spoke BS because my PG showed up positive even after having chemo and a PsMa scan before having Lu177 infusions. So doctor's idea of the word "definitely" was not defining anything. I gave my un-informed consent to the salvation IMRT, it seemed better than doing nothing at the the time. I was first patient in Australia to have such salvation IMRT where EBRT had been primary treatment.

The salvation IMRT involved injection of radio beacons to guide Calypso beam X-ray beam machine. So minor cuts were made by applicator needle into and that caused high amount of bleeding that should not have happened, but it did, and maybe that caused further spread of my Pca but of course I'd never be able to prove it.

The doctor who originally opened me in 2010 to remove PG knew that cutting my PG with Pca spread outside PG capsule was likely to spread my Pca. I think he was correct.

I should have had PG removed in 2004, when Psa was about 3, and before I got Pca, or when amount of Pca was still very low, and unlikely to have spread anywhere.

My older sister found a lump that turned out to be Brca. She didn't muck around just taking out that lump. She had both breasts removed, and she's alive and well 11 years later.

Time I went for a bike ride.

Patrick Turner.

[Dett in reply to Tall_Allen]

Thanks, Allen. If you can stand to revisit this topic, can you address Patrick Turner’s observation elsewhere in this thread...

“St Vincent's Hospital in Sydney had a website page with forecasts about longevity and Gleason scores, and effectiveness of EBRT + ADT as initial treatment, and the web page said that men having Gleason score of over 8 had a 10% probability of surviving more than 5 years.”

Without more information, it’s impossible to determine how they came to this conclusion, but if there is any truth in it then that is extremely discouraging.

[Tall_Allen in reply to Dett]

One can make a nomogram with any data. They could have made the same prediction based on PSA or Tstage. That doesn't make it logical or useful. Certainly, high GS, high PSA, and high T stage all contribute to risk of metastases. And metastases predict survival. But once there are metastases, the original GS, PSA and Tscore no longer matter. Get it?

I'm sure the nomogram he was looking at was only for men who had localized PC, and not for men who were M1

[Dett in reply to Tall_Allen]

Got it in your earlier reply. It can just be very hard to know what to do with claims like this - especially when it’s life and death for a loved one.

[Hidden]

1) Data: "Data were collected from 2004 to 2012. "

2) Published: "Epub 2018 Oct 24."

3) Reservations: "Our study may be limited by the relatively short follow-up (median of 4.0 yr."

4) Objective: "To examine the association between ADT and OS for Gleason 8 versus Gleason 9-10 PCa." (OS is Overall Survival my foot! )

Combining the above points the "validity" of this study can be assessed equal to ZERO.