Long term AR signaling‐targeted therapy with taxane sometimes associated with visceral metastasis in castration‐resistant prostate cancer

[George71]

The present study was conducted to present androgen receptor signaling‐targeted therapy and taxane chemotherapy induce visceral metastasis in castration‐resistant prostate cancer. Researchers retrospectively examined demographic, surgical, pathological, and follow‐up data of prostate cancer (PC) patients treated at Kanazawa University Hospital between January 2000 and December 2016 applying their medical charts. They elucidated the risk factors of visceral metastasis (VM) and the survival of patients with VM. A total of 1364 patients were included in the study. The outcomes of this study demonstrate that, although the sequential use of new androgen receptor signaling‐targeted agents and taxanes for castration‐resistant PC (CRPC) is a standard treatment strategy, it often results in the development of VM.

mdlinx.com/journal-summary/...

[Schwah]

A little over my head. Please explain what the conclusion is and how it might impact treatment for men with Crpc

Schwah

[LearnAll]

"INDUCE visceral mets"??? If that's true..its a bad news. Did they mention which particular androgen receptor signaling targeting agents cause this ? If all of them do this which ones are less likely to do this? Something we need to explore more.

[Stevecavill]

I don’t have access to the full paper, but do you think they may have confused correlation with causation?

[George71 in reply to Stevecavill]

no, it is true -- they cause visceral mets -- IT would include Casodex and taxane chemotherapy

[LearnAll in reply to George71]

I have personally known a few men who have been on Casodex (Bicalutamide) for over 10 years and their PCa is in remission. My guess is that its not a universal phenomenon. In some people , Androgen Receptor Blockers might finally cause visceral mets OR visceral mets are just a manifestation of worsening PCa. At this point, it is not clear.

[Tall_Allen in reply to Stevecavill]

Absolutely. Thanks for pointing out the obvious error in jumping to the wrong conclusion.

[George71]

"although the sequential use of new androgen receptor signaling‐targeted agents and taxanes for castration‐resistant PC (CRPC) is a standard treatment strategy, it often results in the development of VM. "

[GP24]

In the full text I read: "All patients were divided into three groups: patients with treatment history of neither ARST nor taxane, treatment history of either ARST or taxane, and treatment history of both ARST and taxane. Comparison of these three groups confirmed that increased use of ARST or taxane resulted in significantly higher incidence of VM (visceral metastases) (ARST = Abiraterone and enzalutamide were classified as new AR signaling‐targeted agent)

I think the more aggressive the cancer was, the time to resistance was shorter and these patients therefore got more treatments. And the most aggressive tumors caused visceral mets - no surprise.

I see no cause of visceral mets by ARST and taxanes. However, it is known that ARSTs make neuroendocrine differention more likely. But you need to use these in spite of that.

[Tall_Allen in reply to GP24]

"However, it is known that ARSTs make neuroendocrine differention more likely. " The same logical error - it is an association - causation has never been shown.

[Hidden in reply to Tall_Allen]

The longer you live, the more likely it is that your cancer will develop into a more deadly and untreatable form. I don't understand why that is important to point out except to scare people. We have an incurable disease. The goal is to live longer, not to avoid more deadly strains of cancer that may or may not come along later. If I have a treatment that will extend my life, I don't really care about how my cancer is going to evolve.

[noahware in reply to Hidden]

Isn't it possible that the odds an individual's cancer will develop into a more deadly and untreatable form are not simply a function of time, but also a function of treatment modalities?

I want a treatment that will extend my life, and I ALSO care about how my cancer is going to evolve. The two are not mutually exclusive. It certainly makes sense to suppose the development of a more lethal and less treatable form of cancer might offset some of the expected life-extending possibilities of various treatments.

When Dr. Bob Liebowitz said his opinion was that it might be beneficial for patients to try to avoid castrate resistance, I understood the logic, and did not think the only reason he said this was to scare people.

[Tall_Allen in reply to noahware]

It is possible- anything is possible. But it has never been shown to be true. In fact, the opposite has been proven to be true - that early use of stronger meds delays CR. I wouldn't take Dr Bob as an authority on anything.

[noahware in reply to Tall_Allen]

Dr Bob was one of the first and foremost MO advocates of aggressive and early use of stronger meds to delay CR. So you may not take Dr Bob as an authority on anything, but he was the one of the most vocal in suggesting the early use of CAB w/ chemo back in the 1990s.

One might go so far as to say... he was once an authority on the early use of stronger meds as a preferred mode of treatment for men with a goal of not becoming CR.

[Tall_Allen in reply to noahware]

Except he was wrong about CAB, and wrong about testosterone. Hypotheses do not replace clinical evidence.

[noahware in reply to Tall_Allen]

I would need to know exactly what he claimed about CAB and testosterone that was "wrong" since he repeatedly mentioned these were his professional "opinions" when discussing them. Was there some trial where his protocol was tested against SOC, over the long term?

And what does that mean with regard to the fact that he was an early authority on the early use of stronger meds to try to delay CR? You seem to agree with him that attempts to delay CR can be beneficial. He was working without the benefit of 20-20 hindsight that you have, and trying to GENERATE hypotheses rather limiting himself to the (very) few that have already had the luck to get to any kind of rigorous trial.

[George71 in reply to noahware]

in his video Dr. Bob shows how his treatment compared to all others -- he only had one patient in his group become CRPC while all others had many some over 50% became CRPC

[GP24 in reply to Tall_Allen]

I was refering to Himisha Beltran who mentions ADT-induced NEPC (neuroendocrine PCa). She writes that one of several resistance mechanisms is the mutation to neuroendocrine prostate cancer.

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

[Tall_Allen in reply to GP24]

Thanks for the link. I think it's important to note that it is based on mouse and lab studies, not human studies. Also, she notes, it may be reversible with BAT:

"Ralph Buttyan and co-workers were the first to observe that in LNCaP cells, which is by far the most commonly used model in PC research (37), the cells undergo an NE transdifferentiation, when chronically exposed to medium lacking androgens and that restoring androgens back to the medium suppressed this NE transdifferentiation state (30). "

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

Thankfully, treatment emergent NEPC doesn't seem to be as virulent as de novo NEPC.

[George71]

The way I read it -- once you become CRPC -- the sequential use of new androgen receptor signaling‐targeted agents and taxanes (which is a standard treatment strategy), often results in the development of VM.

[George71]

Most Dr's have believed this was the case with Casodex -- once your PSA starts rising on Casodex you should stop taking it because it becomes food for the PCa cells. see Dr. Bob Leibowitz video.

[Tall_Allen in reply to George71]

That is true. It is called bicalutamide withdrawal syndrome and has been known for over 20 years. It is just one of the reasons bicalutamide is little used anymore.

[George71]

NPfisherman see your PM

[Tall_Allen]

This is a flawed logic. It is called Post Hoc Ergo Propter Hoc (after it therefore because of it). It is why retrospective studies like this are useless for treatment decisions. The selection bias is obvious: the men who had the most aggressive disease were given the most treatments, had visceral metastases in spite of it (not because of it), and survived less.

Patients should beware of research posted on this site that doesn't include an analysis of the level and quality of evidence.

[Hidden]

Just because your cancer survives through mutations despite using the best proven treatments doesn't mean that those treatments should be avoided. The argument that treating your cancer leads to more agressive types should be ignored if the alternative is dying sooner. Get the best treatments you can for where you are at now.

This "treatment makes the cancer more aggressive" argument is a one we hear periodically on this forum, often from people who are in a low risk situation. It's easy to tell someone else what treatments they should get when you don't need them yourself.

Of course the cancer is going to evolve and become resistant to whatever we throw at it. That doesn't mean we don't treat it with best proven treatments we have.

A Radiation Oncologist told me he had a patient who was worried about the radiation causing cancer later on. He said "Let's worry about the cancer you have now, not the cancer you might have later."

[noahware in reply to Hidden]

There are four thing to weigh in choosing treatment: known costs and known benefits, and potential costs and potential benefits. When an individual weighs these, he does so objectively AND subjectively.

IF "the alternative is dying sooner" for every individual who declines "best" treatments is a KNOWN cost, I'm not sure why you feel you have to warn men not to kill themselves, as an imperative. (There are laws against suicide, after all, and they don't seem to work.)

But if "the alternative is dying sooner" for a given individual is merely a POTENTIAL cost, then evaluating a variety of information and opinion and weighing that risk for one's self is a subjective and INDIVIDUAL process.

[Hidden]

Bottom line: treat the cancer you have now, not the cancer you might get later.

[noahware in reply to Hidden]

Or, put another way: pursue a treatment now that MIGHT work to extend life, even if it may increase your risk of developing a less treatable and/or more lethal cancer and will DEFINITELY impose the harmful disease of hypogonadism.

Known costs and known benefits, and potential costs and potential benefits.

To NOT consider the cancer you might get later is akin to not making efforts to prevent PC in the first place (which, for all of us, was in our youth viewed as "a cancer we MIGHT get later"). Why should I continue with the same mistake? The last thing I want to do is something that might turn a "cancer I can live with" into a "cancer I will die from."

Those with "advanced PC" are a heterogeneous group, ranging from low Gleason, met burden, and symptom presentation to VERY high Gleason, met burden, and symptom presentation. Those further along the continuum can less afford to theorize about "later" while those not as far along can better afford to. Individuals can proceed accordingly.