When does PC begin to metastasize

Is there a consensus on PSA values at which PC begins to metastasize after failure from curative treatment?

Also, I found the following statement/ opinion from a fellow member in a different forum and it makes sense to me. Do those of you with much more knowledge than me see a fallacy with this reasoning? I'm going to paraphrase to avoid plagiarizing his comment.

In PC, the big concern is mets. By starting ADT early, there's little risk of mets for 2 years. However, not everyone with recurrent PC will get mets. And, if mets do occur, beginning ADT at that time will still provide 2 years of effectiveness. So, why not delay ADT until it's needed?

P.S. I'm aware of TOAD, but the statement still makes logical sense to me. If TOAD concluded that earlier is better, did it also find that ADT delayed the onset of mets after it stopped working?

Thanks, TA, I'm just trying to understand this disease better so I can make a better treatment decision when the time comes (mainly ADT and/or chemo).

I think part of my confusion was understanding what metastasis means. I was confusing metastasis with castrate resistance. I guess what you are saying is that metastasis means that the PC is systemic, but may or may not yet be detectable, whether or not it is castrate resistant.

Am I now correct in thinking that the natural history of progressive disease is, first it is confined/ local, then it metastasizes (spreads to more distant locations), then the mets begin growing tumors in bone and/ or organs?

[The ability of ADT to reduce the micrometastatic burden trumped any selective pressure due to an early start.]

By "selective pressure" do you mean earlier selection towards castrate resistance? That, if any such pressure was there due to an early start, the reduction in metastatic burden was a bigger advantage?

Thanks again.

Reachout,

it is difficult to determine the effect of ADT on the micrometastatic burden. You cannot see nor count these micromets. I am not aware of a study that could determine this effect.

I think ADT will reduce the micrometastatic burden but to what extend? The mets with cells insensitive to ADT will not be affected.

George

Thanks for your replies george and special lady.

I like what you said about slow growth. It really is about doubling time. And I've gone to a Mediterranean diet now to hopefully slow it even more.

I always thought that my psa might come back though coming back at nearly 5 years past my SRT was a surprise. But I also thought that, even if it came back, I'd have a good 8 to 10 years of watchful waiting before is have to make a decision on ADT, maybe when my psa got around 10. What threw me for a loop was my recent visit to my urologist who said he'd like to have an ADT discussion when it gets to 1.0.

What that brings to mind are all the guys here who go on ADT for a couple of years, develop resistance, need more ADT or chemo, and their QOL really suffers. I'm not ready to go down that road yet especially for, as George said, a 5% advantage. But I also respect TAs knowledge and he makes excellent points.

Anyway, I've made appointments for second and third opinions with Walter reed and Johns Hopkins and those places have pretty smart guys, so I'll see what they say. In the meantime, good advice, I'm just going to put this away, have a head of broccoli, and enjoy the weekend

reachout said...
Am I now correct in thinking that the natural history of progressive disease is, first it is confined/ local, then it metastasizes (spreads to more distant locations), then the mets begin growing tumors in bone and/ or organs?

Yes, that pretty much covers it. I'd add that the metastases are continually evolving to castration resistance.

reachout said...
By "selective pressure" do you mean earlier selection towards castrate resistance? That, if any such pressure was there due to an early start, the reduction in metastatic burden was a bigger advantage?

Yes, ADT kills off hormone sensitive cells, leaving a much smaller number of castration resistant cells behind. Eventually, that type of cell predominates. but that happens whether one is on ADT or not.

reachout said...
What that brings to mind are all the guys here who go on ADT for a couple of years, develop resistance, need more ADT or chemo, and their QOL really suffers. I'm not ready to go down that road yet especially for, as George said, a 5% advantage.

This will happen regardless of whether you are on ADT or not - because cancer cells replicate so quickly and they undergo "genetic breakdown" as they do so. ADT sensitivity can last a lot longer in some men than in others.

It is not a 5% "advantage." Researchers use a metric called the "hazard ratio" which compares the hazard (in this case, death) of one treatment to another. In the TOAD study, the 5-year death rate was cut in half. Almost everyone survives at least 5 years with recurrent PC regardless of whether they use ADT or not. The open question is whether that mortality trend observed in the first 5 years will continue over the next 5 years. Trends tend to continue. On the other hand, it is entirely possible that those "early diers" were an anomalous group of very sick men in whom the unchecked cancer burden was just too much (no one died directly of prostate cancer).

I very much agree with Special Lady that intermittent ADT may be all you need. Almost everyone in the TOAD study was on intermittent ADT. I don't know that it's true that PC progresses more slowly in older men; all the data i've seen suggests the opposite. (Although researchers have identified a subgroup of younger men in whom the disease is specially virulent.) Also, PC is often undertreated in older men due to ageism on the part of physicians. It may be the case, however, that ADT is less bothersome to older men. That's just based on my anecdotal observations in my support groups.

One of the more interesting observations from the TOAD study was that the perceived quality of life was no different between those who started early vs those who delayed their ADT start.

www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30426-6/fulltext

I think some additional comments the lead investigator made are worth noting:

Dr. Duchesne said...
No statistically or clinically significant differences in global quality of life or in physical, role or emotional functioning, were found between the immediate and delayed trial arms over the five year period from trial entry. When examining those HRQOL domains relating to possible toxicity of treatment, men starting immediate therapy had clinically significant HRQOL detriments, to be expected, from hot flushes, nipple tenderness or enlargement and lower levels of sexual activity than those in the delayed arm. These differences were evident early, but had essentially disappeared after about two years, reflecting increasing numbers of men in the delayed arm who started therapy, or perhaps ongoing ageing in this older age-group. Interestingly, there were no differences found in the prevalence of ‘feeling less masculine’ or in sexual functioning for those who were sexually active, but low levels of sexual activity were reported in both arms. No other differences were noted.

These findings are interesting for several reasons. This is a group of men who have already experienced a cancer diagnosis, and who have undergone attempted curative therapy that has failed. They may have already experienced a significant detriment in HRQOL related to their primary therapy, followed by a diagnosis of relapse, albeit early and asymptomatic. The low levels of sexual activity in both arms prior to randomisation or to the introduction of hormonal therapy attests to both the effects of prior treatment and possibly to the age-group of this cohort (a median age of 70+ years), although we do not have a control group of men of this age without prostate cancer to compare. It may be that the overall quality of life in the immediate therapy group might have been favourably influenced by the perception that their disease was being brought under control and that nuisance side-effects from therapy were worth putting up with.

Not mentioned in the thread is the role that Gleasons score play in the likelihood of Metastasis spreading outside the prostate gland..The G-9 and G-10 guys are FAR more likely to have their cancers metastasize than the G-6 and G-7 . With G-9 and G-10, the horse is usually out of the barn before the patient even knows there was a horse in the barn.. You gotta get lucky and catch it VERY early to have your primary treatment result in a cure..

The argument for early ADT is that there are hormone sensitive cancer cells and hormone resistant cancer cells. Hormone sensitive cells can mutate to hormone resistant cells so killing them before mutation reduces the cancer burden. The other argument is there is no cancer in which treatment later is better than early treatment.

AK - Your scan found some tumors on your spine. You won't know for sure that they are actually "mets" until after you have a biopsy and it is confirmed to be prostate cells. As the saying goes, "it isn't cancer until they say it's cancer".

In the meantime it will probably help you sleep if you think of them only as "possible" mets. There can also be benign tumors, though they may be rare. As I said in your other thread, you can have more than one kind of cancer. I just found that out today but won't be sure until after the biopsy. So yeah, I get the hard to sleep part.

Don't start digging your own grave just yet, my friend.

Thanks Ken. Good luck with your panel tomorrow. I hope they can give you some helpful information.