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Posted 10/16/2016 5:01 PM (GMT 0)
I am confused on how the time to castrate resistance is determined.

Take my situation.
Start ADT. On it for a year. Go intermittant. off for 9 months (but let's call it a year for simplicity). Go back on for a year. Now off for a year.

I am currently, as far as we know, not castrate resistent. But, for how long so far. I count 4 years since I started it. Does that mean I have beaten the median? This doesn't sound right, since MANY folks on IHT are on it say 3 times before CR.

Mel
Posted 10/16/2016 5:15 PM (GMT 0)
Mel, I think you have beaten the median. From what I understand in those articles, castrate-resistance has only one definition - PSA progression while on HT. If your PSA still falls when you go on HT, then you're not CR. In those studies comparing IHT to CHT, it seems both of them start with a period of HT, so day one of that is day one, time zero, start the clock.

You're probably well aware, but some aren't, that "median" means only that half were more, half were less. It's not the same thing as an average. If two people recurred at 1 year, and two recurred at 10 years, the median could still be either 1 year or 10 years, or any chosen point between. The average would be 22/4, or 5.5 years. They are commonly confused, but mean quite different things especially with something asymptotic, like survival times and so on. You're a math person, but others reading this might benefit from the distinction.

Keep it up, man! I thought it interesting that one of those articles mentioned going on HT for a very short time, only 3 months. You've been on it for a year at a time, why that period? Is that just based on time, or do you have some parameter you watch to indicate on/off periods?
Posted 10/16/2016 6:25 PM (GMT 0)
Redwing:

A year is about standard.

Also the 2-3 years until CR seems too low, since as I said many are on IHT for 2-3 sessions. Given the year on HT, that adds up to a longer time.

Mel
Posted 10/16/2016 7:05 PM (GMT 0)
Mel,

in this trial: Intermittent androgen deprivation for locally advanced and metastatic prostate cancer.... they used a three months induction period: "...received a 3-mo induction treatment" So not everyone does one year as the first period.

I can only cite the studies I read. When I mention these figures in a forum I usually get objections that they are far too low. And I do believe the forum members that their experiences are very different.

My objective is just to point out that the benefit of an ADT is limited in time and you should consider this when you plan your therapy.

As Redwing said, as long as your PSA value does not rise while on ADT you are not castration resistant. However, chances are growing the longer you are on ADT.

George
Posted 10/16/2016 8:37 PM (GMT 0)

George said...
As Redwing said, as long as your PSA value does not rise while on ADT you are not castration resistant. However, chances are growing the longer you are on ADT.

You may not be castrate resistant as far as the hormone sensitive cells are concerned, but keep in mind those castrate insensitive are busy working and throwing off very little PSA.

As I posted in another thread, how long ADT works has to do with the ratio of hormone-sensitive cells to hormone-insensitive cells in the cancer and how fast the cancer grows.


Bobby Mac

Post Edited (Bobby Mac) : 10/16/2016 5:36:42 PM (GMT-6)

Posted 10/16/2016 9:37 PM (GMT 0)
George-

I recommend care in relying on outdated information (from 2008) as you are doing. When we get Level 1 evidence from randomized clinical trials, it supplants such database analyses as you so often site. I would not like to see you or others endanger your health by relying on outdated evidence.

The time to castration resistance you cite is based on data that may be useful in Europe, but not in the US. Because PC is detected earlier in the US now, there is considerable lead time bias. Mel's case is N1 M0, and he can expect a much longer time to distant metastases (M1) and castration resistance than someone who has already been detected to be M1. For cases like yourself - detected as M1 by advanced PET scans - you have also introduced considerable lead time bias, and I don't think any studies have calculated the time to castration resistance with such early detection of mets.

There are several factors that can help predict time to castration resistance, especially initial response to ADT, PSADT, and volume of detected metastases. Maha Hussain's study on iADT in M1 men showed that the amount of time spent on ADT did not affect the time to castration resistance. The Klotz study of iADT in recurrent PC with PSA>3 ng/ml found that median time to castration resistance was 2.57 years for continuous ADT, and 2.18 years for iADT, but that the difference was probably explained by the fact that they had to wait for T levels to become castrate and 3 consecutive rises after that to deem the iADT men castration-resistant. The TOAD study found that early start of ADT increased the time until castration resistance set in. It was delayed in men who used immediate ADT probably because it prevented the evolution of castration-resistant cancer cells.
Posted 10/17/2016 6:57 PM (GMT 0)
Allen,
 
Lupron is available since 1989 and has been used almost unmodified until today. Therefore I think a study from 2008 regarding the efficacy of ADT is still valid. This study by Ross has been cited six times in 2016 alone by separate studies. Using this study does not threaten your health.

The time from the start of ADT to castration resistance is frequently mentioned in US studies too, not just in European studies. E.g. this study from San Francisco, Zejnullah: Approaches to minimize castration in the treatment of advanced prostate cancer - published in 2016 - writes „..... disease progression is universal with a median time to castration resistance of approximately 2 to 3 years depending upon disease state and risk category“. (in the full text).

However, as I mentioned I do not want to prove that these figures are correct, just to point out that the time to castration resistance is limited and it therefore could make sense to delay the start of ADT and save this limited time for later.

You always refer to the Toad trial/study as level 1 evidence. Quite a number of researchers do not think so. The trial was presented by Dr. Duchesne at ASCO 2015. Dr. Higano's remark at ASCO was: …... this is not the first randomized trial comparing immediate and delayed ADT to fall short of its accrual goal. “I think the trends in the TOAD trial do look provocative,” Dr. Higano said. “[But] they lack the statistical power due to short follow-up, too few events, and the hazard ratio does remain unstable.” With other words she considers the study to be underpowered.

Further questions were raised by other researchers and published: van den Bergh (3.4.1.2), Dr. Friedland and Derya Tilki.

Further Fossati wrote regarding this trial: „Taken together, these findings are far from proving a clear survival benefit of immediate versus delayed androgen-deprivation therapy.“

So I am not alone being sceptical regarding the results of the Toad trial.

You mention: „It was delayed in men who used immediate ADT probably because it prevented the evolution of castration-resistant cancer cells.“ - I do not agree. As Haffner: Tracking the clonal origin of lethal prostate cancer has shown, castration-resistant cancer cells can already be in the prostate while the cancer is still confined to the capsule. If they are castration-resistant, ADT cannot stop them from spreading since they are castration-resistant.

George
Posted 10/17/2016 8:21 PM (GMT 0)
George-

You just proved what I was saying - US studies show a longer time to castration resistance (2-3 years, as you just showed!) compared to older European studies. This is because patients have been diagnosed earlier in disease development - called "lead time bias."

You misunderstand the natural history of prostate cancer progression. The disease progresses from hormone sensitive to castration resistant whether one uses ADT or not. Duchesne just proved that starting ADT earlier delays progression.

You misunderstand what "level 1" evidence means. It is a fact, not an opinion. There are sometimes grades attached to the evidence to evaluate its quality, but that is a different thing altogether. Quoting statements from a few oncologists does not change it.

The point is - you cannot use level 4 evidence (professional opinions) to refute Level 1 evidence - only more level 1 evidence can do that. Since you seem to enjoy looking up stuff, I recommend you study "Levels of Evidence." Also, I suggest you approach topics with an open mind, rather than using your confirmation bias only to find evidence that supports your pre-decided opinion. I admit I was shocked when in another post you deliberately changed what authors wrote to support something else you misunderstood. How does that help you or anyone else? Try to think more like a scientist and less like a lawyer - it will help you in the end.

I very much agree that there may be some sub-groups for whom it will not matter much if they start sooner or later. The decision is not automatic. Yet, for most recurrent patients, we now know that earlier start reduces mortality.

ADT certainly does continue to prevent cancer progression even in castration resistant patients. That's why Lupron is always continued even after castration resistance is identified. In fact, in castration-resistant cells, even small amounts of androgens cause them to proliferate. That's why second line hormonals are added to eliminate even more androgens than Lupron alone can.
Posted 10/17/2016 11:59 PM (GMT 0)
My, my what an interesting conversation between two "experts". It looks like "tall allen" and "short george" are going to have to agree to disagree despite the fact that SG is giving out lethal information in TA's opinion.
Posted 10/18/2016 3:45 AM (GMT 0)
Sheepguy, for once I agree with you - I'm done with this thread.
Posted 10/20/2016 7:23 PM (GMT 0)
I had initially mentioned two to three years to castration resistance myself. If you write that I proved what you were saying we seem to have always agreed on that.

You suggested to study "Levels of Evidence". Well, I looked at Burns: The Levels of Evidence and their role in Evidence-Based Medicine He writes: „No matter what the level of evidence for a study, if it is under powered, the interpretation of results is questionable.„

I did not quote different opinions of researchers regarding the findings of the study, just their reviews of the Toad trial. They declared that the study would be under powered.

Also Zejnullah: Approaches to minimize castration in the treatment of advanced prostate cancer mentions the Toad study as reported by Duchesne (full text): „The recently reported phase 3 “Timing of Androgen Deprivation” trial was designed to study whether immediate vs. delayed ADT was associated with improved long-term survival in biochemically relapsed and locally advanced patients for whom definitive local therapy was not an option [17]. Though a statistically significant improvement in OS was observed among patients assigned to immediate ADT, the study was significantly under-powered with relatively few events to definitively address the issue of optimal timing of initiation of treatment “

I just disagreed that ADT with Lupron can prevent the evolution of castration-resistant cancer cells as you had mentioned. However, you now write: „The disease progresses from hormone sensitive to castration resistant whether one uses ADT or not.“ So there seems to be no disagreement. To attack the castration resistant cells you need second line hormonals.

George
Posted 10/29/2016 1:36 PM (GMT 0)
Well, I got some good news on the test results from Mayo. Apparently I misinterpreted something that was said during my visit. They spoke about C11 "uptake" from the scan. One was an increased uptake in the one node that was spotted 2 years ago. Another was a very small uptake in a second femoral node. I assumed that ANY uptake was cancer. Apparently not. That second uptake does NOT rise to that level and in fact is more indicative of a benign situation. In fact, it mentioned a "stable" uptake. In other words, no change from the scan done 2 years previously (although it was never mentioned at all in the previous report). This is good news (ie: better one spot than two!). Dr. King received the disk and, in fact, he is the one who pointed out that the second spot was unlikely to be cancerous. We will soon be discussing tx. options.

Mel
Posted 10/29/2016 9:02 PM (GMT 0)
On face value, stable and "uptake" seems to be oxymorons, but in your case this is indeed good news!
Posted 10/29/2016 10:46 PM (GMT 0)
Mel,

That is really good news!! Look forward to seeing what Dr. KIng recommends.

Robert
Posted 10/30/2016 8:02 PM (GMT 0)
Someone told me 6+ years ago that HT can be effective somewhere between 2 years and 20 years. I think there are a lot of factors in play and each person is different.
Posted 10/30/2016 9:53 PM (GMT 0)
Can anyone here explain what early ADT means. Is it before any mets are found? At what point does "early" no longer apply? Some of us happen to be at the point of making a decision concerning when to start ADT and it would be foolish to start the clock with little or no benefit.
Great thread!

Woody
Posted 10/30/2016 10:13 PM (GMT 0)
Woody,

For me, early was as soon as any PSA was detected (.09) which just happened to be at the same time bone mets were found.

I've seen guys wait until PSA goes > 50 and no mets. And then I've seen everything in between.

Jerry
Posted 10/31/2016 2:38 PM (GMT 0)
Woody,

as you know Allen and I disagree if "early ADT" is the right choice. I think, as Jerry mentioned, "everything in between" is right.

Allen's point of view is based on the TOAD study as published by Duchesne. In this study they defined "early" as starting ADT after "a PSA relapse after previous attempted curative therapy".

This again was defined as "a PSA rise of at least 2 μg/L higher than post-treatment nadir if a patient relapsed after radiotherapy; at least 0.2 μg/L higher than post-treatment nadir if a patient relapsed after radical prostatectomy; and either at least a 0.2 μg/L rise higher than the post-treatment nadir or a PSA that did not fall to lower than 0.2 μg/L if a patient relapsed after radical prostatectomy and salvage radiotherapy."
Please be aware that the majority of the included patients did intermittent ADT.

So this is "early" if you want to use this study as your guideline.

The studies published before that could not determine an advantage for "early".

George

Post Edited (George_) : 10/31/2016 8:44:25 AM (GMT-6)

Posted 10/31/2016 3:00 PM (GMT 0)
Just to assist George_ be helpfully clear...lest there be any confusion.

In the U.S., serum PSA measurements are reported in ng/mL, but the conversion factor is 1 μg/L = 1 ng/mL
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