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ADT for SIX MONTHS plus RT shows significant survival benefit for high risk patients

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Posted 6/30/2014 12:59 PM (GMT 0)
See this link for recent study of the duration of and combination of ADT and RT showing significant survival benefit for patients at intermediate to high risk of PCa progression:

http://www.sciencedaily.com/releases/2014/04/140406214415.htm

Note that the six months of ADT is administered concurrent with administration of RT and a second shot is administered after RT.

I have been searching for something definitive regarding recommended length of ADT and believe this is it!

Bob
Posted 6/30/2014 1:49 PM (GMT 0)
Break60,
At Mayo I had the 6 months of ADT and radiation (IGRT) for high risk
prostate cancer. But my RO said I did NOT need another shot of
Lupron.

Sure hope he was right but I just had my third straight increase in
my PSA.

PhilC
Posted 6/30/2014 2:50 PM (GMT 0)

Bob, you said...
I have been searching for something definitive regarding recommended length of ADT and believe this is it!

Actually, the study compares two lengths of ADT -- 6 months (aka "some") and 0 months (aka "none") -- and demonstrates that some ADT is clearly, clearly better than none. It seems to me that to provide the answer you have been searching for they should have thrown in "more" and "less". It is entirely possible to believe that, good as the results were from 6 months, the results of 12 might have been better and 24 might be better yet.

From my vague recollection of other studies the magic numbers seem to be in the 12 to 18 months range, although those studies may have been done at lower doses of radiation and there is some reason to think one can trade longer ADT for a lower dose of radiation.
Posted 6/30/2014 6:03 PM (GMT 0)
I'm sorry that this isn't the study you were hoping for. This study was among men with localized PC (cT2) who had not had any treatment yet, and were given RT. It shows that 6 months of ADT improved their prognosis over no ADT, as PDA said. Other studies have shown that for primary radiation treatment of high risk disease, 18 months is optimal.

In your case, you are undergoing salvage RT after RP failure. Your stage is pT3b and your GS is 9. The study below is more relevant to your case. They found that "patients who received 6 months of ADT had a 1.8 fold decrease in risk of biochemical failure, distant metastases, PC-specific mortality, and overall mortality, whereas patients who received 24 months of ADT had a 9.8-fold decrease in risk of biochemical failure, distant metastases, PC-specific mortality, and overall mortality."

Duration of Androgen Deprivation Therapy Influences Outcomes for Patients Receiving Radiation Therapy Following Radical Prostatectomy

- Allen
Posted 6/30/2014 6:29 PM (GMT 0)
Once again I have demonstrated my ability to answer almost any question using the Gabby Hayes method.

In Roy Rogers westerns Gabby would frequently be the first on the scene when there is trouble. He would ride in on his trusty Jeep, Jezebel, and squawk and fluster while the victims explained their plight. Once the stage was set, Roy would ride in on Trigger and set things right. I often wondered if Roy was more motivated by sympathy for the ranchers whose cattle were being rustled, or by his desire to go retrieve his side-kick before the episode got too embarrassing.

Thanks, Tall.
Posted 6/30/2014 7:17 PM (GMT 0)
PDA, I am very impressed by your knowledge of Roy Rogers westerns and other esoterica, as well as your knowledge of PC. I think we make a great team, and am happy to play your sidekick as well, although I lack your and Gabby Hayes' comic flair. Happy trails to you.

- Allen
Posted 6/30/2014 7:35 PM (GMT 0)
Does anyone know if there are studies that demonstrate the use of ADT for patients receiving radiation as a secondary therapy?

Specifically, I would like to know if ADT is suggested for those folks undergoing SRT. And if it is suggested, what criteria is used to determine if ADT is warranted? Positive margins? EPE ?
Posted 6/30/2014 7:51 PM (GMT 0)
John,

If you read the abstract that Tall posted again you will see that they are talking about secondary treatment. They start off by saying that there is a fair amount of research about primary treatment which is why they decided to look at secondary treatment (ART and SRT). It is for secondary treatment that they found their significant, if not to say huge benefit to putting up with ADT a while longer.

I don't see where they talk about risk factors (except to say they controlled for them) so it doesn't answer all your questions, but it's pretty compelling for what it does say. You are, theoretically, fairly low risk, but you've already recurred once so I dunno.
Posted 6/30/2014 7:52 PM (GMT 0)
John-

The link I provided addresses that, doesn't it?

But I think what you really want to know is its relevance to your case. ADT has never been shown to be useful with GS6, and not even with GS3+4. The fact that your PSA responded so dramatically and quickly to Avodart suggests that there is either some BPH in the tissue your surgeon left behind or that any GS6 in it is responding to the Avodart. Why not continue on it alone and see how your PSA reacts over time?

- Allen
Posted 6/30/2014 8:30 PM (GMT 0)
Thanks Peter and Tall,

I apologize if I didn't see the relevance of the above posted study for secondary treatments. I over-looked it and upon further reading see it now.

I'm just trying to improve my understanding of the use of ADT in secondary treatments.

As of now, I have not experienced a true "recurrence" of PCa but the indicators are there to suggest it might be likely as I had a focal positive margin, EPE could not be conclusively ruled out, and my PSA has been slowly rising since my RALP three years ago.

I have spoken to my Uro about this as well as with a radiation oncologist, who both agreed that if & when I need SRT, the use of ADT would not be included. But if the studies suggest that ADT along with SRT is the right thing to do, then I want to be prepared with data to show the docs why.
Posted 7/1/2014 3:18 AM (GMT 0)
Allen -

Thank you for that link. It bears on my situation in that I'm headed for SRT with the radiologist recommending 4 months of ADT. So I'm curious about your further comment "ADT has never been shown to be useful with GS6, and not even with GS3+4". Are you suggesting there's evidence that ADT makes no difference in this setting (G3+4, then RP, then biochemical recurrence, then SRT)? or simply that no randomized controlled trials have been done?

I read closely the study you linked to, and though it says there's a nearly 10-fold reduction in overall mortality after adjusting for Gleason, it doesn't give any data on the how the experimental population was stratified by Gleason, and so one can't tell if there were enough G7's to warrant applying this finding to the G7 pool. There doesn't seem to be a longer-format version of this study that I could find; were you able to find anything?

Although my radiologist says 4 months of ADT is enough, this study seems to indicate otherwise.

Thanks,
David
Posted 7/1/2014 6:51 AM (GMT 0)
David,

I wish there were randomized controlled trials that could directly answer your question, since it vexes many. The study I cited was a retrospective analysis, rather than an RCT, and as you noted, it doesn't speak to GS7 separately. I don't have any more details. Perhaps you can write to the authors.

What we know from trials of men who have primary RT treatment is that ADT doesn't improve outcomes and does increase SEs among men whose Gleason score is 3+4 (favorable intermediate risk). In the following study, they found "Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (Freedom From Failure, FFF, 94% vs 95%, respectively; P=.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%).

Is Androgen Deprivation Therapy Necessary in All Intermediate-Risk Prostate Cancer Patients Treated in the Dose Escalation Era?

Similarly, the following study found a benefit to short-term ADT in men with GS4+3, more than half positive cores or multiple risk factors, but no benefit for other intermediate risk men:

High-Dose Radiotherapy With or Without Androgen Deprivation Therapy for Intermediate-Risk Prostate Cancer: Cancer Control and Toxicity Outcomes

The following study also found no improvement in survival among favorable intermediate risk men treated with ADT:

The likelihood of death from prostate cancer in men with favorable or unfavorable intermediate-risk disease

The open question is whether there is any reason to suppose that the cells that are causing the PSA to rise, whether they are in some undissected gland tissue or have locally invaded the prostate fossa, act any differently than tumors in the gland itself with respect to radiation and ADT. It would seem that GS3+4-type cancer cells tend to harbor locally where they are perfectly-well killed off by radiation alone, and adjuvant ADT is not needed to seek out and destroy distant micromets. It may be too that ADT is not needed to radiosensitize such cells. But there is no guarantee that some aren't in systemic circulation where they can only be killed off by a few months of adjuvant ADT.

It's a difficult call. Sorry I can't be of more help.

- Allen
Posted 7/1/2014 2:18 PM (GMT 0)
Tall One,

My intuition is often a bit wobbly but I wonder about your discussion of the behavior of "GS3+4 type cancer cells". My intuition is that you open the bag and count the M&Ms and if there are mostly red and yellow M&Ms then you are a gleason 7. If there are more red ones than yellow then you are a Gleason 4+3, and if more yellow, a 3+4. In my mental model there is red M&M behavior and Yellow M&M behavior and the reason Gleason 4+3 cancers are more aggressive is because there are more of the more aggressive cell types and aggressive growth is, thus, more likely.

This allows for gradations where the difference between 3+4 and 4+3 is a judgement call and it's difficult to justify differences in treatment based on that distinction. This is the reason why I wonder if the fact of a recurrence might be a self-selecting distinction between those sorta-in-the-middle Gleason 7s who do benefit from more aggressive treatment and those who don't.

Of course, I certainly don't actually know anything but when the research doesn't speak to an issue I am often tempted by my admittedly flaky intutition.
Posted 7/1/2014 6:16 PM (GMT 0)
PDA,

I think your intuition is spot on. As you know, the first number has to be more than half of the tumor, and the second number can be anywhere between 5%-49%. In this case, there was no tertiary score reported that might have raised the risk level. Also, there is interobserver variability in counting the cells. So I agree that if the pathology shows 51% grade 3 and 49% grade 4, the situation is different from 95% grade 3 and 5% grade 4, although they are both GS3+4. So, I'm sure you're right that in actuality there are shades of gray, whereas the research used an arbitrary blunt instrument to qualitatively distinguish them based on quantitative measures.

Yet there does seem to be a qualitative difference between GS3+4 and GS4+3, the former known as "favorable intermediate risk" and the latter known as "unfavorable intermediate risk." I know that Epstein at Johns Hopkins believes they should be used as separate categories for risk assessment purposes, rather than lumped together as GS7. It seems to have other clinical consequences in addition to sensitivity to ADT; e.g., LDR brachy monotherapy may be fine for GS3+4, but combo with EBRT may be required for GS4+3.

I don't know anything about why this should be occurring. I suspect that it has something to do with tumor ecology. Tumors are more than just red and green M&Ms - they are interacting red and green M&Ms. We know, for example, that healthy cells in the vicinity of cancer cells influence them towards non-metastatic behavior. Conversely, cancer cells in the vicinity of healthy cells influence them to go rogue. There is some evidence that this occurs through the exchange of an extracellular vesicle called a proteasome. Intercellular communication via vesicles is a fairly new research topic (it garnered the Nobel Prize in Medicine this year) that may someday allow us to turn cancer cells non-cancerous by engineering proteasomes that can do that. You may be interested in perusing the following review article:

Extracellular Vesicles in Prostate Cancer: New Future Clinical Strategies?

So if my conjecture is correct, the tumor ecosystem may reach a tipping point when enough Gleason 4s are present. Before that tipping point is reached, "normal" measures may destroy the cancer, but beyond that point, ADT may be necessary too. Is 50% the right number? I don't know, but it seems to make a difference.

- Allen
Posted 7/1/2014 7:24 PM (GMT 0)
Tall,

I take your point about cellular ecology and a tipping point. It could also be true that GS3+4 and 4+3 preponderances arise from different, as yet unidentified, genetic vulnerabilities and the yellow M&Ms in a GS4+3 are different from those in a GS3+4 regardless of their environment. But it remains true that the Gleason types are based on morphological features of the cells and, even if the two types are distinct, they are in many cases hard to tell apart based on a Gleason score. That being the case if I were a Gleason 7(3+4) looking at a recurrence I would be tempted to think that it represented further evidence beyond the relative preponderances of Mars Candy Red (Gleason 4) vs Mars Candy Yellow (Gleason 3) cells when counted by the pathologist.

I'd want my oncologist to convince me that I didn't want a dab of ADT with my SRT, rather than the other way around.
Posted 7/1/2014 10:46 PM (GMT 0)
Even if the ADT isn't helping the oncological outcome, at least it isn't hurting that. So, having ADT with one's SRT would be a no-brainer if it weren't for those pesky SEs, especially the sexual ones. If a man had pGS 3+3, slow PSA rise, and a positive margin, there wouldn't be a lot of arguments in favor of adding ADT to SRT. If a man were pGS 4+3 with detectable PSA after surgery and possibly other high risk features, adding short term ADT would probably be beneficial. Proscapt seems to be in between those cases, which makes his decision harder. He has to carefully weigh how he feels about taking a risk that ADT is unnecessary to cure the cancer against the probability that potency will be spared. And he has to do it without the benefit of reliable research, or imaging that might pinpoint the cause. For me it would be a tough call.
Posted 7/1/2014 11:19 PM (GMT 0)
Thanks again Allen.

It is a tough call but I'm wavering over a slightly different line than the one you mentioned.

My rad onc is recommending a 4 month round of ADT alongside the RT 70G, and is suggesting that we do nodes as well as prostate bed, though he says it's a borderline situation as far the nodes go. He things I have about a ten percent chance of nodal involvement.

He sent me to a urologist who specializes in ED and treats a lot of prostate cancer guys. The potency doc said that the main cause of ED in this setting is that nocturnal emissions stop, and then adhesions form in the tissue that should normally swell. he said that if I get a VED and use it about 10x per week for about 2 minutes each time that should be enough to keep me limber and able to get things going again once the ADT is done. He's not saying I need to do the VED for intercourse, which would be pretty weird under ADT, but it's just a form of exercise to keep the tissue healthy.

I'm in a weird situation because I have G3+4 hence low intermediate and most of my stats are favorable, except I'm pathological stage T2C and there was cancer in 7 of 8 quadrants so that puts me in high intermediate terrain. The rad onc, one of the highly recommended ones is saying that I should do 4 months of ADT (casodex/lupron) but others (Scholz) said he'd recommend longer and would even add taxotere (partial course) to the ADT. The local Rad Onc opposes the taxo saying it just piles on SE's but there's no evidence it helps in this setting (of course, the CHAARTED trial suggests that it helps earlier, even if not quite this early.)

At this point I'm on a path to radiation with 4 months ADT but wondering if I shouldn't seek to extend that given the research you cited.

David
Posted 7/2/2014 1:08 AM (GMT 0)
Firstly thanks to Tall Allen for posting a link to the IJRO study. I will certainly be bringing that to the attention of my Uro.

I'm in a similar situation to proscapt in that I am G4+3 (revised from G4+5 at Bx) BUT the path report also says "a minor pattern 5 component is also noted in various sections amounting to approx 5% of tumour tissue". Not sure why that then didn't represent a 4+5 - is 5% too small an amount to be of significance?? To me it's a bit like a pilot telling you at 30,000 feet "we have a minor technical difficulty" Nothing is minor at 30,000 feet, and no aggressive cancer cell is insignificant. I would prefer to be treated as a "High risk" patient.

I have completed 6 months of ADT in conjunction with 37 sessions of RT. My Uro originally proposed 12 months, but then revised to 6 months - should have asked why at the time, but was just relieved to be given a reprieve from treatment. However having read that report, I think we should reconsider. Not sure if the almost 2 month hiatus after completion of the first 6 months would have any effect.

I haven't found the SE's from ADT to be a problem, but maybe I haven't hit the worst after only 6 months. In any event, I'd be prepared to put up with another 18 months if it means a better chance of longer term survival.
Posted 7/2/2014 3:28 AM (GMT 0)
Chask - the rule for how these things are classified is that if there is more 3 than 5 you'd be termed a 4+3 with tertiary 5; if there is more 5 than 3, you'd be termed a 4+5.
Posted 7/2/2014 5:01 AM (GMT 0)
Thanks proscapt, that makes sense, and also explains why the Bx score can be so different from the final pathology. At Bx a particular core may have a predominance of a 5, but that may just be a small part of the whole tumour.
Posted 7/2/2014 5:04 AM (GMT 0)
Chask- You are right that anything below 5% is too low to be put in the Gleason score. What you have is called a "tertiary 5." Some studies have found that tertiary 5s bump up your risk level, so a 4+3+5 is sometimes interpreted as a risk somewhere close to a GS9. But again, there is no research to support 2 years of ADT for it. Also, high dose of radiation can probably substitute for longer adjuvant ADT. But all this is a matter of judgment.

Gleason pattern 5 is the strongest pathologic predictor of recurrence, metastasis, and prostate cancer–specific death in patients receiving salvage radiation therapy following radical prostatectomy

- Allen
Posted 7/2/2014 5:40 AM (GMT 0)
David,

I think it's great that you're starting on penile rehab now. It certainly can't hurt.

I'm glad to see you got 70 Gy of SRT - a lot of guys don't get enough. 15% risk of nodal involvement (by the Roach formula) is usually set as the lower limit for whole pelvis radiation. Neoadjuvant ADT seems to help with that, but adjuvant ADT does not.

The CHAARTED study is irrelevant to your case - it deals with the setting of metastases only. Perhaps what Dr. Scholz is referring to is RTOG 0621. It included men, unlike yourself, who had a GS≥7 and a PSA nadir after RP of >.2, and men who has GS≥8 and PSA nadir<.2 and ≥pT3 -- so all the men in that study were at higher risk than you. They gave them docetaxel+ADT along with their SRT and 3-yr freedom from progression was 71%. There were some significant morbidities. My guess is that the nomogram is already showing higher predicted freedom from progression for your case.

Adjuvant radiation, androgen deprivation, and docetaxel for high-risk prostate cancer post-prostatectomy: Results of RTOG 0621.

Since I think that it's questionable whether the research justifies even 4 months of adjuvant ADT in your case, I certainly don't see any justification there for wanting even longer ADT. Docetaxel seems like way overkill to my layman's eyes. However, it's not all about the numbers. You have to feel comfortable with and live with your decision.
Posted 7/3/2014 6:14 AM (GMT 0)
Thanks Allen

You are certainly well informed! Thanks for the additional link. I will check that out.

The roach formula puts me at about 13% odds of nodal involvement, that's why I'm on the borderline between irradiating nodes and not irradiating nodes. I was advised to radiate the nodes in my case. The explanation was that for a relatively young guy (59 years) in otherwise good health the incremental morbidity of whole pelvic vs. fossa-only is very small but the incremental likelihood of lasting remission is significant. Although mathematically, the nomogram gives me about 70-80% odds of 6 years without biochemical recurrence.

Where did you see the distinction between neoadjuvant and adjuvant ADT with SRT? In my case what has been recommended to me is a bit of both: start ADT, then after 2 months of ADT begin 7 weeks / 35 days of SRT. and continue with the ADT through the radiation. So it is really two months of neoadjuvant ADT and then nearly 2 months of adjuvant ADT for a total of 4 months.
Posted 7/3/2014 1:02 PM (GMT 0)

Tall Allen said...

...

Yet there does seem to be a qualitative difference between GS3+4 and GS4+3, the former known as "favorable intermediate risk" and the latter known as "unfavorable intermediate risk." I know that Epstein at Johns Hopkins believes they should be used as separate categories for risk assessment purposes, rather than lumped together as GS7. It seems to have other clinical consequences in addition to sensitivity to ADT; e.g., LDR brachy monotherapy may be fine for GS3+4, but combo with EBRT may be required for GS4+3.

..
- Allen

I hapened to be reading the Johns Hopkins Summer 2014 Prostate Dsorders update and can piggy back on what Tall Allen alluded to:

Epstein suggests Prognostic Groups:

Prognostic Groups I: Gleason score 2-6
Prognostic Groups II - Gleason 7 (3+4)
Prognostic Groups III - Gleason 7(4+3)
Prognostic Groups IV - Gleason 8
Prognostic Groups V - Gleason 9-10

which in effect gives less weight to Gleason 6 and points toward viability of AS when lumped in with non cancer Gleason scores

and more weight to subject at heand Gleason 7 (4+3) being much higher risk due to prevelance of "4"

than Gleason 7 (3+4) where the "4" in in minority - anywhere between 5% and 49% as pointed out above.

LupronJim
Posted 7/3/2014 5:13 PM (GMT 0)
David,

When I said "Neoadjuvant ADT seems to help with that [whole pelvis radiation], but adjuvant ADT does not," I was referring to a study done by Roach himself. He looked at 4 different cases among high risk men with Roach scores>15% undergoing initial radiation treatment (not salvage).

1. neoadjuvant/concurrent hormone therapy (NHT) with whole pelvis RT (WPRT): WPRT+NHT
2. NHT with Prostate-only RT (PORT): PORT+NHT
3. adjuvant hormone therapy for 4 months starting after RT (AHT) with WPRT: WPRT+AHT
4. AHT with PORT: PORT+AHT

What he found surprised him. "there is an effect of hormone therapy timing in that both end points of progression free survival as well as overall survival trend toward statistical significance in favor of WPRT + NHT over WPRT + AHT... Another clear observation is that WPRT + AHT is the least desirable option with regards to overall survival."

He tries to explain it:

Roach said...
So why would WPRT appear to be beneficial when hormone therapy is given neoadjuvantly and concurrently as in Arm 1, yet detrimental to survival when hormones are given adjuvantly? And why don’t we see that interaction in the PORT arms (Arms 2 & 4)?

One possible explanation for the benefit of WPRT + NHT over WPRT + AHT may lie in the immune modulation of anti-androgen therapy. Mercader et al have shown that anti-androgen ablation therapy results in T-cell infiltration of the prostate which increases apoptosis. This peaks at about 3–4 weeks into treatment with hormone therapy. It may be possible that T-cell infiltration occurs within the involved lymph nodes, such that there is an increase in apoptosis preradiation therapy and during radiation therapy which may make the radiation therapy more effective at the doses used to treat the lymph nodes. Since we do not see a statistical difference in PORT + NHT vs. PORT + AHT the above phenomena may be dose dependent, such that the doses of 70 Gy are high enough that we cannot see the effects. Other authors have noted a beneficial effect of intratumoral T-cells in other malignancies such as ovarian carcinoma.

Given that there is no question that there is an interaction between timing of hormone therapy and radiation therapy field size in this patient population, one is left with the question of how best to treat these patients. Based on this analysis and the randomized trials to date which show a benefit to radiation therapy and hormone therapy in this patient population, it is clear that NHT+WPRT remains the standard of care. Further follow up will help elucidate this stance with regards to cause specific and overall survival.

He brings up two very important points, imho: (1) that radiation dose and HT are to some extent interchangeable, and (2) there is an abscopal effect caused by immune system activation that is augmented by the combination of RT with neoadjuvant/concurrent HT.

So it seems that HT confers its greatest benefit during the neoadjuvant/concurrent treatment, even in high-risk men.

You can read his full study at the following link:

An Update of the Phase III Trial Comparing Whole-Pelvic (WP) to Prostate Only (PO) Radiotherapy and Neoadjuvant to Adjuvant Total Androgen Suppression (TAS): Updated Analysis of RTOG 94-13, with Emphasis on Unexpected Hormone/Radiation Interactions

- Allen
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