Prostate Cancer Genomics (e.g. DECIPHER)

[Gfunk6]

I am increasingly seeing prostate cancer patients who had have these tests performed. They are, at times, incongruent with the Gleason Score, PSA, and ultrasound/MRI/DRE results. In those cases, is there any good evidence to escalate treatment?

For instance, if I have a patient who has favorable intermediate risk prostate cancer who would otherwise receive brachytherapy/SBRT is there justification to dose escalate with brachy + IMRT + ADT?

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[scarbrtj]

"...not ready for clinical use."

 

[BobbyHeenan]

"...not ready for clinical use."

Like this paper, everything I've read/heard both in print or in off-the-record conversation with the prostate gurus suggest these aren't ready for prime time routine clinical use yet.

There is a really good article this month in red journal regarding an evidence based approach for ADT with XRT in the post prostatectomy setting. This type of approach (table 3 is great) using a combo of PSA and gleason score is generally what I've been using to guide rec's rather than a decipher test....

https://www.redjournal.org/article/S0360-3016(18)31032-0/fulltext?dgcid=raven_jbs_etoc_email

 

[BobbyHeenan]

I am increasingly seeing prostate cancer patients who had have these tests performed. They are, at times, incongruent with the Gleason Score, PSA, and ultrasound/MRI/DRE results. In those cases, is there any good evidence to escalate treatment?

For instance, if I have a patient who has favorable intermediate risk prostate cancer who would otherwise receive brachytherapy/SBRT is there justification to dose escalate with brachy + IMRT + ADT?

My previous post was in regards to post-prostatectomy decipher...but in this setting you're talking about there is a lot of good debate about if dose escalation with brachy is worth it anyway - hotly debated in JCO....

http://ascopubs.org/doi/abs/10.1200/JCO.2018.78.6236

There has never been shown in a randomized trial to be a survival or distant mets benefit to brachy boost, but more people are pushing for this in spite of this lack of survival or distant met or prostate specific mortality benefit and at the cost of increasing side effects.

I think the debate is fascinating and I struggle with this in my patients. If they are "borderline" candidates for brachy (ie large-ish prostate, AUA symptoms score >10) I've really not been pushing it.

Aside - I swear I'm not Dr. Spratt - but I have found these articles compelling.

 

[evilbooyaa]

The Spratt editorial cited above was quite soundly responded to by his (former) mentor, Zelefsky.

http://ascopubs.org/doi/full/10.1200/JCO.18.00626#affiliationsContainer

My favorite lines:
"Of note, Dr Spratt is a principal investigator of NRG-GU006, in which BFS is the primary end point."

"We agree with a recent statement by Spratt et al14 published elsewhere that contrasts with the commentary's perspective; for appropriate high-risk patients, we should “strongly consider the addition of brachytherapy [to EBRT] as the gold standard treatment approach.” Furthermore, we concur with his initial conclusion concerning ASCENDE-RT that “although follow-up is short, it is highly plausible that comparable benefits will be seen in DM [distant metastasis] and OS as this trial matures.”"

"Thus, in contrast to the critique offered by Spratt and Carroll,6 the American Brachytherapy Society and the American Radium Society Appropriate Use Criteria Genitourinary Committee endorse the ASCO/CCO guidelines pertaining to the utility of brachytherapy combined with EBRT"

Always funny when somebody publishes that both sides of an argument are correct, depending on their mood that day.

 

[Chartreuse Wombat]

I am increasingly seeing prostate cancer patients who had have these tests performed. They are, at times, incongruent with the Gleason Score, PSA, and ultrasound/MRI/DRE results. In those cases, is there any good evidence to escalate treatment?

For instance, if I have a patient who has favorable intermediate risk prostate cancer who would otherwise receive brachytherapy/SBRT is there justification to dose escalate with brachy + IMRT + ADT?

All of the evidence (which is largely retrospective with small number of patients and few events) supports that these tests are prognostic but not predictive (at least to date). In other words, none of them have been prospectively validated to be able to determine therapy. I see patients like you describe all of the time (meaning 3-4 times a month). My answer is that we don't know whether we should intensify therapy based on one of these tests. The prospective studies are ongoing in multiple clinical contexts. The NCCN says to "consider molecular testing if low risk or favorable intermediate risk" which is a soft endorsement. UpToDate is more circumspect.

Disclosure: I have no COI with any vendor selling/developing these tests.

 

[medgator]

Some of the reps in our area have been pushing it hard, esp in the post op setting, stating that it is validated and Medicare payable. Have not seen many GUs ordering it however

 

[RickyScott]

The Spratt editorial cited above was quite soundly responded to by his (former) mentor, Zelefsky.

http://ascopubs.org/doi/full/10.1200/JCO.18.00626#affiliationsContainer

My favorite lines:
"Of note, Dr Spratt is a principal investigator of NRG-GU006, in which BFS is the primary end point."

"We agree with a recent statement by Spratt et al14 published elsewhere that contrasts with the commentary's perspective; for appropriate high-risk patients, we should “strongly consider the addition of brachytherapy [to EBRT] as the gold standard treatment approach.” Furthermore, we concur with his initial conclusion concerning ASCENDE-RT that “although follow-up is short, it is highly plausible that comparable benefits will be seen in DM [distant metastasis] and OS as this trial matures.”"

"Thus, in contrast to the critique offered by Spratt and Carroll,6 the American Brachytherapy Society and the American Radium Society Appropriate Use Criteria Genitourinary Committee endorse the ASCO/CCO guidelines pertaining to the utility of brachytherapy combined with EBRT"

Always funny when somebody publishes that both sides of an argument are correct, depending on their mood that day.

I find myself favoring Spratt. It is highly likely in the next few years, that we will see more data for the expanded use of adjuvant zytiga and other agents in the unfavorable localized setting. How are we going integrate brachy then? Fundamentally, I find treatment Intensification with a well tolerated systemic agent- that will also have local benefits- like zytiga is more compelling. Zelefsky's view is shaped by being good at brachy, while many of the other thought leaders in prostate cancer cant do implants very well. Its his schtick, but at the end of the day, it is the distant disease that gets you.

 

[evilbooyaa]

I find myself favoring Spratt. It is highly likely in the next few years, that we will see more data for the expanded use of adjuvant zytiga and other agents in the unfavorable localized setting. How are we going integrate brachy then? Fundamentally, I find treatment Intensification with a well tolerated systemic agent- that will also have local benefits- like zytiga is more compelling. Zelefsky's view is shaped by being good at brachy, while many of the other thought leaders in prostate cancer cant do implants very well. Its his schtick, but at the end of the day, it is the distant disease that gets you.

But if that's really the case, and rises in bPFS are being driven by metastatic disease (without a local component), wouldn't ASCENDE-RT have shown bPFS improvements in the EBRT arm, since that group got 2 years of ADT, as opposed to 1 year in the BT arm?

If you kill the local disease, you stop it from re-seeding distant mets when it recurs.

I think, why not both? I honestly think that local intensification is necessary - current studies doing SBRT vs BT boost will let us know if we can avoid BT.

 

[Chartreuse Wombat]

But if that's really the case, and rises in bPFS are being driven by metastatic disease (without a local component), wouldn't ASCENDE-RT have shown bPFS improvements in the EBRT arm, since that group got 2 years of ADT, as opposed to 1 year in the BT arm?

If you kill the local disease, you stop it from re-seeding distant mets when it recurs.

I think, why not both? I honestly think that local intensification is necessary - current studies doing SBRT vs BT boost will let us know if we can avoid BT.

The duration of ADT was the same in both arms of ASCENDE-RT. The only difference was brachy as boost versus continued external as boost. The paper has been criticized because the duration of ADT is only 1 year and 70% of patients were high risk. Remember this trial did not attempt to answer a question about ADT so that is a weak criticism in my view. The trial suggests that brachy delivers a higher biologic dose with an increase in morbidity. The problem is that the trial is unlikely to ever show a survival difference with less than 400 patients.

 

[medgator]

But if that's really the case, and rises in bPFS are being driven by metastatic disease (without a local component), wouldn't ASCENDE-RT have shown bPFS improvements in the EBRT arm, since that group got 2 years of ADT, as opposed to 1 year in the BT arm?

If you kill the local disease, you stop it from re-seeding distant mets when it recurs.

I think, why not both? I honestly think that local intensification is necessary - current studies doing SBRT vs BT boost will let us know if we can avoid BT.

At least our specialty is trying to answer these questions. There are some urologists that believe RP helps "debulk" pCa, esp in high risk disease... with no data of course.

And as long as they are the diagnosing physicians, they will remain in the drivers seat for the management of pCa outside of academic centers.

 

[nkmiami]

But if that's really the case, and rises in bPFS are being driven by metastatic disease (without a local component), wouldn't ASCENDE-RT have shown bPFS improvements in the EBRT arm, since that group got 2 years of ADT, as opposed to 1 year in the BT arm?

If you kill the local disease, you stop it from re-seeding distant mets when it recurs.

I think, why not both? I honestly think that local intensification is necessary - current studies doing SBRT vs BT boost will let us know if we can avoid BT.

I did not read the ASCEND trial, but is it possible that the brachy just knocks the PSA down lower, and longer by killing more psa producing normal prostate tissue, so that local failures just take longer to register (masked) with nadir + 2 definition? The time frame from local to distant disease to death in prostate cancer is so long, (and getting even longer with the newer agents: NEJM - Error),

 

[BobbyHeenan]

I think the brachy boost debate is really compelling and good points on all sides.

I think the lack of OS benefit is something to consider and should not be taken lightly, but one point of contention I have with the Spratt points is when he talks about salvage brachy. In my area even the academic centers within driving distance are not really doing much of this that I am aware of. I am certainly not comfortable in my practice doing this and with my patient population no way they can get to MSKCC to have their brachy salvage....so I think for us simpletons out here in private practice in God's country, relying on salvage brachy just isn't a feasible option right now.

 

[OTN]

You can do salvage SBRT for prostate cancer if you don't have the ability to do brachy. Some decent data suggesting it's tolerated better than I would have assumed. I've done it once and (fingers crossed) so far so good.

 

[evilbooyaa]

The duration of ADT was the same in both arms of ASCENDE-RT. The only difference was brachy as boost versus continued external as boost. The paper has been criticized because the duration of ADT is only 1 year and 70% of patients were high risk. Remember this trial did not attempt to answer a question about ADT so that is a weak criticism in my view. The trial suggests that brachy delivers a higher biologic dose with an increase in morbidity. The problem is that the trial is unlikely to ever show a survival difference with less than 400 patients.

Ah, you're right. I was mistaken. Was thinking about the JAMA analysis from Kishan, where median ADT in the EBRT arm was 2 years while it was 1 year in BT boost.

 

[Palex80]

Recurrence free survival or freedom from PSA progression is not a strong enough argument for me to go for a potentially more toxic treatment. ADT has a proven OS benefit in subsets of patients when used together with RT, the data of HDR brachy are less convincing.

 

[nkmiami]

for gleason 8s/high risk in protecT and pivot trials, radiation/surgery did not provide an overall survival benefit at 10 years vs watchful waiting; so how can you expect radiation dose intensification to provide a survival benefit, especially with all the new hormonal agents that are stretching out the course of disease.

 

[Palex80]

for gleason 8s/high risk in protecT and pivot trials, radiation/surgery did not provide an overall survival benefit at 10 years vs watchful waiting; so how can you expect radiation dose intensification to provide a survival benefit, especially with all the new hormonal agents that are stretching out the course of disease.

There were hardly any Gleason 8 tumors in those trials. If I recall correctly, almost 80% of the patients in PROTECT had a GS6 tumor.

 

[Chartreuse Wombat]

for gleason 8s/high risk in protecT and pivot trials, radiation/surgery did not provide an overall survival benefit at 10 years vs watchful waiting; so how can you expect radiation dose intensification to provide a survival benefit, especially with all the new hormonal agents that are stretching out the course of disease.

Both of these studies were woefully underpowered. In ProTecT 2% of patients had Gleason 8 or higher (about 40 total distributed over three arms). The best evidence for dose escalation is the NCIC and Swedish studies that compare ADT to ADT + XRT and found an OS benefit for the addition of XRT. So 70 Gy is better an 0 Gy.

 

[nkmiami]

Both of these studies were woefully underpowered. In ProTecT 2% of patients had Gleason 8 or higher (about 40 total distributed over three arms). The best evidence for dose escalation is the NCIC and Swedish studies that compare ADT to ADT + XRT and found an OS benefit for the addition of XRT. So 70 Gy is better an 0 Gy.

point well taken. Still in swedish trial, with nearly 1000 pts, if 70 Gy + hormones vs 0 Gy + hormones provides 10% os benefit at 10 years, how much of a survival gain can we realistically expect from imrt/igrt 80Gy + hormones vs external/brachy + hormones. Whatever small delta that is, I also agree, will likely be more than offset by adding one of the newer hormonal agents.

 

[Chartreuse Wombat]

I agree on that point. Just wanted to point out that locoregional treatment (even though only 70 Gy) does change the natural history. Despite the authors of ASCENDE-RT belief that the difference in biochemical recurrence will lead to survival differences, I am very skeptical. First with <400 patients there is limited power for a survival endpoint. Second, RTOG 0126 with 1500 patients and a similar difference in biochemical recurrence favoring the high dose arm demonstrated no survival advantage (although distant metastases were decreased). Given competing co-morbidities in the prostate cancer population it will be very difficult to show survival benefits beyond 70Gy + ADT. I am hoping that more potent androgen suppression will allow for shorter courses of LHRH without a change in efficacy. The problem is that a non-inferioirty study of this sort would have to be very large and no one is interested in funding that study.

 

[Palex80]

. I am hoping that more potent androgen suppression will allow for shorter courses of LHRH without a change in efficacy. The problem is that a non-inferioirty study of this sort would have to be very large and no one is interested in funding that study.

Astellas?

They made more than 2 billion dollars with Enzalutamide in 2016.
https://www.astellas.com/en/ir/ar2017/pdf/2017AR_43_en.pdf

 

[MegaVoltagePhoton]

point well taken. Still in swedish trial, with nearly 1000 pts, if 70 Gy + hormones vs 0 Gy + hormones provides 10% os benefit at 10 years, how much of a survival gain can we realistically expect from imrt/igrt 80Gy + hormones vs external/brachy + hormones. Whatever small delta that is, I also agree, will likely be more than offset by adding one of the newer hormonal agents.

What is the overall survival advantage of 36 months hormonal therapy vs 18 months? of 36 months vs 6 months?

Also, if you want to be a stickler, point out the OS benefit for adding Zytiga upfront in patients with nonmetastatic disease, and also point out the inclusion criteria for nonmetastatic patients being enrolled on Stampede to begin with (closer to very high risk than just high risk).

So, there's a lot of cognitive dissonance here with promoting advanced ADT (which is costly and not benign either). If you're against brachy boost because of just a PFS benefit, then you can't simultaneously be for Zytiga upfront in run of the mill high risk

 

[nkmiami]

What is the overall survival advantage of 36 months hormonal therapy vs 18 months? of 36 months vs 6 months?

Also, if you want to be a stickler, point out the OS benefit for adding Zytiga upfront in patients with nonmetastatic disease, and also point out the inclusion criteria for nonmetastatic patients being enrolled on Stampede to begin with (closer to very high risk than just high risk).

So, there's a lot of cognitive dissonance here with promoting advanced ADT (which is costly and not benign either). If you're against brachy boost because of just a PFS benefit, then you can't simultaneously be for Zytiga upfront in run of the mill high risk

Those are all good points. Its just my overall bias that intensification should come from systemic component once you have delivered 80 Gy to a tumor (and sometimes more if you are giving a few percent extra to mri disease).

 

[cpants]

Where I have seen utility is in patients with adverse pathologic features on RP in helping to make the decision between adjuvant XRT or early salvage strategy. For example, post RP you have a patient with Gleason 3+4 and SVI/EPE, negative margins, with undectable postop PSA. There is good data for adjuvant radiation in this situation, but significant possible morbidity and the trials are all from before the supersensitive PSA assays were available. Does it really make a difference if you hold off on radiation until the patient's PSA is 0.05? This is a current area of controversy/research.

 

[medgator]

Where I have seen utility is in patients with adverse pathologic features on RP in helping to make the decision between adjuvant XRT or early salvage strategy. For example, post RP you have a patient with Gleason 3+4 and SVI/EPE, negative margins, with undectable postop PSA. There is good data for adjuvant radiation in this situation, but significant possible morbidity and the trials are all from before the supersensitive PSA assays were available. Does it really make a difference if you hold off on radiation until the patient's PSA is 0.05? This is a current area of controversy/research.

Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer

 

[cpants]

Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer

Did you post this implying this settles the question? It doesn't. The study is interesting, but it's a cohort study with several significant design limitations and likely significant selection bias favoring ART.

First of all, to be valid, they needed to compare a cohort of men managed with initial observation and planned ESRT for biochemical recurrence to a cohort of men managed with ART. Many of the men were likely cured with surgery alone in the ART column, but NONE of the men in the ESRT cohort were cured by surgery alone by definition. Obviously, it's a cohort with worse disease regardless of their propensity matching. They unsuccessfully try to address this severe limitation in the discussion.

Presumably, many/most of the deaths in this time frame were non-cancer related. They did not consider comorbidities in their propensity matching. Again, big problem.

86% of the cohort had positive margin status. We know from EROTC, ARO, SWOG trials that the R1 subgroup benefits most from ART, so for that reason alone their conclusions may not be able to be generalized to the general population with adverse path.

Anyway, like I said, it's an area of active research. Several RCT's are currently looking at this question.

 

[evilbooyaa]

Did you post this implying this settles the question? It doesn't. The study is interesting, but it's a cohort study with several significant design limitations and likely significant selection bias favoring ART.

First of all, to be valid, they needed to compare a cohort of men managed with initial observation and planned ESRT for biochemical recurrence to a cohort of men managed with ART. Many of the men were likely cured with surgery alone in the ART column, but NONE of the men in the ESRT cohort were cured by surgery alone by definition. Obviously, it's a cohort with worse disease regardless of their propensity matching. They unsuccessfully try to address this severe limitation in the discussion.

Presumably, many/most of the deaths in this time frame were non-cancer related. They did not consider comorbidities in their propensity matching. Again, big problem.

86% of the cohort had positive margin status. We know from EROTC, ARO, SWOG trials that the R1 subgroup benefits most from ART, so for that reason alone their conclusions may not be able to be generalized to the general population with adverse path.

Anyway, like I said, it's an area of active research. Several RCT's are currently looking at this question.

Agree with everything you said. Adjuvant vs early salvage is TBD pending RCT results. While we currently have more data in favor aRT, but nothing overtly wrong with pursuing one over the other, IMO.

 

[scarbrtj]

This is a current area of controversy/research.

Not to sound like a simpleton, but in a way to research this further is dumb. First, I know of no oncological scenario wherein it's been shown that patients at risk of recurrence had any oncological benefit to delaying therapy versus early initiation of recurrence-preventing therapy. None. Second, in addition to what medgator said above, the preponderance of the data supports ART vs salvage. (Questions are rarely really settled, are they.) So what would I do with a non-confirmatory RCT, or two, in the future? Ignore it. I'd continue offering ART vs wait on a detectable PSA. The incidence of recurrence with "adverse path" and R0 hints that not nearly as many folks are truly R0 as we think with adverse path. Re: "significant possible morbidity," I just don't see that as a major deterrent; I'd call it a low-risk morbidity or something or other.

 

[evilbooyaa]

Not to sound like a simpleton, but in a way to research this further is dumb. First, I know of no oncological scenario wherein it's been shown that patients at risk of recurrence had any oncological benefit to delaying therapy versus early initiation of recurrence-preventing therapy. None. Second, in addition to what medgator said above, the preponderance of the data supports ART vs salvage. (Questions are rarely really settled, are they.) So what would I do with a non-confirmatory RCT, or two, in the future? Ignore it. I'd continue offering ART vs wait on a detectable PSA. The incidence of recurrence with "adverse path" and R0 hints that not nearly as many folks are truly R0 as we think with adverse path. Re: "significant possible morbidity," I just don't see that as a major deterrent; I'd call it a low-risk morbidity or something or other.

While there isn't a benefit per se, not all 'delays' in therapy lead to worse oncologic outcome, surveillance in stage I seminoma begs to differ.

What cpants is saying is that they're looking at people who required salvage RT. What percentage of people got surgery, had those high-risk factors, were observed, and never recurred? Rememeber that even in the adjuvant trials, 50% of high-risk patients randomized to obs didn't develop biochemical recurrence. The retrospective review is looking at the 50% of people in that group who did recur. Versus 100% of the people who got adjuvant. Not to say it's a crap study, but you can't replace RCTs with retrospective studies.

If there was a non-inferiority trial comparing the two (I haven't looked up all the details for the ongoing ones) that said early salvage was non-inferior to adjuvant (especially across all subgroups - to me there's a hypothetical difference between SVI, ECE, +SM, and +pN in terms of potential difference between adjuvant and early salvage), then I would discuss that with patients.

This is like the Japanese ES-SCLC PCI trial - is there a difference between 'adjuvant' (PCI after first-line chemo) and 'early salvage' (regular ongoing surveillance and treat at first sign of progression)?
This is like rectal cancer watch and wait - is there a difference, in patients who get 'definitive' chemoRT and a cCR, between 'adjuvant' surgery or 'early salvage' surgery?
This is like the Mahajan SRS vs obs trial in post-op brain tumors - there's no difference in survival between patients treated adjuvantly (post-op) and early salvage (observed, regular MRIs, treat at recurrence). Both are reasonable options.

 

[scarbrtj]

While there isn't a benefit per se, not all 'delays' in therapy lead to worse oncologic outcome, surveillance in stage I seminoma begs to differ.

Of course. Yet the data has shown with some pretty convincing statistically sign. advantages (p<0.001 etc etc) to ART vs salvage. Not one trial, seminoma included, has shown recurrence, OS, etc. advantage to salvage vs ART. (Cancer advantage... toxicity advantages are another story.) Non-inferior, sure; benefit, no.

If there was a non-inferiority trial comparing the two (I haven't looked up all the details for the ongoing ones)

I'm skeptical (and too lazy to Google) there's a true non-inferiority trial looking at this. 'Cause the trial would have to be designed/phrased such that "A difference of 5% [my arbitrary number] or more in PFS does not exist ART vs salvage," and such a hypothesis--that salvage is non-inferior to ART--would run quite counter to the prevailing data and previous trials. EDIT: I don't think this particular situation is quite as similar to PCI, rectal, brain mets 'cause the statistical signal from the ART vs salvage trials for PFS has been very, very strong.

 

[cpants]

Not to sound like a simpleton, but in a way to research this further is dumb. First, I know of no oncological scenario wherein it's been shown that patients at risk of recurrence had any oncological benefit to delaying therapy versus early initiation of recurrence-preventing therapy. None. Second, in addition to what medgator said above, the preponderance of the data supports ART vs salvage. (Questions are rarely really settled, are they.) So what would I do with a non-confirmatory RCT, or two, in the future? Ignore it. I'd continue offering ART vs wait on a detectable PSA. The incidence of recurrence with "adverse path" and R0 hints that not nearly as many folks are truly R0 as we think with adverse path. Re: "significant possible morbidity," I just don't see that as a major deterrent; I'd call it a low-risk morbidity or something or other.

Well, I agree with you that there is likely no oncological benefit to delaying therapy, there are significant non-oncological benefits to delaying (or avoiding altogether) radiation in these patients. Despite your making light of the morbidity associated with ART, it is substantial. I would call double the rates of GU/GI toxicity, BNC/urethral stricture, and incontinence a big deal. Talk to some patients with bladder neck contractures, the majority of whom are miserable and incontinent and require multiple procedures just to avoid retention.

I'm aware of the data supporting the use of ART for high risk pathological features. You will notice that in my post I referred to the 3 RCT's included in the meta-analysis you posted, and I have read all 3. It is not controversial that ART is beneficial to patients with adverse pathological features (R1, T3). If early salvage with supersensitive PSA (not available at time of above trials) produces similar oncologic outcomes, there would be significant quality of life gains for the patients and avoidance of unnecessary treatment in the substantial portion of men that are cured by RP alone. Hence, the controversy and the research interest in this question.

There are some parallels here to the early days of active surveillance which was extremely controversial.

 

[nkmiami]

Well, I agree with you that there is likely no oncological benefit to delaying therapy, there are significant non-oncological benefits to delaying (or avoiding altogether) radiation in these patients. Despite your making light of the morbidity associated with ART, it is substantial. I would call double the rates of GU/GI toxicity, BNC/urethral stricture, and incontinence a big deal. Talk to some patients with bladder neck contractures, the majority of whom are miserable and incontinent and require multiple procedures just to avoid retention.

I'm aware of the data supporting the use of ART for high risk pathological features. You will notice that in my post I referred to the 3 RCT's included in the meta-analysis you posted, and I have read all 3. It is not controversial that ART is beneficial to patients with adverse pathological features (R1, T3). If early salvage with supersensitive PSA (not available at time of above trials) produces similar oncologic outcomes, there would be significant quality of life gains for the patients and avoidance of unnecessary treatment in the substantial portion of men that are cured by RP alone. Hence, the controversy and the research interest in this question.

There are some parallels here to the early days of active surveillance which was extremely controversial.

I havent really seen urethral stricture, bladder neck contracture or incontinence developing after adjuvant xrt, but I am sure it worsens ED. I thought on the swog and eurpopean trials that there was no real difference in long term toxicity and they had large fields without ct planning and no imrt. Anyway, I am not sure all T3a and positive margin need adjuvant (unless G8/9), but I think every T3b needs adjuvant xrt.

 

[scarbrtj]

Despite your making light of the morbidity associated with ART, it is substantial. I would call double the rates of GU/GI toxicity, BNC/urethral stricture, and incontinence a big deal. Talk to some patients with bladder neck contractures, the majority of whom are miserable and incontinent and require multiple procedures just to avoid retention. I'm aware of the data supporting the use of ART for high risk pathological features. You will notice that in my post I referred to the 3 RCT's included in the meta-analysis you posted, and I have read all 3. If early salvage with supersensitive PSA (not available at time of above trials) produces similar oncologic outcomes, there would be significant quality of life gains for the patients and avoidance of unnecessary treatment in the substantial portion of men that are cured by RP alone. Hence, the controversy and the research interest in this question.

Dang, well I read the papers too and didn't see one mention of the word "incontinence" in any of the papers. Think how tricky, and/or unfair, it would be to attribute incontinence to XRT in a guy who got XRT after a prostatectomy. These very high-grade toxicities you mention were unmentioned in the 3 RCTs; we can certainly assume these risks are <1% so it makes sense that I have never seen them in any patient I've treated (maybe that's part of my problem!). So the QOL gains of avoiding XRT wouldn't be 1) significant and 2) would have to be weighed against the potential QOL loss (ie CaP recurrence).

I started looking for active trials on the issue and couldn't find any. Would like to know if they do exist now; I think their main drawback and/or reason we will never get an answer to the dilemma you pose (wait on a PSA >0.000 after surgery, or treat?) will be what Swanson (SWOG) and friends said back in 2009:

"This study points out two challenges for the academic and clinical trials community. The first is that important therapeutic advances in the management of localized prostate cancer require large numbers of patients and just as importantly prolonged follow-up. The hundreds of publications involving case series of patients treated with and without radiotherapy could not accurately compare outcomes of treatment due to inherent selection biases and unmeasured disease and patient-related variables. In the absence of initiating and completing these randomized studies, optimal patient care cannot be attained. To that end, the second challenge will be to build upon the observations of this study. One suggestion would be to randomize patients with T3N0M0 prostate cancer to either adjuvant radiotherapy or to salvage radiotherapy as soon as an ultrasensitive PSA is positive. We have examined possible study designs such as this and have found that to test whether delayed radiotherapy is not inferior to immediate radiotherapy (defined as a metastasis-free survival hazard ratio of delayed/immediate of ≤ 1.10) and using rates of failure as seen in this study, a two-sided alpha of 0.05 and a power of 90%, and an accrual over 8 years with 9 additional years of follow-up would require a sample size of 8300. With the poor track record of accrual of patients with localized prostate cancer to clinical trials in the US, unless there is a fundamental change in the structure of clinical trials, it is unlikely that such a trial will be started or completed."

 

[cpants]

Dang, well I read the papers too and didn't see one mention of the word "incontinence" in any of the papers. Think how tricky, and/or unfair, it would be to attribute incontinence to XRT in a guy who got XRT after a prostatectomy. These very high-grade toxicities you mention were unmentioned in the 3 RCTs; we can certainly assume these risks are <1% so it makes sense that I have never seen them in any patient I've treated (maybe that's part of my problem!). So the QOL gains of avoiding XRT wouldn't be 1) significant and 2) would have to be weighed against the potential QOL loss (ie CaP recurrence).

I started looking for active trials on the issue and couldn't find any. Would like to know if they do exist now; I think their main drawback and/or reason we will never get an answer to the dilemma you pose (wait on a PSA >0.000 after surgery, or treat?) will be what Swanson (SWOG) and friends said back in 2009:

"This study points out two challenges for the academic and clinical trials community. The first is that important therapeutic advances in the management of localized prostate cancer require large numbers of patients and just as importantly prolonged follow-up. The hundreds of publications involving case series of patients treated with and without radiotherapy could not accurately compare outcomes of treatment due to inherent selection biases and unmeasured disease and patient-related variables. In the absence of initiating and completing these randomized studies, optimal patient care cannot be attained. To that end, the second challenge will be to build upon the observations of this study. One suggestion would be to randomize patients with T3N0M0 prostate cancer to either adjuvant radiotherapy or to salvage radiotherapy as soon as an ultrasensitive PSA is positive. We have examined possible study designs such as this and have found that to test whether delayed radiotherapy is not inferior to immediate radiotherapy (defined as a metastasis-free survival hazard ratio of delayed/immediate of ≤ 1.10) and using rates of failure as seen in this study, a two-sided alpha of 0.05 and a power of 90%, and an accrual over 8 years with 9 additional years of follow-up would require a sample size of 8300. With the poor track record of accrual of patients with localized prostate cancer to clinical trials in the US, unless there is a fundamental change in the structure of clinical trials, it is unlikely that such a trial will be started or completed."

I don't have time to go pull the toxicity data from the 3 RCT's right now, but to prove I'm not making it up please see below quote from the meta-analysis of the trials that YOU POSTED above.

With ART compared with WS, there was significantly increased toxicity of any grade (50% vs. 38.6%), grade 2 or greater GU toxicity (17.1% vs. 10.3%), grade 2 or greater GI toxicity (2.5% vs. 1.1%), urinary stricture rates (11.1% vs. 5.7%) and, urinary incontinence (6.9% vs. 2.7%).

No one is trying to blame the incontinence on XRT, but it's pretty logical that there will be worse toxicity from patients who have multimodal treatment, and that is also reflected in the data. As much as I respect your anecdotal evidence that you've never seen these complications, I'm going to go with my own experience and the literature. If you haven't seen strictures and incontinence in patients that you've treated, you probably aren't treating very many patients or following them up for very long after treatment. Many rad oncs have an observer bias with regard to complications because they don't necessary follow the patients over years. These toxicities can evolve over several years or longer.

Two randomized controlled trials are currently looking at this ART vs ESRT: RAVES and RADICALS. I guess you didn't look that hard.

 

[scarbrtj]

I don't have time to go pull the toxicity data from the 3 RCT's right now, but to prove I'm not making it up please see below quote from the meta-analysis of the trials that YOU POSTED above.



No one is trying to blame the incontinence on XRT, but it's pretty logical that there will be worse toxicity from patients who have multimodal treatment, and that is also reflected in the data. As much as I respect your anecdotal evidence that you've never seen these complications, I'm going to go with my own experience and the literature. If you haven't seen strictures and incontinence in patients that you've treated, you probably aren't treating very many patients or following them up for very long after treatment. Many rad oncs have an observer bias with regard to complications because they don't necessary follow the patients over years. These toxicities can evolve over several years or longer.

Two randomized controlled trials are currently looking at this ART vs ESRT: RAVES and RADICALS. I guess you didn't look that hard.

Ha, I didn't look hard but thank you. RADICALS looks worthwhile but RAVES seems worthless. Doesn't a urinary stricture rate of ~11% with postop RT sound totally out of bounds... If I knew one out of ten guys were going to get strictures and all that bother with postop RT, I'd never give it; but if you see that rate of course it's going to color one's thoughts. Another way to look at that data is one would have to treat 20 guys to give a single stricture (abs diff ~11% vs ~6% stricture, NNT about 1/0.05 = 20 therefore), arguably still quite high and yes as you say "doubles" the toxicity but you have to treat 20 men to give one a problem; yet the NNTs to avoid a progression with ART are a lot lower (as few as 3-5 men need to be treated to help one). If you look at the SWOG and German and EORTC studies, and "pull the toxicity data," nowhere does one get a sense of "gives pause" toxicity. The toxicity data is all over the place (and sans IMRT); the PFS benefits have been steady and more statistically significant (esp when looking at higher grade toxicities). At the end of the day, I won't say every but almost every time ART has been compared to salvage, ART is better. The toxicity talk seems to be the only mental barrier to accepting the ART vs salvage superiority premise, and it can be overwrought... in my experience. I will return to this thread in the mid to late 2020's when RADICALS comes out and recant if untrue. In the meantime I'll be over here following NCCN guidelines, treating all T3a/b's, etc.

 

[RickyScott]

Ha, I didn't look hard but thank you. RADICALS looks worthwhile but RAVES seems worthless. Doesn't a urinary stricture rate of ~11% with postop RT sound totally out of bounds... If I knew one out of ten guys were going to get strictures and all that bother with postop RT, I'd never give it; but if you see that rate of course it's going to color one's thoughts. Another way to look at that data is one would have to treat 20 guys to give a single stricture (abs diff ~11% vs ~6% stricture, NNT about 1/0.05 = 20 therefore), arguably still quite high and yes as you say "doubles" the toxicity but you have to treat 20 men to give one a problem; yet the NNTs to avoid a progression with ART are a lot lower (as few as 3-5 men need to be treated to help one). If you look at the SWOG and German and EORTC studies, and "pull the toxicity data," nowhere does one get a sense of "gives pause" toxicity. The toxicity data is all over the place (and sans IMRT); the PFS benefits have been steady and more statistically significant (esp when looking at higher grade toxicities). At the end of the day, I won't say every but almost every time ART has been compared to salvage, ART is better. The toxicity talk seems to be the only mental barrier to accepting the ART vs salvage superiority premise, and it can be overwrought... in my experience. I will return to this thread in the mid to late 2020's when RADICALS comes out and recant if untrue. In the meantime I'll be over here following NCCN guidelines, treating all T3a/b's, etc.

I treat at least 2 postop prostates a month and we follow them and I just havent seen a case in practice or training and that is hundreds of pts. I am too lazy to look up RTOG postop trials but I dont recall anythinh like this. The only toxicity that I think is underreported is cystitis, but I have always been anal about checking bladder is full on daily cone beams as sometimes these pts have limited bladder capacities.

 

[Krukenberg]

Ha, I didn't look hard but thank you. RADICALS looks worthwhile but RAVES seems worthless. Doesn't a urinary stricture rate of ~11% with postop RT sound totally out of bounds... If I knew one out of ten guys were going to get strictures and all that bother with postop RT, I'd never give it; but if you see that rate of course it's going to color one's thoughts. Another way to look at that data is one would have to treat 20 guys to give a single stricture (abs diff ~11% vs ~6% stricture, NNT about 1/0.05 = 20 therefore), arguably still quite high and yes as you say "doubles" the toxicity but you have to treat 20 men to give one a problem; yet the NNTs to avoid a progression with ART are a lot lower (as few as 3-5 men need to be treated to help one). If you look at the SWOG and German and EORTC studies, and "pull the toxicity data," nowhere does one get a sense of "gives pause" toxicity. The toxicity data is all over the place (and sans IMRT); the PFS benefits have been steady and more statistically significant (esp when looking at higher grade toxicities). At the end of the day, I won't say every but almost every time ART has been compared to salvage, ART is better. The toxicity talk seems to be the only mental barrier to accepting the ART vs salvage superiority premise, and it can be overwrought... in my experience. I will return to this thread in the mid to late 2020's when RADICALS comes out and recant if untrue. In the meantime I'll be over here following NCCN guidelines, treating all T3a/b's, etc.

RADICALS will answer all the major remaining questions in the post-op setting. It’s a factorial trial testing adjuvant vs early salvage as well as no adt vs short term adt vs longer adt. Will certainly be practice changing when it lands

 

[evilbooyaa]

As long as it meets accrual goals. Always tough to ask so many questions all at once - see RTOG 9403.

 

[Krukenberg]

As long as it meets accrual goals. Always tough to ask so many questions all at once - see RTOG 9403.

It’s a U.K./Canada trial so that alone tells you that it will accrue. RTOG would surely muck it up if they had tried.

 

[Chartreuse Wombat]

Verbatim from the RADICALS website

We are delighted to inform you that RADICALS closed to recruitment on 30th December 2016. The trial randomised 2840 patients to RADICALS-HD and 1396 patients to RADICALS-RT. This is a huge achievement and we would like to say thank you to all the patients who participated in the trial and the trial teams at our recruiting centres.

Congrats to the group but this may not be large enough to answer the questions asked. Now we wait.

 

[RO2019]

if people want to do adjuvant, then fine, go for it, but wish I understood what people think we are losing with an early salvage approach. With close PSA follow-up, you are going to treat the patients who need it, and not treat the patients who don't.


I would just encourage people not to put too much stock in that early salvage vs. adjuvant JAMA onc multi-institutional retrospective paper. You have to be dense not to expect that the salvage arm would do worse. these patients had worse biology by definition, because they were all people who failed, vs adjuvant which is made up of people who were going to fail as well as people whose biology was more favorable.

even the authors of that paper say its majorly flawed.

 

[scarbrtj]

but wish I understood what people think we are losing with an early salvage approach

Potentially, lost QOL by not offering the (relatively short-lived) toxicity of RT instead of the toxicity of more risk of recurrence, tx of recurrence, etc.

this may not be large enough to answer the questions asked.

True; SWOG, and math, say the N of something like RADICALS needed to be 8000+ patients to answer the question so the trial is more likely to show salvage inferiority or fail to find salvage non-inferiority.

 

[evilbooyaa]

Verbatim from the RADICALS website

We are delighted to inform you that RADICALS closed to recruitment on 30th December 2016. The trial randomised 2840 patients to RADICALS-HD and 1396 patients to RADICALS-RT. This is a huge achievement and we would like to say thank you to all the patients who participated in the trial and the trial teams at our recruiting centres.

Congrats to the group but this may not be large enough to answer the questions asked. Now we wait.

Agree with scarbrtj that it seems like an insufficient sample size, but depends on what their non-inferiority margin is I suppose. Look forward to the results for a definitive answer.