RT Better than RP For Very High Risk Disease?

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MegaVoltagePhoton

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New paper out in JAMA showing better survival with RT+BT, and same survival with RT vs RP, in Gleason 9: Disease Progression and Mortality in Gleason 9-10 Prostate Cancer After Definitive Treatment.

Very interesting to see the pendulum swing. There was also this JCO paper last week showing identical outcomes for RP vs RT+BT: http://ascopubs.org/doi/abs/10.1200...id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed

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Very interesting, thanks for sharing. Lots of HDR patients in this paper.
 
Plenty of equipoise now for a trial. Maybe it can be completed at the VA?
 
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Preoperative characteristics of high-Gleason disease predictive of favourable pathological and clinical outcomes at radical prostatectomy. - PubMed - NCBI

Am I reading this right? These guys- (who invented the prostatectomy)- seem to have 4% cure rate in the G9 group at 10 years?
Yes, which is why (if I am fortunate enough to see these men before the prostate is removed) I ask men what the surgeon has told them about the cure rate with RP alone. If they don't know I tell them it is <5%.
 
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Would love the opinions of our urologist colleague @DoctwoB on these findings.

Interesting study, definitely merits an RCT, and the data coming out of EBRT/Brachy/ADT studies has been impressive to date. Need to read it more closely, as only have access abstract when not at work. One thing that jumps out at me, however, is horrible BCR free survival and survival outcomes in the RP cohort. Most long term studies of high risk patients suggest that 50-80% will have a BCR depending on how high risk is defined.

For example the MSKCC normograms would give a patient with pathological Gleason 9 pT3aN0 patient a 30% 10 year BCR free survival and 9% PCSM risk at 15 years (this study found 12% at 5 years) Hell, even pN1 patients have a 10-15% rate of never having a BCR.

So I’m intrigued and need to read this more closely, but at first glance something seems fishy, at least in the RP cohort.
 
Interesting study, definitely merits an RCT, and the data coming out of EBRT/Brachy/ADT studies has been impressive to date. Need to read it more closely, as only have access abstract when not at work. One thing that jumps out at me, however, is horrible BCR free survival and survival outcomes in the RP cohort. Most long term studies of high risk patients suggest that 50-80% will have a BCR depending on how high risk is defined.

For example the MSKCC normograms would give a patient with pathological Gleason 9 pT3aN0 patient a 30% 10 year BCR free survival and 9% PCSM risk at 15 years (this study found 12% at 5 years) Hell, even pN1 patients have a 10-15% rate of never having a BCR.

So I’m intrigued and need to read this more closely, but at first glance something seems fishy, at least in the RP cohort.

Read the whole study, same concerns as above. Also a 40% positive surgical margin rate is pretty atrocious, even in high risk disease (10-15% in most series). Another issue that may have contributed to these poor outcomes is that only 40% of the RP patients saw radiation in the adjuvant or salvage setting (mostly salvage). There is a strong argument to be made for adjuvant xrt in all of these patients, and the fact that 56% of them had a BCR but never got XRT is just bad care. There is no way that those recurrences were mostly distant if their PSA was followed appropriately.

Finally it would really be good to see toxicity outcomes and QOL outcomes. One could see a situation where people with no baseline voiding issues are better off with XRT/Brachy, whole high baseline LUTs are better with RP. Also I’m concerned about the long term sequelae. I have 3 patients on my service right now with refractory hemorrhagic cystitis a decade after radiation which is a complication I believe to be under-reported, we average 1-2 at any time at this hospital, and that’s with regular EBRT, long term results of super dose escalated therapy could be problematic

Overall a very interesting study, and the EBRT + Brachy data looks excellent, it’s just hard to know what to make of the RP outcomes in comparison when they are so much worse then almost every other published series.
 
Read the whole study, same concerns as above. Also a 40% positive surgical margin rate is pretty atrocious, even in high risk disease (10-15% in most series). Another issue that may have contributed to these poor outcomes is that only 40% of the RP patients saw radiation in the adjuvant or salvage setting (mostly salvage). There is a strong argument to be made for adjuvant xrt in all of these patients, and the fact that 56% of them had a BCR but never got XRT is just bad care. There is no way that those recurrences were mostly distant if their PSA was followed appropriately.

Finally it would really be good to see toxicity outcomes and QOL outcomes. One could see a situation where people with no baseline voiding issues are better off with XRT/Brachy, whole high baseline LUTs are better with RP. Also I’m concerned about the long term sequelae. I have 3 patients on my service right now with refractory hemorrhagic cystitis a decade after radiation which is a complication I believe to be under-reported, we average 1-2 at any time at this hospital, and that’s with regular EBRT, long term results of super dose escalated therapy could be problematic

Overall a very interesting study, and the EBRT + Brachy data looks excellent, it’s just hard to know what to make of the RP outcomes in comparison when they are so much worse then almost every other published series.


I do respect that you honestly read the paper. But some of your concerns I think are missing the overall point. The outcomes are bad because they looked at a very high risk group. There are very few series with exclusively Gleason 9 patients. There was a Harvard paper (Tsao 2015) that just reported outcomes of 8 vs 9-10 without comparing surg vs rt, and outcomes for the 9-10 were the same as in this current paper. Also a
Urology series by Misop Han in 2016 or so, with same finding. The point is, having biopsy Gleason is a bad predictive factor. Heck, even look at the multi institutional paper validating the New GGG. Then look at the grade 5
Tumor bcrfs after surgery. So even what you said in your first post doesn’t ring true—surgical data support high bcrfs, dmfs, and css in this group.

Also your point about “low use of postoperative rt”. Look at patterns of care data — that’s not a low rate st all. And more practically, how many times are surgical patients really told “you’ll have radiation at least 50% of the time” after surgery? Surgery patients are told “you can get radiation after surgery but not the other way around, so get surgery now” I doubt many patients know to EXPECT postop rt. In any case low rates of postop rt is the reality in practice

Just my 2 cents. I think it’s not the surgery arm that surprises me (also, ebrt patients without bt did just as bad). It’s the size of the difference to me that is shocking and probably reflects some kind of bias. But, I believe there is at least a difference
 
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I whole-heartedly disagree that G9-10 disease is going to recur locally rather than systemically most of the time. That flies in the face of everything we know about gleason score and how it relates to development of distant metastatic disease.

Also, this is a review of purely academic institutions with mostly good track records (UCLA, Cleveland Clinic, Hopkins, Dana-Farber, Fox Chase, Mt. Sinai, Michigan, Beaumont) with the only ones I don't recognize being the one from Norway and the West Virginia one. Despite what is reported in series as being 10-15% (and I'd like you to cite that this is in truly 'high-risk' disease), these aren't chump urologist out in the community, and they're still getting 40%+ SM.

Patterns of care consistently show, on a national level, that salvage radiation is woefully underused, and the 40% of patients who got radiation after surgery is higher than the general population. This is our frustration, as a specialty, with urologists all across this country. Urology frequently sells unimodality therapy to a patient that has a 75-90% chance of requiring multimodality therapy.

That is why nearly all of us are in favor of multi-disciplinary clinics where a patient with prostate cancer meets with surgeon, rad onc, med-onc all on the same day, prior to being scheduled for surgery. Guess where the push back to this is coming from?
 
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I whole-heartedly disagree that G9-10 disease is going to recur locally rather than systemically most of the time. That flies in the face of everything we know about gleason score and how it relates to development of distant metastatic disease.

Also, this is a review of purely academic institutions with mostly good track records (UCLA, Cleveland Clinic, Hopkins, Dana-Farber, Fox Chase, Mt. Sinai, Michigan, Beaumont) with the only ones I don't recognize being the one from Norway and the West Virginia one. Despite what is reported in series as being 10-15% (and I'd like you to cite that this is in truly 'high-risk' disease), these aren't chump urologist out in the community, and they're still getting 40%+ SM.

Patterns of care consistently show, on a national level, that salvage radiation is woefully underused, and the 40% of patients who got radiation after surgery is higher than the general population. This is our frustration, as a specialty, with urologists all across this country. Urology frequently sells unimodality therapy to a patient that has a 75-90% chance of requiring multimodality therapy.

That is why nearly all of us are in favor of multi-disciplinary clinics where a patient with prostate cancer meets with surgeon, rad onc, med-onc all on the same day, prior to being scheduled for surgery. Guess where the push back to this is coming from?

Of course many of these patients recur distantly. However the vast majority will have a undetectable PSA initially then have a slowly rising PSA with negative CT and bone scan. Of course some of these are undetected micro metastatic disease, yet level one evidence says that salvage or adjuvant radiation significantly improve outcomes. This was inadequately utilized here and I agree that many urologists undersell the likelihood of needing XRT to high risk patients.

However the fact that suboptimal care is often given doesn’t mean we should base our decisions on the assumption that we are going to provide suboptimal care. Adherence to ADT is also poor, that doesn’t mean we should not treat people with radiation.

I’m sorry but no matter what the institution or Gleason grade 40% PSM rate is unacceptable. For all comers our institutional rate is 6-10%, high risk closer to 20. Likewise the 96% BCR rate and 12% PCSM rate in 5 years is unspeakably high compared to all prior studies, including prospective and randomized trials. We should be looking at a ~70% 10 year BCR rate and 10% PCSM rate at 15 years. This is not new data and is well established in the literature for Gleason 9 or 10 disease. I’ll provide citations later. It’s a small group so it’s easy to cherry pick studies with higher or lower rates. That’s why the bio stats folks at MSK and others aggregate the data, and that’s what they came up with in their normograms.

I’m not discounting this study at all. The outcomes in the Brachy group were excellent in a large series. But you’re going to have a hard time finding surgeons to buy into the RP outcomes, it just flies in the face of our prior literature (of course we have our bias as wel). Also would love to see the toxicity data. I will say though that many of it residents have been poo pooing missing other cases to learn to do BrachyI’m going to make sure I’m very comfortable with Brachy before I graduate.
 
Just to clarify, I want series that ONLY look at high-risk. Preferably looking at only Gleason 9/10, but I know that's hard because everything gets grouped as 'high risk' despite the fact high risk is a heterogeneous patient population.
Low/Intermediate risk is not on trial here.

Quick search from my perspective:

Early oncological outcomes of robot-assisted radical prostatectomy for high-grade prostate cancer. - PubMed - NCBI

G8 - 40% +SM, G9 - 63% +SM

Predictors of biochemical recurrence in pT3b prostate cancer after radical prostatectomy without adjuvant radiotherapy. - PubMed - NCBI

High-risk Prostate Ca - 40% + SM

Comparison of positive surgical margin rates in high risk prostate cancer: open versus minimally invasive radical prostatectomy. - PubMed - NCBI

Comparison of techniques for prostatectomy, including RALP, in high-risk patients - 41.4 - 53% +SM depending on technique

Assessments of Neoadjuvant Hormone Therapy Followed by Robotic-Assisted Radical Prostatectomy for Intermediate- and High-Risk Prostate Cancer. - PubMed - NCBI

This one is a bit of a stretch, I'll admit. Intermediate and high-risk patients - Those who got surgery alone had a 91%(!!) +SM, those who got neoadjuvant hormonal therapy had 37%

Robot-assisted radical prostatectomy in low- and high-risk prostate cancer patients. - PubMed - NCBI

This is the one study I can find that supports your percentages. 40 high-risk patients operated on, only 20% +SM. However, only 13 out of those 40 were high-risk because of Gleason 9-10.


These are all urological series, and I look forward to seeing what additional citations there are that I was not able to find on my pubmed search.

I do want to say that I do appreciate you coming on this forum, in a somewhat hostile environment, to provide a counterpoint against the echo chamber of "lol urologists gotta pay for their yachts/college funds/retirement" in regards to this topic.

In regards to your toxicity claim - ASCENDE-RT (ASCENDE-RT: An Analysis of Treatment-Related Morbidity for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost with a Dose-Escalated E... - PubMed - NCBI) showed higher toxicity with brachy than external beam + ADT alone (meaning the brachy worsened toxicity). However, if we're making people live longer with their high-risk prostate cancer, that has to stand for something? It's certainly a discussion of the higher risk of G3+ Urinary toxicity with brachytherapy at 5 years (18% vs 5% incidence), but persistent prevalence was down to 8.6 vs 2.2% at 5 years.
 
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Of course many of these patients recur distantly. However the vast majority will have a undetectable PSA initially then have a slowly rising PSA with negative CT and bone scan. Of course some of these are undetected micro metastatic disease, yet level one evidence says that salvage or adjuvant radiation significantly improve outcomes. This was inadequately utilized here and I agree that many urologists undersell the likelihood of needing XRT to high risk patients.

However the fact that suboptimal care is often given doesn’t mean we should base our decisions on the assumption that we are going to provide suboptimal care. Adherence to ADT is also poor, that doesn’t mean we should not treat people with radiation.

I’m sorry but no matter what the institution or Gleason grade 40% PSM rate is unacceptable. For all comers our institutional rate is 6-10%, high risk closer to 20. Likewise the 96% BCR rate and 12% PCSM rate in 5 years is unspeakably high compared to all prior studies, including prospective and randomized trials. We should be looking at a ~70% 10 year BCR rate and 10% PCSM rate at 15 years. This is not new data and is well established in the literature for Gleason 9 or 10 disease. I’ll provide citations later. It’s a small group so it’s easy to cherry pick studies with higher or lower rates. That’s why the bio stats folks at MSK and others aggregate the data, and that’s what they came up with in their normograms.

I’m not discounting this study at all. The outcomes in the Brachy group were excellent in a large series. But you’re going to have a hard time finding surgeons to buy into the RP outcomes, it just flies in the face of our prior literature (of course we have our bias as wel). Also would love to see the toxicity data. I will say though that many of it residents have been poo pooing missing other cases to learn to do BrachyI’m going to make sure I’m very comfortable with Brachy before I graduate.

I'm sorry, but again you are making baseless statements. There are not "multiple" series that can refute the data in that multi-institutional paper. It is by far the largest dataset for Gleason 9-10 and the second largest is a smaller series from the lead author (which had similar surgical outcomes). Clinical Outcomes for Patients with Gleason Score 9-10 Prostate Adenocarcinoma Treated With Radiotherapy or Radical Prostatectomy: A Multi-institut... - PubMed - NCBI

Then there is a Hopkins paper looking at GS 8 and GS 9-10 separately, the rate of PCSM with median followup of 3 years in biopsy GS 9-10 patients that got surgery was already 14%. Did the Hopkins urologist balk before they published their own urology paper? New Prostate Cancer Grading System Predicts Long-term Survival Following Surgery for Gleason Score 8-10 Prostate Cancer. - PubMed - NCBI Since you keep mentioning that the rate should be that high only at 15 years?

Then there is a Dana Farber paper, again on just GS 9-10, that found high met rate (not distinguishing between RT and RP, but pooled rate of 40% met rate at 5 years. J Urol. 2015 Jul;194(1):91-7.

The big Memorial JCO paper from 2010, on the other hand, presumably which influences the memorial nomograms, included 140 surgical patients with GS 8-10 disease, not splitting out the 9-10. So you're comfortable pooling them together even though multiple new papers support they are different? Metastasis after radical prostatectomy or external beam radiotherapy for patients with clinically localized prostate cancer: a comparison of clinic... - PubMed - NCBI

And finally -- our group just had a GU Tumor Board which was a little hilarious, but the urologists weren't really focused on outcomes in the surgery group. They are focused on outcomes in the brachy boost group and whether those are real. They acknowledge the surgical results are probably accurate, and pointed out that there are prominent urologists on the paper.

The point is, people pool GS9-10 with other high risk while it is a distinct more aggressive cancer and probably needs more aggressive treatment. So taking rates from random high risk series is irrelevant. The data in the paper are valid and expected for 9-10 disease.
 

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I wouldnt call Pat Walsh's series cherry picking of data. If you talk to some urologists, they think surgery followed by horomones radiation (trimodality) is a optimal care, although there is very sparse data on this.
 
I wouldnt call Pat Walsh's series cherry picking of data. If you talk to some urologists, they think surgery followed by horomones radiation (trimodality) is a optimal care, although there is very sparse data on this.
Plenty of anecdotal experience that it carries the worst morbidity
 
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With ASCENDE and this data along with the recent JCO NCDB analysis (Rusthoven et al. JCO 2018) my personal opinion is that you are no longer following evidence base medicine for high risk prostate cancer if you do not offer a brachytherapy boost or addition of abiraterone. Of course numerous caveats regarding comorbidities, life expectancy, AUA score and the just barely high risk patients (ie those guys with the incident 4+4 in <1mm). Also I would be shocked if any more than handful of residents are well versed in LDR, its quite skill intensive and in the hands of practitioners from high volume centers (ie >=3 a week) toxicities are very manageable.
 
With ASCENDE and this data along with the recent JCO NCDB analysis (Rusthoven et al. JCO 2018) my personal opinion is that you are no longer following evidence base medicine for high risk prostate cancer if you do not offer a brachytherapy boost or addition of abiraterone. Of course numerous caveats regarding comorbidities, life expectancy, AUA score and the just barely high risk patients (ie those guys with the incident 4+4 in <1mm). Also I would be shocked if any more than handful of residents are well versed in LDR, its quite skill intensive and in the hands of practitioners from high volume centers (ie >=3 a week) toxicities are very manageable.
Since when did most urologists start caring about EBM? There's data published in the NEJM documenting use of ADT by urologists correlated to reimbursement back in the day.... others in community practice will perform cryo, hifu etc for upfront management etc
 
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Since when did most urologists start caring about EBM? There's data published in the NEJM documenting use of ADT by urologists correlated to reimbursement back in the day.... others in community practice will perform cryo, hifu etc for upfront management etc

I think the comment was likely based for ROs that aren't offering brachy boost for high-risk prostate Ca due to whatever reason.

We know urologists are gonna do whatever they want, but as a field, we should hopefully see utilization of brachy boost increase.
 
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