High risk prostate fractionation

[taserlaser]

Disclosure, I don’t treat GU, but had a lot of experience with 60 Gy / 20 fr in training. Nothing untoward really that was unexpected. I like the 20 fr SIB for the pts with nodes which has had some outcome data on it but less experience with that.

One thought experiment, and a lot of questions I have which are more theoretical in nature, are more about the radiobiology of hypofractionation. Emperically we have data to show it works well, especially in prostate cancer. However, one wonders if the tumor in its entirety has all the same ‘growth pattern’ or responds with the same a/b ratio, or if there are subpopulations within it. Some or the majority of cells may respond to a lower a/b ratio regimen with hypofrac, and others may respond better or have an intrinsic higher a/b ratio. I wonder about the patterns of failure of these treatments, and if we can learn anything from prostates with them.

Some of the more recent trials like ASCENDE and the planned ASCENDE where it’s BT vs SBRT boost, combine both a portion of conventionally fractionated treatment, as well as a large hypofrac component which may treat both subpopulations of tumors, if in fact that is a good model or way of thinking about things (or not). In addition to the dose escalation, this in my mind is also a possible explanation to the success of ASCENDE.

In other tumor sites, I wonder about the biology of local failures like this. Take small cell lung ca, maybe the resistant subpopulation has a low a/b and while we are great at killing the super rapid cells, obviously that’s not all it takes. The 60 Gy dose escalation work that’s being done there is interesting for sure.

Anyways, those are my musings from a simple, non GU rad onc. Would love to hear more from the armchair radiobiologists.

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[deleted1116990]

It’s not controversial in 2022

Well that settles it, then.

That said, I don't follow the logic of going out of your way to conventionally fractionate 3 prostate patients a year for a few extra 77427s to boost your RVU bonus an extra 5k or something. I understand the rationale of a freestanding high volume prostate center treating all of their patients like this to make payroll and cover their debts while still making a profit, but unless you are also doing 20 fraction whole brain and bone met, why are you bothering to do this on a select few patients just for a small $$$ bump?

But still, there are legitimate, non-RVU padding reasons to conventionally fractionate prostate. I have treated a fair amount on a fixed salary in the past.

 

[Linaculous]

Biology clearly matters significantly in prostate cancer as we see from the broad spectrum of treatment options we offer patients from active surveillance, local therapy, and aggressive local therapy combined with ADT and maybe also including nodes as well. So if biology matters, potentially less aggressive biology of 88% of patients on CHHiP may affect our interpretation when it comes to the 12% that were higher risk.

You're right that there is plenty of hypofractionation data with great experiences, but none randomized a majority of high risk patients to conventional versus hypo other than HYPRO. I appreciate that for some, that may be sufficient to treat without randomized data in a cohort representative of high risk biology, while for some it is not. Randomized data is important, because we commonly jump to assuming certain prostate cancer regimens are better, without looking at the factors that may explain some of it. Very different clinical situation and study, but look at POP-RT, they had excellent results and biochemical control rates in both arms (prostate only versus prostate plus nodes), but look at the fact that 80% of patients had PSMA-PET done as part of staging - clearly something like this affected eligibility on the trial (excluded lots of metastatic patients) and affects outcomes when we compare their results to other trials, but at least both arms on the study were fairly compared. It would not be fair to compare those arms directly to another study which did not have the same eligibility criteria.

Suffice to say, I think this is a controversy that exists in this field, and it is alright to disagree on the management. Importantly, however, not wanting to hypofractionate high risk patients is a reasonable philosophy one may have from an academic, non-business, perspective as well. Some may just want definitive randomized data comparing the two fractionation regimens and showing the same control without any increased toxicity in this cohort before making the switch.

Don't sleep on Regina Elena NCI Rome
Smaller trial but all high-risk


To cast my vote, I do 60-62 and 44 in 20 fractions routinely, unless doing combo or SBRT

 

[jondunn]

Look do whatever fractionation you want but to suggest hypofrac is ‘controversial’ is silly

But some of you also view 2 gy a fraction as ‘hypofrac’

 

[salubalu]

It’s not controversial in 2022

That being said all
Options in NCCN, so yeah

Im better than the GUIDELINES!!! 😛

 

[salubalu]

Look do whatever fractionation you want but to suggest hypofrac is ‘controversial’ is silly

But some of you also view 2 gy a fraction as ‘hypofrac’

You know what’s silly saying 81 gy in 1 gy per fraction is gentler…and there was a patient who said his doc said that…I’m sure they became good friends over the treatment course…I guess it being gentler isn’t a lie…

 

[jondunn]

You know what’s silly saying 81 gy in 1 gy per fraction is gentler…and there was a patient who said his doc said that…I’m sure they became good friends over the treatment course…I guess it being gentler isn’t a lie…

Sounds like Florida

 

[medgator]

Sounds like Florida

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[Pointless]

I suppose you have some points there about short course rectal, which I do not do. Also, 8 Gy x1 just flat doesn't work in good performing patients and the data proves this with the re-treatment rate; I only use this fractionation for patients that are on their way to hospice and need some quick (but non-durable) pain relief.

I guess I feel that prostate is different in the sense that there is a flood of high quality data confirming equivalence between conventional and hypofrac such that I really don't see a plausible argument for 1.8 Gy fraction size anymore and it is definitely an inconvenience for the patient. As was pointed out above, you really are just getting a few extra OTV charges... is that worth it?

 

[jondunn]

'8 gy x 1 just flat doesn't work' is a wild statement

 

[Chartreuse Wombat]

Dose matters.

I prefer to treat high risk with a 2 fraction SBRT boost (20 Gy) followed by 46 Gy in 23 fractions to the pelvis.

Otherwise I will prefer to treat with conventional fractionation and give a slight SIB in the 85-90 range to the gross disease on MRI/PSMA pet.

Fiducials, spaceOAR, daily CBCT.

Have results been published? The linked paper is just a description of the retrospectively registered study.

 

[Burt Radnolds]

Don't sleep on Regina Elena NCI Rome
Smaller trial but all high-risk


To cast my vote, I do 60-62 and 44 in 20 fractions routinely, unless doing combo or SBRT

Every time this topic comes up and people say no data exists I always drop that study. Recent-ish publication in JCO and no one seems to know about it.

https://ascopubs.org/doi/10.1200/JCO.2016.70.4189

 

[thecarbonionangle]

Some of you folks say the quiet part out loud in this thread, very interesting!!!!

 

[Chartreuse Wombat]

Funny thing is...

The zealots for pelvic treatment say POP-RT to justify pelvic treatment...OK more toxicity no OS whatever

But POP-RT hypofractionated the primary

?

 

[masrawy]

Every time this topic comes up and people say no data exists I always drop that study. Recent-ish publication in JCO and no one seems to know about it.

https://ascopubs.org/doi/10.1200/JCO.2016.70.4189

You seem very knowledgeable about this study. May you please explain how this population applies to what we would consider NCCN High Risk? All patients were organ confined and most were Gleason 7 or less according to the table? Additionally all these patients had very good baseline GI/GU symptoms. Is this a typical population you see of high risk patients?

Is this really the data that you think is a slam dunk “gotcha!” moment?

From the manuscript methods:
“All biopsy specimens were reviewed by an institutional uropathologist who assigned a GS ≤ 7 (3 + 4) in 83 (49%) of patients, and a GS ≥ 7 (4 + 3) in 85 (51%) of patients. The median iPSA was 14.58 ng/mL (IQR, 10 to 25 ng/mL), with a slightly higher value in the hypofractionation than conventional fractionation group (16 v13 ng/mL; P = .063). No patients complained of relevant (> G1) symptoms at baseline.”

 

[masrawy]

Look do whatever fractionation you want but to suggest hypofrac is ‘controversial’ is silly

But some of you also view 2 gy a fraction as ‘hypofrac’

Saying that there is a controversy regarding fractionation or dose is not saying that hypofrac is wrong. It’s a different philosophy and interpretation of data. Get off your high horse and consider that maybe there are GU experts at notable academic institutions that still do conventional frac for high risk prostate cancer. Be open minded and don’t call people silly because you simply don’t agree with them.

 

[jondunn]

Saying that there is a controversy regarding fractionation or dose is not saying that hypofrac is wrong. It’s a different philosophy and interpretation of data. Get off your high horse and consider that maybe there are GU experts at notable academic institutions that still do conventional frac for high risk prostate cancer. Be open minded and don’t call people silly because you simply don’t agree with them.

‘ there are GU experts at notable academic institutions that still do conventional frac for high risk prostate cancer.’


You say this like it means something?

Am i Supposed to be impressed by these people?

 

[medgator]

I guess I feel that prostate is different in the sense that there is a flood of high quality data confirming equivalence between conventional and hypofrac such that I really don't see a plausible argument for 1.8 Gy fraction size anymore and it is definitely an inconvenience for the patient. As was pointed out above, you really are just getting a few extra OTV charges... is that worth it?

Breast hypofx is truly better for patients with less toxicity. That's why evilcore mandates 16 or less for intact breast but you can still get conventional prostate fx approved. There's no good reason for conv fx in intact breast anymore

None of the hypofx trials have proven the superiority of it compared to conventional fx, unlike breast. Cheaper and more convenient, but not better, and out IRL, many of us have seen the difference in acute gi tox

 

[Palex80]

I would really like to listen to arguments against hypofractionation for high-risk disease.

Is it because of increased toxicity? It was noted, that in HYPRO high-risk patiets had more toxicity. If that is the argument, how do you explain it? Is it because of the PTV size (high-risk patients need cocerage of the seminal vesicles, thus increasing the PTV?)? If so, is there a cutoff (PTV-wise in ml, where you would not offer hypofractionation)? There's certainly nothing in terms of biology to expect there, the rectum in patient with high-risk disease will not show different toxicity than the rectum in patient with intermediate-risk disease if exposed to the same dose.

Is it because of doubts concerning efficacy? Do you question that the a/b ratio in high-risk disease is higher, as has been proposed by some researchers, and thus hypofractionation for high-risk disease would result in inferior BED?
Both RTOG 0415 and CHHiP included intermediate risk patients and only few high-risk patients.
May I remind you of the Arcangeli-trial (a.ka. "the mother of all hypofractionation RCTs in prostate cancer" - 40x2Gy vs. 20 x 3.1Gy). This is the first published trial which served as the prototype to initiate all the other phase III trials. Final results presented a few years ago: Moderate Hypofractionation in High-Risk, Organ-Confined Prostate Cancer: Final Results of a Phase III Randomized Trial - PubMed
This trial was only for high-risk patients and showed no detremental effect when using hypofractionation in term of efficacy, with a trend in favor of hypofractionation. Toxicity was same too.

 

[Pointless]

'8 gy x 1 just flat doesn't work' is a wild statement

Is it wild? So, you routinely use 8 Gy x 1 with good success in people who have a life expectancy >6 months? The data itself shows a 2x re-treatment rate, so not sure why this is "wild".

 

[medgator]

Is it wild? So, you routinely use 8 Gy x 1 with good success in people who have a life expectancy >6 months? The data itself shows a 2x re-treatment rate, so not sure why this is "wild".

The "experts" argue that was by physician choice because they were worried it wasn't working well, which is a crazy argument imo, im not treating someone's bone met again because I'm worried that 8x1 isn't going to work, i am re treating because the patient has pain again

 

[Pointless]

The "experts" argue that was by physician choice because they were worried it wasn't working well, which is a crazy argument imo, im not treating someone's bone met again because I'm worried that 8x1 isn't going to work

Right. I am all for hypofractionation and will readily adopt anything that increases efficacy or convenience without cost to efficacy... 8 Gy x 1 does neither in my experience, except in cases where durable palliation is not a concern due to prognosis.

 

[masrawy]

I would really like to listen to arguments against hypofractionation for high-risk disease.

Is it because of increased toxicity? It was noted, that in HYPRO high-risk patiets had more toxicity. If that is the argument, how do you explain it? Is it because of the PTV size (high-risk patients need cocerage of the seminal vesicles, thus increasing the PTV?)? If so, is there a cutoff (PTV-wise in ml, where you would not offer hypofractionation)? There's certainly nothing in terms of biology to expect there, the rectum in patient with high-risk disease will not show different toxicity than the rectum in patient with intermediate-risk disease if exposed to the same dose.

Is it because of doubts concerning efficacy? Do you question that the a/b ratio in high-risk disease is higher, as has been proposed by some researchers, and thus hypofractionation for high-risk disease would result in inferior BED?
Both RTOG 0415 and CHHiP included intermediate risk patients and only few high-risk patients.
May I remind you of the Arcangeli-trial (a.ka. "the mother of all hypofractionation RCTs in prostate cancer" - 40x2Gy vs. 30 x 2.1Gy). This is the first published trial which served as the prototype to initiate all the other phase III trials. Final results presented a few years ago: Moderate Hypofractionation in High-Risk, Organ-Confined Prostate Cancer: Final Results of a Phase III Randomized Trial - PubMed
This trial was only for high-risk patients and showed no detremental effect when using hypofractionation in term of efficacy, with a trend in favor of hypofractionation. Toxicity was same too.

You all keep citing the same one study without looking at the breakdown of patients in it. First of all only 24% or so (like 20 or so patients in each arm!) had Gleason 8+ disease. They mostly included Gleason 7 disease and even included some Gleason 6 disease. The median PSA was 14.58. All had organ confined disease (none with SV or EPE). Look at the breakdown of patients… Finally, this was a very well selected group of patients with baseline excellent symptoms (in terms of LUTS for instance). At least read the methods!

Again, are we talking about the same patients? How are the patients on this trial considered high risk by NCCN criteria?

 

[Palex80]

You all keep citing the same one study without looking at the breakdown of patients in it. First of all only 24% or so (like 20 or so patients in each arm!) had Gleason 8+ disease. They mostly included Gleason 7 disease and even included some Gleason 6 disease. The median PSA was 14.58. All had organ confined disease (none with SV or EPE). Look at the breakdown of patients… Finally, this was a very well selected group of patients with baseline excellent symptoms (in terms of LUTS for instance). At least read the methods!

Again, are we talking about the same patients? How are the patients on this trial considered high risk by NCCN criteria?

Are you trolling? Here are the characteristics of the patients in the Arcangeli trial, from the original paper, published 2010 [PMID 20047800]

 

[salubalu]

gas prices from conventional fractionation is an acute toxicity 😛…I usually offer conventional if they have electric cars though…

 

[masrawy]

Yea they weren’t forthright in the initial publication, look at the 2017 update where they break it down:

Here’s the link to the 2017 update. Pull up Table 1. How many are Gleason 8+ in this table? Only about a quarter. And look at the average PSA. And again majority organ confined. So you don’t believe their updated JCO paper patient characteristics?? https://ascopubs.org/doi/10.1200/JCO.2016.70.4189?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0pubmed

 

[masrawy]

Are you trolling? Here are the characteristics of the patients in the Arcangeli trial, from the original paper, published 2010 [PMID 20047800]
View attachment 357289

Not trolling, see post above.

 

[Palex80]

Yea they weren’t forthright in the initial publication, look at the 2017 update where they break it down:

View attachment 357290

Here’s the link to the 2017 update. Pull up Table 1. How many are Gleason 8+ in this table? Only about a quarter. And look at the average PSA. And again majority organ confined. So you don’t believe their updated JCO paper patient characteristics?? https://ascopubs.org/doi/10.1200/JCO.2016.70.4189?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0pubmed

Wonderful. Now have a look at your post:
"All patients were organ confined and most were Gleason 7 or less according to the table"

I see 13% T3s there.

Regardless of that, would you mind telling me what your issue is against hypofractionation?
Are you concerned about lack of efficacy in high-risk disease?

 

[masrawy]

Wonderful. Now have a look at your post:
"All patients were organ confined and most were Gleason 7 or less according to the table"

I see 13% T3s there.

Regardless of that, would you mind telling me what your issue is against hypofractionation?
Are you concerned about lack of efficacy in high-risk disease?

Okay… so you agree that the majority on this “mother of all studies” (as you or someone else called it lol) are still not NCCN high risk? That part is settled now, right? No issue with hypofractionation for high risk disease, I just don’t think the data supports it compared to data for low and intermediate risk disease, and there is at least one randomized trial which included majority high risk patients and showed concern for increased toxicity with it (be it due to larger PTVs, inclusion of entire SVs for whatever else reason). Do what you want ultimately. NCCN allows for both, and for a reason.

 

[jondunn]

it does NOT make sense to have your concern be tox in regards to speecifically high risk.

what about high risk prostate cancer makes you specifically concerned that it is associated with more tox than compared to intermediate or low?

it doesn't pass the smell test.

 

[masrawy]

it does NOT make sense to have your concern be tox in regards to speecifically high risk.

what about high risk prostate cancer makes you specifically concerned that it is associated with more tox than compared to intermediate or low?

it doesn't pass the smell test.

Focusing on potential causes for increased toxicity among high risk patients:
1. Commonly for low risk we treat the prostate alone, for intermediate we treat prostate + proximal SV and for high risk we treat prostate + entire SV. Therefore there’s a larger volume being treated in high risk.
2. High risk patients may present more commonly with more LUTS symptoms (at least this is what I see in real life) especially with bulky disease. Some of this can be improved with ADT to shrink the prostate down, but some is persistent. Maybe this contributes?
3. During treatment potentially higher tumor burden in high risk patients may be associated with more peritumoral edema or other inflammatory effects. I don’t know. But it is plausible.

 

[Palex80]

Okay… so you agree that the majority on this “mother of all studies” (as you or someone else called it lol) are still not NCCN high risk? That part is settled now, right?

You should take a look at the inclusion criteria of the trial from the original publication. This trial did include high risk patients. It just did not include those high risk patients, that you wanted to see in the trial (T3s, high gleason). It appears to me, that many patients went into the trial with a PSA > 20ng/ml as a sole risk factor. Patients with mutliple risk factora were certainly underrepresented.

No issue with hypofractionation for high risk disease, I just don’t think the data supports it compared to data for low and intermediate risk disease, and there is at least one randomized trial which included majority high risk patients and showed concern for increased toxicity with it (be it due to larger PTVs, inclusion of entire SVs for whatever else reason). Do what you want ultimately.

This very sentence is a contradiction in itself.
You do have issues with hypofractionation for high risk disease.
It appears that toxicity is the main issue. I need to question however, if quoting HYPRO is a good idea, since hypofractionation schedules recommended nowadays are not HYPRO-like.
I also need to question if the true long term toxicity with modern techniques (fiducials, CBCT, adaptive RT, SpaceOAR) - or combinations of those) will be what was seen in the trials which did not have those tools in place.

NCCN allows for both, and for a reason.

Of course it does. But saying that it‘s wrong is something I am not comfortable with. Normofractionation is ok, I have some patients who want it and they get did, I don‘t deny it. But my first recommendation is moderate hypofractionation.

 

[masrawy]

You should take a look at the inclusion criteria of the trial from the original publication. This trial did include high risk patients. It just did not include those high risk patients, that you wanted to see in the trial (T3s, high gleason). It appears to me, that many patients went into the trial with a PSA > 20ng/ml as a sole risk factor. Patients with mutliple risk factora were certainly underrepresented.

This very sentence is a contradiction in itself.
You do have issues with hypofractionation for high risk disease.
It appears that toxicity is the main issue. I need to question however, if quoting HYPRO is a good idea, since hypofractionation schedules recommended nowadays are not HYPRO-like.
I also need to question if the true long term toxicity with modern techniques (fiducials, CBCT, adaptive RT, SpaceOAR) - or combinations of those) will be what was seen in the trials which did not have those tools in place.

Of course it does. But saying that it‘s wrong is something I am not comfortable with. Normofractionation is ok, I have some patients who want it and they get did, I don‘t deny it. But my first recommendation is moderate hypofractionation.

I did look at the inclusion criteria that they used, and, again, they are not modern high risk criteria. The median PSA was 15ng/mL, yet you cite that as they must have had a PSA of > 20 as a sole factor, which is not the case. Can you tell me how many had that factor of PSA>20? Reviewing closely shows that most of these patients would today be considered intermediate or unfavorable intermediate risk by NCCN criteria.

This is the Italian trial’s definition of high risk directly from their protocol:
2.1 Definition of high risk tumors
The patients with high risk tumors are those with an iPSA > 20 ng/ml or GS
>7, or T-stage >2c, or with the presence of at least 2 of the following clinical factors: iPSA 11-20 ng/ml, T= 2c, GS=7 (20).

Given that the median PSA was only about 15ng/mL, and less than 25% had Gleason 8 or higher disease, many of their patients met their own inclusion criteria because of the last sentence above, however, that does not make one high risk by today’s NCCN accepted definition (not my own). Having T2c disease, PSA of 15 and GS of 7 does not make you NCCN high risk… It would make you NCCN intermediate risk.

From NCCN:
Intermediate Risk:
Has all of the following:
• No high-risk group
features
• No very-high-risk
group features
• Has one or more intermediate risk
factors (IRFs): cT2b–cT2c Grade Group 2 or 3 PSA 10–20 ng/mL

Favorable intermediate
Has all of the following:
• 1 IRF
• Grade Group 1 or 2
• <50% biopsy cores
positive (eg, <6 of 12 cores)

Unfavorable intermediate
Has one or more of the following:
• 2 or 3 IRFs
• Grade Group 3
• ≥ 50% biopsy cores
positive (eg, ≥ 6 of 12 cores)f


High Risk:
Has no very-high-risk features and has exactly one high-risk feature:
• cT3a OR
• Grade Group 4 or Grade Group 5 OR
• PSA >20 ng/mL

Very High:
Has at least one of the following:
• cT3b–cT4
• Primary Gleason pattern 5
• 2 or 3 high-risk features
• >4 cores with Grade Group 4 or 5


To your second point about toxicity not being applicable because of common dose and fractionation being different today and utilizing hydrogel spacers, I agree, you could certainly be right here and we feel more comfortable with hypofractionation when using spacers. However many high risk patients SHOULD NOT get spacers. As you know, if there is concern for EPE, there is a theoretical concern that spacers could actually displace some of this disease more posteriorly away from the PTV and therefore it is usually discouraged. It’s actually one of the criteria to not place spacers.

Finally, I am not saying hypofractionation is wrong for high risk disease, I am saying that it has less support compared to low and intermediate risk disease based on available data and there are plausible academic reasons why. There are many things we as physicians do without strong data, or sometimes without any available data at all. It doesn’t mean it’s wrong. Your philosophy is that extrapolated data is sufficient and that toxicity data is no longer applicable because of SpaceOAR (even though spacers should probably be avoided in patients with concern for T3 disease/EPE) and my philosophy is why risk it if we don’t absolutely know in this patient population. We can agree to disagree, and that is common in medicine and it is okay.

 

[medgator]

I did look at the inclusion criteria that they used, and, again, they are not modern high risk criteria. The median PSA was 15ng/mL, yet you cite that as they must have had a PSA of > 20 as a sole factor, which is not the case. Can you tell me how many had that factor of PSA>20? Reviewing closely shows that most of these patients would today be considered intermediate or unfavorable intermediate risk by NCCN criteria.

This is the Italian trial’s definition of high risk directly from their protocol:
2.1 Definition of high risk tumors
The patients with high risk tumors are those with an iPSA > 20 ng/ml or GS
>7, or T-stage >2c, or with the presence of at least 2 of the following clinical factors: iPSA 11-20 ng/ml, T= 2c, GS=7 (20).

Given that the median PSA was only about 15ng/mL, and less than 25% had Gleason 8 or higher disease, many of their patients met their own inclusion criteria because of the last sentence above, however, that does not make one high risk by today’s NCCN accepted definition (not my own). Having T2c disease, PSA of 15 and GS of 7 does not make you NCCN high risk… It would make you NCCN intermediate risk.

From NCCN:
Intermediate Risk:
Has all of the following:
• No high-risk group
features
• No very-high-risk
group features
• Has one or more intermediate risk
factors (IRFs): cT2b–cT2c Grade Group 2 or 3 PSA 10–20 ng/mL

Favorable intermediate
Has all of the following:
• 1 IRF
• Grade Group 1 or 2
• <50% biopsy cores
positive (eg, <6 of 12 cores)

Unfavorable intermediate
Has one or more of the following:
• 2 or 3 IRFs
• Grade Group 3
• ≥ 50% biopsy cores
positive (eg, ≥ 6 of 12 cores)f


High Risk:
Has no very-high-risk features and has exactly one high-risk feature:
• cT3a OR
• Grade Group 4 or Grade Group 5 OR
• PSA >20 ng/mL

Very High:
Has at least one of the following:
• cT3b–cT4
• Primary Gleason pattern 5
• 2 or 3 high-risk features
• >4 cores with Grade Group 4 or 5


To your second point about toxicity not being applicable because of common dose and fractionation being different today and utilizing hydrogel spacers, I agree, you could certainly be right here and we feel more comfortable with hypofractionation when using spacers. However many high risk patients SHOULD NOT get spacers. As you know, if there is concern for EPE, there is a theoretical concern that spacers could actually displace some of this disease more posteriorly away from the PTV and therefore it is usually discouraged. It’s actually one of the criteria to not place spacers.

Finally, I am not saying hypofractionation is wrong for high risk disease, I am saying that it has less support compared to low and intermediate risk disease based on available data and there are plausible academic reasons why. There are many things we as physicians do without strong data, or sometimes without any available data at all. It doesn’t mean it’s wrong. Your philosophy is that extrapolated data is sufficient and that toxicity data is no longer applicable because of SpaceOAR (even though spacers should probably be avoided in patients with concern for T3 disease/EPE) and my philosophy is why risk it if we don’t absolutely know in this patient population. We can agree to disagree, and that is common in medicine and it is okay.

Spaceoar is a toxicity de facto, according to some... Both clinically and financially

 

[Palex80]

Reviewing closely shows that most of these patients would today be considered intermediate or unfavorable intermediate risk by NCCN criteria.

It is true, that some of the patients would have qualified as unfavorable intermediate risk by today's criteria. We can't break it down, since we don't have all the data. We do now however, that 2/3 of the patients had a PSA >20 ng/ml. That is high-risk by today's criteria too.

To your second point about toxicity not being applicable because of common dose and fractionation being different today and utilizing hydrogel spacers, I agree, you could certainly be right here and we feel more comfortable with hypofractionation when using spacers. However many high risk patients SHOULD NOT get spacers. As you know, if there is concern for EPE, there is a theoretical concern that spacers could actually displace some of this disease more posteriorly away from the PTV and therefore it is usually discouraged. It’s actually one of the criteria to not place spacers.
...
Your philosophy is that extrapolated data is sufficient and that toxicity data is no longer applicable because of SpaceOAR (even though spacers should probably be avoided in patients with concern for T3 disease/EPE) and my philosophy is why risk it if we don’t absolutely know in this patient population.

My second point was not about spacers only. I listed CBCT, fiducials, adaptive RT and spacers as possible reasons why toxicity will be lower today than in early 2000s, when many of these trials ran. You chose not to include my quote in your post, probably for this reason.
Here is my quote:
I also need to question if the true long term toxicity with modern techniques (fiducials, CBCT, adaptive RT, SpaceOAR) - or combinations of those) will be what was seen in the trials which did not have those tools in place.
Yet, you chose to talk about only spacers. Of course spacers are not a great idea if you have manifest T3 disease.
But would I be comfortable having a spacer in a T1c GS8 tumor? Yes.
I find it striking that you chose to ignore CBCT, fiducials and adaptive RT. All these tools will influence toxicity, making any possible benefits of normofractionation (which do not exist anyhow) - not visible.

The way you carry out this debate is certainly not ideal.

Finally, I am not saying hypofractionation is wrong for high risk disease, I am saying that it has less support compared to low and intermediate risk disease based on available data and there are plausible academic reasons why. There are many things we as physicians do without strong data, or sometimes without any available data at all. It doesn’t mean it’s wrong.

I find it wonderful, how you skipped the financial issue. We both know that normofractionation pays a lot better than hypofractionation. This is the elephant in the room. In my opinion it's a bit like that flawed argument we had when START B came out and people started sayind "We can't use it in G3 disease", out of concerns it may not be as effective. Data later came out that proved that argument wrong.

 

[masrawy]

It is true, that some of the patients would have qualified as unfavorable intermediate risk by today's criteria. We can't break it down, since we don't have all the data. We do now however, that 2/3 of the patients had a PSA >20 ng/ml. That is high-risk by today's criteria too.



My second point was not about spacers only. I listed CBCT, fiducials, adaptive RT and spacers as possible reasons why toxicity will be lower today than in early 2000s, when many of these trials ran. You chose not to include my quote in your post, probably for this reason.
Here is my quote:
I also need to question if the true long term toxicity with modern techniques (fiducials, CBCT, adaptive RT, SpaceOAR) - or combinations of those) will be what was seen in the trials which did not have those tools in place.
Yet, you chose to talk about only spacers. Of course spacers are not a great idea if you have manifest T3 disease.
But would I be comfortable having a spacer in a T1c GS8 tumor? Yes.
I find it striking that you chose to ignore CBCT, fiducials and adaptive RT. All these tools will influence toxicity, making any possible benefits of normofractionation (which do not exist anyhow) - not visible.

The way you carry out this debate is certainly not ideal.


I find it wonderful, how you skipped the financial issue. We both know that normofractionation pays a lot better than hypofractionation. This is the elephant in the room. In my opinion it's a bit like that flawed argument we had when START B came out and people started sayind "We can't use it in G3 disease", out of concerns it may not be as effective. Data later came out that proved that argument wrong.

Can you please show me where it says 2/3 of patients had PSA >20 on the Italian trial? I honestly can’t see that anywhere. Is that your estimate? Because it seems wrong. All I see is the median being 15. That’s median, not mean. Doesn’t median mean the middle number? Doesn’t that by definition mean that at least 50% on the trial had a PSA <20?

I didn’t purposefully ignore your comment
about daily CBCTs and fiducials, but I am not aware (or was not) aware of its usage on these trials or not and when that switch was made. And adaptive RT is not established for prostate cancer and I am not going to go into it - it certainly doesn’t save the patients money either.

In terms of the elephant in the room, I am not compensated differently and I’m not RVU based. I use conventional fractionation for high risk patients based on my interpretation of data. If you’re going to talk about financial toxicity, then maybe those who know about the finances more than me can comment, but daily CBCTs, fiducials, spacers, and certainly adaptive RT also pose financial toxicity.

For the record, I almost always hypofractionate my prostate cancer patients, except for high risk because I believe that it is better for the many reasons discussed above. I don’t get paid any differently, I do it because I believe it’s better. I don’t care if you agree with me or not.

 

[Palex80]

Can you please show me where it says 2/3 of patients had PSA >20 on the Italian trial? I honestly can’t see that anywhere. Is that your estimate? All I see is the median being 15.

I already posted the table before, but sure:

This is from the 2010 paper.
68% in conventional group and 58% in hypofractionated group, makes 64% for the total group. That is roughly 2/3 of all patients.

I didn’t purposefully ignore your comment
about daily CBCTs and fiducials, but I am not aware (or was not) aware of its usage on these trials or not and when that switch was made. And adaptive RT is not established for prostate cancer and I am not going to go into it - it certainly doesn’t save the patients money either.

Fiducials and CBCT were not mandated in the moderated hypofractionation trials. They were certainly not available in many trial centers, bear in mind that these trials ran 15-20 years ago.

Of course adaptive is not established, yet. But benefits can already be seen in early trials. And it is what is already happening in some places.

 

[masrawy]

I already posted the table before, but sure:
View attachment 357306
This is from the 2010 paper.
68% in conventional group and 58% in hypofractionated group, makes 64% for the total group. That is roughly 2/3 of all patients.


Fiducials and CBCT were not mandated in the moderated hypofractionation trials. They were certainly not available in many trial centers, bear in mind that these trials ran 15-20 years ago.

Of course adaptive is not established, yet. But benefits can already be seen in early trials. And it is what is already happening in some places.

Can you reconcile how those numbers make sense in 2010 yet in 2017 they report a median of 15? Is that fishy? Isn’t the median the middle number in a list (versus mean being the average). If that is the case, based on the 2017 numbers, wouldn’t 50% or more be below a PSA of 15? Maybe you can explain the math.

 

[Palex80]

Can you reconcile how those numbers make sense in 2010 yet in 2017 they report a median of 15? Is that fishy? Isn’t the median the middle number in a list (versus mean being the average). If that is the case, based on the 2017 numbers, wouldn’t 50% or more be below a PSA of 15? Maybe you can explain the math.

I have no idea. Maybe the mixed up mean and median. Go ahead and write a letter.

 

[RSAOaky]

I suppose you have some points there about short course rectal, which I do not do. Also, 8 Gy x1 just flat doesn't work in good performing patients and the data proves this with the re-treatment rate; I only use this fractionation for patients that are on their way to hospice and need some quick (but non-durable) pain relief.

I guess I feel that prostate is different in the sense that there is a flood of high quality data confirming equivalence between conventional and hypofrac such that I really don't see a plausible argument for 1.8 Gy fraction size anymore and it is definitely an inconvenience for the patient. As was pointed out above, you really are just getting a few extra OTV charges... is that worth it?

Money is certainly not my primary motivation, it’s just a bit of cognitive dissonance on my part. I think it’s also why older attendings are reluctant to change the way they do things. Maybe in the back of their mind they have the notion that they will take a financial hit for hypofractionating, but with conventional fractionation they know the constraints, they know what toxicity to expect and when to expect it, they’re comfortable with it, patients do well, and patients don’t really complain, so what’s the impetus to learn something new? There is no motivation other than to save patients a few hours of treatment.

Also just so you know the financial impact of hypofracing for me it’s 16 CBCT’s, 3 OTVs = 22.71 wRVUs = $1,255.63. Not money I’m going to cry about losing but also about what I’d be paid for an entire day’s work if I were to do a locum.

I treat 30 prostates a year, I hypofrac 27 of them. That’s about $34k I don’t get paid every year for “choosing wisely.” I think sometimes we gaslight ourselves about the financial impact of hypofractionation. It’s significant, but it’s easier to focus on the time we’re saving the patient than the money we’re losing ourselves. TBH, my patients don’t really care.

We love to shame the “community practice” for their treatment patterns but we are simply a product of our system. Hypofractionation studies have all come from health systems (Canada, UK) and individuals (American Academia) who directly benefit from them, and been foisted upon the rest of us who directly suffer. We’re forced to reckon with the ethical dilemma of whether to do what’s right for patients for less money or do what’s not wrong for more. We’re shamed by physicians that don’t have to face the same dilemmas because they’re compensated entirely differently. At the end of the day we are products of the system that we practice in, so don’t hate the player hate the game.

 

[Fpg1245]

Money is certainly not my primary motivation, it’s just a bit of cognitive dissonance on my part. I think it’s also why older attendings are reluctant to change the way they do things. Maybe in the back of their mind they have the notion that they will take a financial hit for hypofractionating, but with conventional fractionation they know the constraints, they know what toxicity to expect and when to expect it, they’re comfortable with it, patients do well, and patients don’t really complain, so what’s the impetus to learn something new? There is no motivation other than to save patients a few hours of treatment.

Also just so you know the financial impact of hypofracing for me it’s 16 CBCT’s, 3 OTVs = 22.71 wRVUs = $1,255.63. Not money I’m going to cry about losing but also about what I’d be paid for an entire day’s work if I were to do a locum.

I treat 30 prostates a year, I hypofrac 27 of them. That’s about $34k I don’t get paid every year for “choosing wisely.” I think sometimes we gaslight ourselves about the financial impact of hypofractionation. It’s significant, but it’s easier to focus on the time we’re saving the patient than the money we’re losing ourselves. TBH, my patients don’t really care.

We love to shame the “community practice” for their treatment patterns but we are simply a product of our system. Hypofractionation studies have all come from health systems (Canada, UK) and individuals (American Academia) who directly benefit from them, and been foisted upon the rest of us who directly suffer. We’re forced to reckon with the ethical dilemma of whether to do what’s right for patients for less money or do what’s not wrong for more. We’re shamed by physicians that don’t have to face the same dilemmas because they’re compensated entirely differently. At the end of the day we are products of the system that we practice in, so don’t hate the player hate the game.

Why stop at mod hypo which will clearly be out of vogue in 5 years? Try 5fx everything which is clearly where this convo is going. See how much you lose from that or how much “time” you are saving. Pretty soon you’ll have so much time in your hands you can retrain. Better yet 0fx. It’s not about money until you realize that you won’t even have a department to go to at some point. It’s an ethical problem but not a hard one.

 

[Palex80]

Take small cell lung ca, maybe the resistant subpopulation has a low a/b and while we are great at killing the super rapid cells, obviously that’s not all it takes. The 60 Gy dose escalation work that’s being done there is interesting for sure.

There are data for SCLC LD using 2.66-2.75 Gy daily in single daily fractions.
They did not look better (or worse actually) than 30 x 1.5 Gy, delivered twice per day.

 

[taserlaser]

There are data for SCLC LD using 2.66-2.75 Gy daily in single daily fractions.
They did not look better (or worse actually) than 30 x 1.5 Gy, delivered twice per day.

Yes, thank you. Very much accustomed to moderately hypofrac SCLC treatment in residency, and then paradoxically we changed to 2Gy/fr after CONVERT (don’t ask me).

More of a hypothetical radiobiological musing, but how I’ve had it explained to me from more senior ROs was they thought it was more of a ‘dose over shorter period of time’ effect.

I guess at the end of the day, dose is dose.

 

[Palex80]

More of a hypothetical radiobiological musing, but how I’ve had it explained to me from more senior ROs was they thought it was more of a ‘dose over shorter period of time’ effect.

I guess at the end of the day, dose is dose.

Acceleration.

Can he achieved through hypofractionation or hyperfractionation.

 

[taserlaser]

Acceleration.

Can he achieved through hypofractionation or hyperfractionation.

That’s the word I’m looking for. Clearly I need an afternoon coffee haha.

 

[SneakyBooger]

Conventional.

Dr. D'Amico on The MedNet.org in 2017:

"There is a lack of level of level 1 evidence since all trials to date testing non-inferiority were primarily in low or int risk and very few high risk (CHHiP trial) men and in that later trial they only received 3 to 6 mos and not 28 to 36 mos of ADT. Also the f/u is still too short to asses clinically meaningful endpoints like DM and PCSM and finally we do not have long enough f/u yet to assess late GU toxicity."

I would add late GI toxicity to that last statement also.

I find it concerning when a non inferiority trial reports negative results given that 85% of all non inferiority trials are positive.

 

[medgator]

Conventional.

Dr. D'Amico on The MedNet.org in 2017:

"There is a lack of level of level 1 evidence since all trials to date testing non-inferiority were primarily in low or int risk and very few high risk (CHHiP trial) men and in that later trial they only received 3 to 6 mos and not 28 to 36 mos of ADT. Also the f/u is still too short to asses clinically meaningful endpoints like DM and PCSM and finally we do not have long enough f/u yet to assess late GU toxicity."

I would add late GI toxicity to that last statement also.

I find it concerning when a non inferiority trial reports negative results given that 85% of all non inferiority trials are positive.

Careful you're going to trigger a few on here

 

[Palex80]

Conventional.

Dr. D'Amico on The MedNet.org in 2017:

"There is a lack of level of level 1 evidence since all trials to date testing non-inferiority were primarily in low or int risk and very few high risk (CHHiP trial) men and in that later trial they only received 3 to 6 mos and not 28 to 36 mos of ADT. Also the f/u is still too short to asses clinically meaningful endpoints like DM and PCSM and finally we do not have long enough f/u yet to assess late GU toxicity."

I would add late GI toxicity to that last statement also.

I find it concerning when a non inferiority trial reports negative results given that 85% of all non inferiority trials are positive.

There have been numerous updates since 2017 and no update points to more chronic toxicity or increased failure rates.
There were also several Phase II trials with hypofractionation performed before those Phase III trials and no „surprises“ were seen there also, with follow-up times of decades by now.

 

[deleted1111261]

This is debating existence of God, but with less data and more dogma

 

[SneakyBooger]

• LATE EFFECTS TAKE 10+ YEARS TO EVOLVE
• NCCN B Cell NHL Guidelines, Page NHODG-D 1 of 4
• “late effects, which take 10+ years to evolve.”