Late GI Toxicity after EBRT w/ ENI w/ mod hypo regimen discussion

[NotMattSpraker]

Very interesting slide I saw on the Toot.

I chuckled a little at the question mark haha, as if considering conventional fractionation to minimize toxicity is some kind of mysterious behavior unique to our species, the United States Radiation Oncologist

Obviously I am right there with him being frustrating with US COI, but perhaps UK and Canadian oncologists... like... maybe dont throw stones right in the middle of your glass house that is burning down?

What exactly are these systems incentivizing?

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[Gfunk6]

Very interesting slide I saw on the Toot.

I chuckled a little at the question mark haha, as if considering conventional fractionation to minimize toxicity is some kind of mysterious behavior unique to our species, the United States Radiation Oncologist

Obviously I am right there with him being frustrating with US COI, but perhaps UK and Canadian oncologists... like... maybe dont throw stones right in the middle of your glass house that is burning down?

What exactly are these systems incentivizing?

View attachment 386325

Well, I don't really want my patients to have the best oncologic outcomes so I eschew brachytherapy boost.

On the other hand, with conventional fractionation:

 

[thesauce]

Very interesting slide I saw on the Toot.

I chuckled a little at the question mark haha, as if considering conventional fractionation to minimize toxicity is some kind of mysterious behavior unique to our species, the United States Radiation Oncologist

Obviously I am right there with him being frustrating with US COI, but perhaps UK and Canadian oncologists... like... maybe dont throw stones right in the middle of your glass house that is burning down?

What exactly are these systems incentivizing?

View attachment 386325

Who would possibly want to decrease late GI toxicity?

 

[metallica81788]

Who would possibly want to decrease late GI toxicity?

Only greedy snake oil salesmen!

 

[Ray D. Ayshun]

They should poll the radoncs in the room. See which they'd want for themselves.

 

[Palex80]

Does moderate hypofractionation really lead to more late GI toxicity?

In my understanding, only RTOG 0415 and HYPRO showed more late GI toxicity with hypofractionation.
In CHHiPP, rates were the same.
In PROFIT they were even lower with moderate hypofractionation (although not significant).

 

[RadOncDoc21]

They should poll the radoncs in the room. See which they'd want for themselves.

This! Patients sometimes ask me what I would prefer for myself and I’m always like well if ain’t broke, don’t fix it for a lot of the things we do. In the grand scheme of things, if patients were able to come in everyday for treatments, why today, are they less able to do it?

I find it toxic, I have to be present babysitting a LINAC because of fear of a whistleblower.

 

[Aphtalyfe]

This! Patients sometimes ask me what I would prefer for myself and I’m always like well if ain’t broke, don’t fix it for a lot of the things we do. In the grand scheme of things, if patients were able to come in everyday for treatments, why today, are they less able to do it?

I find it toxic, I have to be present babysitting a LINAC because of fear of a whistleblower.

So no brachy boost?

 

[thesauce]

Does moderate hypofractionation really lead to more late GI toxicity?

In my understanding, only RTOG 0415 and HYPRO showed more late GI toxicity with hypofractionation.
In CHHiPP, rates were the same.
In PROFIT they were even lower with moderate hypofractionation (although not significant).

pHART2-RCT trial (PMID 37979707) came out recently and supports conventional fractionation over hypofrac based on lower incidence of grade 3+ toxicity

 

[Burt Radnolds]

pHART2-RCT trial (PMID 37979707) came out recently and supports conventional fractionation over hypofrac based on lower incidence of grade 3+ toxicity

Kudos to the trial designers for appropriately naming it the PHART trial, given it showed increased rectal toxicity for hypofrac over conv fx. Incredible foresight there.

 

[Palex80]

pHART2-RCT trial (PMID 37979707) came out recently and supports conventional fractionation over hypofrac based on lower incidence of grade 3+ toxicity

So we now weight a randomized phase 2 trial with 180 (!) patients higher than then landmark phase 3 trial with >3000 patients?

 

[evilbooyaa]

Does moderate hypofractionation really lead to more late GI toxicity?

In my understanding, only RTOG 0415 and HYPRO showed more late GI toxicity with hypofractionation.
In CHHiPP, rates were the same.
In PROFIT they were even lower with moderate hypofractionation (although not significant).

When treating prostate ALONE there is no consistent difference in late toxicity. Most likely the late GI toxicity is similar. There is some chance that late GI toxicity is worse with mod hypo, although I believe one trial actually showed late GI was worse with conventional. So I'm willing to call it a wash.

Mod hypo consistently shows worse acute GI toxicity.

All of this is reflected in the mod hypo ASCO/ASTRO/AUA guidelines that were published in 2018: https://www.auajournals.org/doi/pdf/10.1097/JU.0000000000000071

So we know weight a randomized phase 2 trial with 180 (!) patients higher than then landmark phase 3 trial with >3000 patients?

When treating prostate + NODES, mod hypo is more toxic than conventional fx. We all *thought* that it would be fine to extrapolate to treating prostate + nodes with mod hypo despite the fact NONE of CHhiPP/PROFIT/RTOG 0415 (most commonly used mod hypo regimens) did ENI.

There is ONE trial that has evaluated prostate + nodes with conventional vs mod hypo. And that trial showed an increase in late toxicity with mod hypo.

For me, now, based on pHART, prostate RT, when including ENI should be done with conventional based on that trial. Mod hypo is a more toxic treatment based on the randomized data (limited compared to treating prostate alone) that we have.

This will not overcome the 'feelings' and 'in my hands' that people like to claim about mod hypo with nodal coverage.

 

[Palex80]

When treating prostate + NODES, mod hypo is more toxic than conventional fx. We all *thought* that it would be fine to extrapolate to treating prostate + nodes with mod hypo despite the fact NONE of CHhiPP/PROFIT/RTOG 0415 (most commonly used mod hypo regimens) did ENI.

There is ONE trial that has evaluated prostate + nodes with conventional vs mod hypo. And that trial showed an increase in late toxicity with mod hypo.

For me, now, based on pHART, prostate RT, when including ENI should be done with conventional based on that trial. Mod hypo is a more toxic treatment based on the randomized data (limited compared to treating prostate alone) that we have.

This will not overcome the 'feelings' and 'in my hands' that people like to claim about mod hypo with nodal coverage.

So, what type of increased GI toxicity was that? Rectal GI toxicity?

 

[MidwestRadOnc]

Given that nodes are treated with conventional fractionation (50.4 Gy in 28 fractions with SIB to prostate to 70 Gy), what is the mechanism that causes increased GI toxicity of this regimen vs. treating nodes to 50.4 Gy in 28 fractions then sequentially boosting to 40-45 fractions? It doesn't seem that it is the fact that there is a nodal field that is causing the issue.

 

[BobbyHeenan]

Given that nodes are treated with conventional fractionation (50.4 Gy in 28 fractions with SIB to prostate to 70 Gy), what is the mechanism that causes increased GI toxicity of this regimen vs. treating nodes to 50.4 Gy in 28 fractions then sequentially boosting to 40-45 fractions? It doesn't seem that it is the fact that there is a nodal field that is causing the issue.

Good question.

?shifts to align to prostate that pulls the nodal CTV further into bowel? Though I guess that phenomenon still occurs if you have a sequential plan too?
I do this regimen but that is one of the reasons I don't like some of these SBRT/elective nodal/SIB treatments that boost involved nodes..

It's probalby more the fact that you come off the nodes for the last couple of weeks in teh sequential long course and then you're measuring toxicity at end of treatment when they haven't had nodal xrt for weeks? I'd have to look at when the toxicity is measured/what time point. I don't know the studies that well.

Not the same situation, but I see these great dose maps/DVH's for node + disease with SIB...but we can have some decent sized shifts on a prostate or prostate bed if there is variable bladder filling/stool/gas, etc. Any shift plus rotation (you're talking about many cm's from iso to node target if iso is in the prostate...and small rotations can result in big changes to target far from iso)....

So for these case I like to do sequential boost, different iso on the node/prostate/bed after we hit 50.4

 

[MidwestRadOnc]

Good question.

?shifts to align to prostate that pulls the nodal CTV further into bowel? Though I guess that phenomenon still occurs if you have a sequential plan too?
I do this regimen but that is one of the reasons I don't like some of these SBRT/elective nodal/SIB treatments that boost involved nodes..

It's probalby more the fact that you come off the nodes for the last couple of weeks in teh sequential long course and then you're measuring toxicity at end of treatment when they haven't had nodal xrt for weeks? I'd have to look at when the toxicity is measured/what time point. I don't know the studies that well.

Not the same situation, but I see these great dose maps/DVH's for node + disease with SIB...but we can have some decent sized shifts on a prostate or prostate bed if there is variable bladder filling/stool/gas, etc. Any shift plus rotation (you're talking about many cm's from iso to node target if iso is in the prostate...and small rotations can result in big changes to target far from iso)....

So for these case I like to do sequential boost, different iso on the node/prostate/bed after we hit 50.4

This also raises a good question of what PTV margin are you using on your nodal volume. Anyone doing 5mm routinely? I typically place Iso around the top of the SVs when treating nodes.

 

[BobbyHeenan]

This also raises a good question of what PTV margin are you using on your nodal volume. Anyone doing 5mm routinely? I typically place Iso around the top of the SVs when treating nodes.

I still use 5mm on nodes because I'm worried more about toxicity than elective nodal benefit I guess.
Hard to be dogmatic on this stuff IMO. I also will under cover if adjacent bowel I'm worried about in elective areas.

 

[RadOncDoc21]

So no brachy boost?

Ceasar study showed more toxicity with brachy boost. I’m not a strong advocate for brachy in prostate though. Not only have I seen some failures (monotherapy) but severe urethra damage.

 

[Ray D. Ayshun]

Can GI tox be increased simply because the rectum is right behind the prostate (getting 70/28 vs 79/44)? Is it GI toxicity or SB toxicity and how do you differentiate those 2?

 

[evilbooyaa]

So, what type of increased GI toxicity was that? Rectal GI toxicity?

From their discussion (because they don't document otherwise in the trial):

"Although not a primary endpoint, there was a numerically higher and statistically significant difference in grade 3 late GI toxicity (rectal bleeding) in the MH arm compared with the CF group, and patients should be counseled about this potentially important difference, although it did not result in a difference in patient-reported quality of life, perhaps due to the low absolute number of patients experiencing these late toxicities. This difference occurred despite a smaller PTV margin in the MH arm."

Given that nodes are treated with conventional fractionation (50.4 Gy in 28 fractions with SIB to prostate to 70 Gy), what is the mechanism that causes increased GI toxicity of this regimen vs. treating nodes to 50.4 Gy in 28 fractions then sequentially boosting to 40-45 fractions? It doesn't seem that it is the fact that there is a nodal field that is causing the issue.

Nodal coverage of the obturators and upper presacrals increases dose to the rectum/sigmoid area compared to treating prostate alone in the intermediate range (V40-50). Unclear if the rectum can recover easier at conventional Fx doses vs mod hypo daily doses.

Good question.

?shifts to align to prostate that pulls the nodal CTV further into bowel? Though I guess that phenomenon still occurs if you have a sequential plan too?
I do this regimen but that is one of the reasons I don't like some of these SBRT/elective nodal/SIB treatments that boost involved nodes..

It's probalby more the fact that you come off the nodes for the last couple of weeks in teh sequential long course and then you're measuring toxicity at end of treatment when they haven't had nodal xrt for weeks? I'd have to look at when the toxicity is measured/what time point. I don't know the studies that well.

Not the same situation, but I see these great dose maps/DVH's for node + disease with SIB...but we can have some decent sized shifts on a prostate or prostate bed if there is variable bladder filling/stool/gas, etc. Any shift plus rotation (you're talking about many cm's from iso to node target if iso is in the prostate...and small rotations can result in big changes to target far from iso)....

So for these case I like to do sequential boost, different iso on the node/prostate/bed after we hit 50.4

It's rectal bleeding, LATE rectal bleeding requiring procedural intervention, that's the differential toxicity. None of that applies to your hypotheticals.

This also raises a good question of what PTV margin are you using on your nodal volume. Anyone doing 5mm routinely? I typically place Iso around the top of the SVs when treating nodes.

5mm w/ daily IGRT if the distance from where I am lining up (prostate/SVs) is not too far to the edge of nodal basins. 7mm if it's really far.

Can GI tox be increased simply because the rectum is right behind the prostate (getting 70/28 vs 79/44)? Is it GI toxicity or SB toxicity and how do you differentiate those 2?

It's rectal toxicity - see top of this post.

I have moved this to its own thread as I think it is a valuable discussion to save for posterity and not get lost in the wasteland that is the Rad Onc Twitter thread.

 

[ramsesthenice]

Given that nodes are treated with conventional fractionation (50.4 Gy in 28 fractions with SIB to prostate to 70 Gy), what is the mechanism that causes increased GI toxicity of this regimen vs. treating nodes to 50.4 Gy in 28 fractions then sequentially boosting to 40-45 fractions? It doesn't seem that it is the fact that there is a nodal field that is causing the issue.

Im with you, it doesn't immediately make sense. Not sure shifting/margins etc adequately explain it to me either. I think Evilbooyaa did a good job summarizing our experience above. True, the only RCT which used nodes said mod hypo is worse. But, we have already established with 3 very large trials in prostate alone that this particular signal can be quite variable. My confidence in this particular finding being consistently replicated in future studies is not particularly high.

 

[Haybrant]

From their discussion (because they don't document otherwise in the trial):

"Although not a primary endpoint, there was a numerically higher and statistically significant difference in grade 3 late GI toxicity (rectal bleeding) in the MH arm compared with the CF group, and patients should be counseled about this potentially important difference, although it did not result in a difference in patient-reported quality of life, perhaps due to the low absolute number of patients experiencing these late toxicities. This difference occurred despite a smaller PTV margin in the MH arm."



Nodal coverage of the obturators and upper presacrals increases dose to the rectum/sigmoid area compared to treating prostate alone in the intermediate range (V40-50). Unclear if the rectum can recover easier at conventional Fx doses vs mod hypo daily doses.



It's rectal bleeding, LATE rectal bleeding requiring procedural intervention, that's the differential toxicity. None of that applies to your hypotheticals.


5mm w/ daily IGRT if the distance from where I am lining up (prostate/SVs) is not too far to the edge of nodal basins. 7mm if it's really far.


It's rectal toxicity - see top of this post.

I have moved this to its own thread as I think it is a valuable discussion to save for posterity and not get lost in the wasteland that is the Rad Onc Twitter thread.

where do you guys stand again on hydrogel, why so against it but then scared about your rectal doses, even low doses (V40-50!?)

 

[medgator]

From their discussion (because they don't document otherwise in the trial):

"Although not a primary endpoint, there was a numerically higher and statistically significant difference in grade 3 late GI toxicity (rectal bleeding) in the MH arm compared with the CF group, and patients should be counseled about this potentially important difference, although it did not result in a difference in patient-reported quality of life, perhaps due to the low absolute number of patients experiencing these late toxicities. This difference occurred despite a smaller PTV margin in the MH arm."



Nodal coverage of the obturators and upper presacrals increases dose to the rectum/sigmoid area compared to treating prostate alone in the intermediate range (V40-50). Unclear if the rectum can recover easier at conventional Fx doses vs mod hypo daily doses.



It's rectal bleeding, LATE rectal bleeding requiring procedural intervention, that's the differential toxicity. None of that applies to your hypotheticals.


5mm w/ daily IGRT if the distance from where I am lining up (prostate/SVs) is not too far to the edge of nodal basins. 7mm if it's really far.


It's rectal toxicity - see top of this post.

I have moved this to its own thread as I think it is a valuable discussion to save for posterity and not get lost in the wasteland that is the Rad Onc Twitter thread.

I wonder if fiducials were mandated. I go very tight on my posterior margin even with hypo and don't have a problem sans gel.

The data suggests fiducials+cbct vs cbct alone is more reproducible and less error prone and I totally believe it. Much easier for therapists to match the posterior rectal wall interface with the fiducials there to help

 

[gvsudew]

Good question.

?shifts to align to prostate that pulls the nodal CTV further into bowel? Though I guess that phenomenon still occurs if you have a sequential plan too?
I do this regimen but that is one of the reasons I don't like some of these SBRT/elective nodal/SIB treatments that boost involved nodes..

It's probalby more the fact that you come off the nodes for the last couple of weeks in teh sequential long course and then you're measuring toxicity at end of treatment when they haven't had nodal xrt for weeks? I'd have to look at when the toxicity is measured/what time point. I don't know the studies that well.

Not the same situation, but I see these great dose maps/DVH's for node + disease with SIB...but we can have some decent sized shifts on a prostate or prostate bed if there is variable bladder filling/stool/gas, etc. Any shift plus rotation (you're talking about many cm's from iso to node target if iso is in the prostate...and small rotations can result in big changes to target far from iso)....

So for these case I like to do sequential boost, different iso on the node/prostate/bed after we hit 50.4

Agreed. Setup can be an issue when hypofrac sib to pelvis with gross nodes. I can't see how it isn't compromise and or require bigger setup margins posteriorly on prostate at rectal interface.

 

[Palex80]

where do you guys stand again on hydrogel, why so against it but then scared about your rectal doses, even low doses (V40-50!?)

 

[thesauce]

Kudos to the trial designers for appropriately naming it the PHART trial, given it showed increased rectal toxicity for hypofrac over conv fx. Incredible foresight there.

The foresight was not that incredible. It doesn't take a genius to know that would be the outcome- it is basic radiobiology. More dose per day leads to higher late complications.

We are taught alpha/beta and are made to take boards specifically on this topic and then have hypofrac shoved down our throats. Cognitive dissonance at its finest.

 

[thesauce]

So we now weight a randomized phase 2 trial with 180 (!) patients higher than then landmark phase 3 trial with >3000 patients?

Should we just ignore it?

My threshold for convenience over potentially severe toxicity seems to be very different from yours.

Why risk it? I would choose conventional for myself all day long and I would encourage my family and friends to do the same.

 

[Haybrant]

Agreed. Setup can be an issue when hypofrac sib to pelvis with gross nodes. I can't see how it isn't compromise and or require bigger setup margins posteriorly on prostate at rectal interface.

Huh? What is G3 toxicity to colon that hyofrac SIB is going to cause an issue. Elective nodes arent really hypofrac'd and all trials arent going to let you blow through large bowel/small bowel metrics. This must all be rectal.

 

[evilbooyaa]

Huh? What is G3 toxicity to colon that hyofrac SIB is going to cause an issue. Elective nodes arent really hypofrac'd and all trials arent going to let you blow through large bowel/small bowel metrics. This must all be rectal.

We don't necessarily know why (yet), but we have one randomized datapoint that states that it is the case. Given our specialty's worship of randomized control trials, how is anyone ignoring this data, in favor of their 'feelings' or 'in my hands'?

Hope the trial authors do a deep dosimetric dive to see if there's a dose threshold that predicts for this. My speculation is that it is something in the 40-50Gy range in the first 25 treatments to the rectum that is affecting this.

Folks can speculate about potential benefits of the goo to lower this risk, no data.

 

[Palex80]

I don't really understand the findings of PHART2.

CTV-PTV margins in the normofractionated were considerably larger, yet there was higher toxicity? How do we explain that?
This goes against everything we know so far concerning margins and their impact on toxicity.

I don't really understand why only the hypofractionated patients got fiducials and daily CBCT-matching on fiducials, while the normofractionated patients received no fiducials and CBCT-matching was conducted on soft tissue. Could this possibly have an influence?

 

[evilbooyaa]

I don't really understand the findings of PHART2.

CTV-PTV margins in the normofractionated were considerably larger, yet there was higher toxicity? How do we explain that?
This goes against everything we know so far concerning margins and their impact on toxicity.

I don't really understand why only the hypofractionated patients got fiducials and daily CBCT-matching on fiducials, while the normofractionated patients received no fiducials and CBCT-matching was conducted on soft tissue. Could this possibly have an influence?

Are we just ignoring the benefits of fractionation? Or conversely, the radiobiological downsides of giving radiation more quickly?

The self-flagellation will never end! Only Rad Oncs carry the water for something that is worse for patients AND worse for the Rad Onc (at least in US billing practices)!

That being said, to TRY to see the other side and figure out a way to discount what is arguably the opposite result (they set up the MH group for better success than the CF group) - Perhaps if the fiducials were placed transrectally, that could influence late rectal toxicity?

 

[NotMattSpraker]

Are we just ignoring the benefits of fractionation? Or conversely, the radiobiological downsides of giving radiation more quickly?

Were not ignoring them per se. We are recognizing them, but allowing for some flexibility to help clinics with less resources (to draw patients from hundreds of miles away)

 

[medgator]

Are we just ignoring the benefits of fractionation? Or conversely, the radiobiological downsides of giving radiation more quickly?

The self-flagellation will never end! Only Rad Oncs carry the water for something that is worse for patients AND worse for the Rad Onc (at least in US billing practices)!

That being said, to TRY to see the other side and figure out a way to discount what is arguably the opposite result (they set up the MH group for better success than the CF group) - Perhaps if the fiducials were placed transrectally, that could influence late rectal toxicity?

Fiducials are better for igrt imo, mandated if kv but even with cbct they are better and more reproducible.

Image-guided radiotherapy (IGRT) for prostate cancer comparing kV imaging of fiducial markers with cone beam computed tomography (CBCT) - PubMed

Cone-beam computed tomography and kV fiducial imaging are similar; however, more than one-fourth of CBCT and kV shifts differed enough to affect target coverage. This was even more pronounced with smaller margins (3 mm). Fiducial imaging requires less daily physician input, is less...

pubmed.ncbi.nlm.nih.gov

Evaluation of kV Cone-Beam CT Performance for Prostate... : American Journal of Clinical Oncology

ue-based automatic alignment as compared with manual alignment using intraprostatic fiducials. Methods and Materials: All patients were treated on an Elekta Synergy S linear accelerator with kilovoltage CBCT. All alignments were performed using the x-ray volume imaging system and associated...

journals.lww.com

Unless someone can't come off anticoagulation for a good reason (recent mi, stents, mechanical valve etc) everyone in my practice gets them placed, either with me or the referring GU.

 

[Palex80]

Are we just ignoring the benefits of fractionation? Or conversely, the radiobiological downsides of giving radiation more quickly?

Well, if that's the explanation, then why don't the majority of the other phase III trials on hypofractionation show a diference in late toxicity?
What's so different about this trial?

Help me understand why 68 Gy in 25 fractions to the rectum are worse than 78 Gy in 39 fractions, when at the same time 60 Gy in 20 fractions were not worse than 74 Gy in 37 fractions (CHHiP). You are saying that it has to do with treating the nodes, but how does this work from the radiation biology point of view?

 

[Tigerstang]

The foresight was not that incredible. It doesn't take a genius to know that would be the outcome- it is basic radiobiology. More dose per day leads to higher late complications.

We are taught alpha/beta and are made to take boards specifically on this topic and then have hypofrac shoved down our throats. Cognitive dissonance at its finest.

Thank you thank you thank you. I have been saying this for years.

Hypofrac data only looks good because we never do long term studies.

 

[evilbooyaa]

Well, if that's the explanation, then why don't the majority of the other phase III trials on hypofractionation show a diference in late toxicity?
What's so different about this trial?

Help me understand why 68 Gy in 25 fractions to the rectum are worse than 78 Gy in 39 fractions, when at the same time 60 Gy in 20 fractions were not worse than 74 Gy in 37 fractions (CHHiP). You are saying that it has to do with treating the nodes, but how does this work from the radiation biology point of view?

Because there is a lot we don't know about rectal constraints and toxicity.

What if the V40 of rectum over 25 fractions, when combined with a V60 in 25 fractions, are both necessary to be elevated to put patient at risk for late toxicity? This is something that would be seen only in this trial and NOT in CHhiPP

I don't know the answer as to WHY. The above is wild speculation. I know the answer is that based on our current evidence base, it DID.

And to have an entire specialty continue to state that things that exist, in randomized data, try to definitively state that it simply CANNOT be true because it does not agree with our pre-conceived notions and things that we think we know based on previous similar (but NOT identical) trial data, is the worst type of dogma we can practice.

Before this trial, I thought "mod hypo to the prostate has only been studied in prostate only patients, but meh, 45-50Gy in 25-28fx, probably fine, we do it when doing sequential boosts, in other pelvic cancers (even with chemo!), it's probably fine"

Now we have randomized data, which is one data point, predicting a 14%(!) G3+ late GI toxicity rate, reportedly driven by rectal bleeding.
Maybe the Canadians are super quick to Argon Plasma Coagulation or other procedural intervention (which would be CTCAE G3 tox) on anyone with rectal bleeding.

All I know is that the Canadians are incentivized to prove that everything is safer to be given faster (just like the UK), to the point where they treated the mod hypo patients with fiducials, better immobilization, smaller margins, and more frequent IGRT.

And Mod hypo STILL LOST the toxicity battle.

But because this goes against the dogma that has been pushed so fervently over the past 2-3 decades in prostate cancer.... suddenly it's the trial's fault? We're going to ignore and keep doing things the way we used to?

Ask yourself why you (both Palex as well as the 'proverbial' you to those reading) are so resistant to even considering changing practice based on this trial.

Just imagine with me for a second - if results were reversed, where conventional Fx caused MORE late toxicity, would that not be a nail in the coffin of conventional Fx (the way 40/15 for WBI has LESS toxicity than 50/25 Fx WBI)?

I'm not saying no patient should ever be treated with a mod hypo regimens with nodes again. If a patient who needs nodes radiated wants a faster treatment and is willing to accept toxicity difference, then sure. But we had equipoise in the setting of NO ENI data. And now we have data that offends our sensibilities. And we're going to choose to ignore it?

C'mon man.

 

[medgator]

79.2/44 4 LYFE (do plenty of 28 fxs well)

This isn't breast cancer guys and gals

 

[thesauce]

Were not ignoring them per se. We are recognizing them, but allowing for some flexibility to help clinics with less resources (to draw patients from hundreds of miles away)

No. Hypofrac has been entirely pushed by the large academic centers with lots or resources and the best insurance contracts imaginable so they can make even more money by drawing patients away from community centers by offering more toxic treatments and not telling patients these risks.

 

[thesauce]

Well, if that's the explanation, then why don't the majority of the other phase III trials on hypofractionation show a diference in late toxicity?
What's so different about this trial?

Help me understand why 68 Gy in 25 fractions to the rectum are worse than 78 Gy in 39 fractions, when at the same time 60 Gy in 20 fractions were not worse than 74 Gy in 37 fractions (CHHiP). You are saying that it has to do with treating the nodes, but how does this work from the radiation biology point of view?

Every one of these studies I’ve seen show a numerically higher toxicity with hypofrac, but the p value is not <0.05. Could just be statistical manipulation (using whatever test works) to say it’s non-inferior. I mean, what are the chances that they all have numerically higher toxicity in the hypofrac group, but they are all not found to be (statistically) more toxic?

 

[thesauce]

79.2/44 4 LYFE (do plenty of 28 fxs well)

This isn't breast cancer guys and gals

I have no problem doing 5 or 28 if they are fully informed - it’s their body. But they have to be informed and few choose a more toxic treatment in exchange for a short-term convenience. Some do and I’ll respect their wishes.

 

[Palex80]

Every one of these studies I’ve seen show a numerically higher toxicity with hypofrac, but the p value is not <0.05. Could just be statistical manipulation (using whatever test works) to say it’s non-inferior. I mean, what are the chances that they all have numerically higher toxicity in the hypofrac group, but they are all not found to be (statistically) more toxic?

CHIIP had over 3000 patients. No increase in late GI toxicity was noted. I‘m gonna place my bets on that trial and not the 180 phase II study.

 

[Palex80]

Because there is a lot we don't know about rectal constraints and toxicity.

What if the V40 of rectum over 25 fractions, when combined with a V60 in 25 fractions, are both necessary to be elevated to put patient at risk for late toxicity? This is something that would be seen only in this trial and NOT in CHhiPP

Well we do know the V40 and V60 of rectum in CHIiP in 20 fractions seemingly play no role. So, why should I care about 25 fractions?

I understand the argument that delivering low doses to all of the rectum with ENI may change the profile of acute AEs and this would perhaps explain higher rates of diarrhea. But we also know that rectal bleeding comes from high doses to the rectum.
We have thousands of patients who had doses in the range of 40/50 Gy (think rectum, think endometrial), and no issues with rectal bleeding popped up there.

I don't know the answer as to WHY. The above is wild speculation. I know the answer is that based on our current evidence base, it DID.

It is a phase II trial. The chance of this being a random finding is large.


I still fail to understand the biology, and so do the authors in the Discussion section. If I cannot explain something, I am reluctant to accept it.


Last but least: leave the discussion on political issues, the battle between academia and small centers out of this argument. Honestly, I don’t care about this.

Discuss the science.

How does a V40 in the upper rectum / sigma induce more rectal bleeding in the lower rectum with hypofractionated treatment? How does this happen?

 

[ramsesthenice]

Well we do know the V40 and V60 of rectum in CHIiP in 20 fractions seemingly play no role. So, why should I care about 25 fractions?

I understand the argument that delivering low doses to all of the rectum with ENI may change the profile of acute AEs and this would perhaps explain higher rates of diarrhea. But we also know that rectal bleeding comes from high doses to the rectum.
We have thousands of patients who had doses in the range of 40/50 Gy (think rectum, think endometrial), and no issues with rectal bleeding popped up there.


It is a phase II trial. The chance of this being a random finding is large.


I still fail to understand the biology, and so do the authors in the Discussion section. If I cannot explain something, I am reluctant to accept it.


Last but least: leave the discussion on political issues, the battle between academia and small centers out of this argument. Honestly, I don’t care about this.

Discuss the science.

How does a V40 in the upper rectum / sigma induce more rectal bleeding in the lower rectum with hypofractionated treatment? How does this happen?

100% agree about late rectal bleeding and high dose. Not saying I completely ignore V50 (because it’s don’t love acute toxicities or sloppy plans) but all the fancy modeling which insists V50 is an INDEPENDENT predictor of bleeding…mathematical garbage. I now have over 50 w/w rectal patients with at least 3 year follow up. Rectal V50 is almost 100% in all of them (I take the whole mesorectum to 50). Yet I have seen exactly 0 instances of late rectal bleeding. Never seen it any GYN patients who only got while pelvic (ie, no Brachy). When the V60 and V70 are zero, the risk of late bleeding is negligible. IE, V50 is independent of nothing. Does it matter in the context of plans with higher total doses or is it just another metric of the high dose volume that the models don’t actually correct for? No one knows for sure.

Also, not trying to be the pacifist here, but are a decent number of us also doing a middle ground here? FLAME style treatment is half way between mod hypo and conventional (to the whole gland) and is probably superior to either with respect to control.

 

[thesauce]

I still fail to understand the biology, and so do the authors in the Discussion section. If I cannot explain something, I am reluctant to accept it.

Evidence-based medicine is not intuitive. If all we had to do was what made sense, we wouldn’t have had to go to school for 13 years.

 

[thesauce]

Last but least: leave the discussion on political issues, the battle between academia and small centers out of this argument. Honestly, I don’t care about this.

Discuss the science.

Unfortunately, these lines are entirely blurred. There is an agenda and that agenda does, if even subconsciously (let’s hope so), skew results. I know for a fact it skews the chances of publication.

Try and open a standard-fractionation dose-escalation study. I know someone who had it turned down because it “wasn’t the direction of the field.” Basically admitting that the science is irrelevant and what matters is what certain people want to see happen.

The endpoint they were looking for was actually improved PFS by the way, not just equivalence like all these non-inferiority trials. The fact that academics are building their careers on NOT improving Oncologic outcomes is very very sad.

 

[RadOncDoc21]

Unfortunately, these lines are entirely blurred. There is an agenda and that agenda does, if even subconsciously (let’s hope so), skew results. I know for a fact it skews the chances of publication.

Try and open a standard-fractionation dose-escalation study. I know someone who had it turned down because it “wasn’t the direction of the field.” Basically admitting that the science is irrelevant and what matters is what certain people want to see happen.

The endpoint they were looking for was actually improved PFS by the way, not just equivalence like all these non-inferiority trials. The fact that academics are building their careers on NOT improving Oncologic outcomes is very very sad.

💯

 

[evilbooyaa]

Well we do know the V40 and V60 of rectum in CHIiP in 20 fractions seemingly play no role. So, why should I care about 25 fractions?

I understand the argument that delivering low doses to all of the rectum with ENI may change the profile of acute AEs and this would perhaps explain higher rates of diarrhea. But we also know that rectal bleeding comes from high doses to the rectum.
We have thousands of patients who had doses in the range of 40/50 Gy (think rectum, think endometrial), and no issues with rectal bleeding popped up there.


It is a phase II trial. The chance of this being a random finding is large.


I still fail to understand the biology, and so do the authors in the Discussion section. If I cannot explain something, I am reluctant to accept it.


Last but least: leave the discussion on political issues, the battle between academia and small centers out of this argument. Honestly, I don’t care about this.

Discuss the science.

How does a V40 in the upper rectum / sigma induce more rectal bleeding in the lower rectum with hypofractionated treatment? How does this happen?

First bolded - I will try to going forward.

Second bolded - I don't know, but until I have OTHER data comparing this scenario this will be what I tell patients.

What will you tell patients? "Oh, this group ran a randomized trial, saw statistically worse rectal bleeding requiring procedural intervention in the mod hypo arm, but I think it's nonsense because it doesn't make sense compared to other SIMILAR data that we evaluate"

I don't know the why. But to ignore the data (in absence of other data points) because we don't know the why is not something I can get on-board with.

 

[Palex80]

First bolded - I will try to going forward.

Second bolded - I don't know, but until I have OTHER data comparing this scenario this will be what I tell patients.

What will you tell patients? "Oh, this group ran a randomized trial, saw statistically worse rectal bleeding requiring procedural intervention in the mod hypo arm, but I think it's nonsense because it doesn't make sense compared to other SIMILAR data that we evaluate"

I don't know the why. But to ignore the data (in absence of other data points) because we don't know the why is not something I can get on-board with.

Well, the far larger POP-RT trial, with moderate hypofractionation, did not show these high rates of rectal bleeding.
Actually, I am not aware of any other trial with or without ENI in the prostate field with hypofractionation that managed to demonstrate 13.5% grade III gasttointestinal toxicity. How do we explain this?

 

[evilbooyaa]

Well, the far larger POP-RT trial, with moderate hypofractionation, did not show these high rates of rectal bleeding.
Actually, I am not aware of any other trial with or without ENI in the prostate field with hypofractionation that managed to demonstrate 13.5% grade III gasttointestinal toxicity. How do we explain this?

I would really caution against cross trial comparisons here. POP-RT used RTOG grading criteria for toxicity IIRC, which are harder to get to G2 and especially G3 toxicity compared to CTCAE.

Again, maybe the Canadians pull the trigger on procedural intervention very early, and maybe some of these patients could be more conservatively managed. But I'd expect the trigger to be the same regardless of what arm these interventions were on.

I'm not saying that the G3+ rectal toxicity rate is truly going to be 14% in all centers worldwide. Just saying that it appears that the late GI toxicity is higher.

No other prostate trial has done mod hypo with ENI compared to conv fx w/ ENI.