Protons = bad choice for IDH-mutated gliomas?

[Palex80]

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It's merely an abstract and not a detailed final analysis, but there's something very wrong happening here...

https://academic.oup.com/neuro-oncology/article/27/Supplement_5/v102/8318267

The NIFS (new treatment for either tumor progression or therapy effects) in the entire cohort had an HR of 3.07 (p<0.01), in favor of photons.

For WHO grade 2 glioma, no significant differences were seen in any of the outcomes.
For WHO grade 3 glioma results were: NIFS HR=5.0 (p<0.01), OS HR=5.0 (p<0.01), PFS HR=4.0 (p<0.01) and PsPFS HR=3.1 (p<0.01), all favoring photons. In WHO grade 3 glioma, 5-year OS and PFS were 59.2% and 34.1% for protons, and 83.9% and 79.1% for photons, respectively.

Median follow up is also rather short (44.2 months), which may make any PFS differences for grade 2 gliomas very hard to notice (all patients got chemotherapy too).

 

[BobbyHeenan]

It's merely an abstract and not a detailed final analysis, but there's something very wrong happening here...

https://academic.oup.com/neuro-oncology/article/27/Supplement_5/v102/8318267

The NIFS (new treatment for either tumor progression or therapy effects) in the entire cohort had an HR of 3.07 (p<0.01), in favor of photons.

For WHO grade 2 glioma, no significant differences were seen in any of the outcomes.
For WHO grade 3 glioma results were: NIFS HR=5.0 (p<0.01), OS HR=5.0 (p<0.01), PFS HR=4.0 (p<0.01) and PsPFS HR=3.1 (p<0.01), all favoring photons. In WHO grade 3 glioma, 5-year OS and PFS were 59.2% and 34.1% for protons, and 83.9% and 79.1% for photons, respectively.

Median follow up is also rather short (44.2 months), which may make any PFS differences for grade 2 gliomas very hard to notice (all patients got chemotherapy too).

I would guess steroids (?were they counted as next intervention?), surgery, or bevacizumab for necrosis, seen even more at a higher dose level on G3's versus not seen as much in G2's. I guess it was not randomized, so maybe bigger tumors more likely to be sent for protons?

There is just so much smoke rising across many treatment sites that biologically at the Bragg peak (often the interface of tumor/normal tissue) there is a lot of damage/inflammation with protons....seen in breast (rib fracture, implant/reconstruction), mandible necrosis, and peds brainstem enhancement. I'm told there are planning ways to minimize this, but until we can model it clearly these types of reports just keep popping up.

 

[Palex80]

I would guess steroids (?were they counted as next intervention?), surgery, or bevacizumab for necrosis, seen even more at a higher dose level on G3's versus not seen as much in G2's. I guess it was not randomized, so maybe bigger tumors more likely to be sent for protons?

There is just so much smoke rising across many treatment sites that biologically at the Bragg peak (often the interface of tumor/normal tissue) there is a lot of damage/inflammation with protons....seen in breast (rib fracture, implant/reconstruction), mandible necrosis, and peds brainstem enhancement. I'm told there are planning ways to minimize this, but until we can model it clearly these types of reports just keep popping up.

Absolutely correct, I presume the interventions were partly due to pseudoprogressions and necrosis due to protons.
However, the PFS endpoints are also very much in favor of photons. Unless patients actually died because of more proton-side-effects (which would be events for PFS), why is there such a big difference in terms of progression?

In WHO grade 3 glioma, 5-year OS and PFS were 59.2% and 34.1% for protons, and 83.9% and 79.1% for photons, respectively.

That's a lot of difference!

 

[TheWallnerus]

I would legit be nervous to use protons all the time especially if somehow protons got cheap and achievable for non academic centers. The high reimbursement and beautiful isodose lines onscreen have turned out to be Scylla and Charybdis?

 

[BobbyHeenan]

Absolutely correct, I presume the interventions were partly due to pseudoprogressions and necrosis due to protons.
However, the PFS endpoints are also very much in favor of photons. Unless patients actually died because of more proton-side-effects (which would be events for PFS), why is there such a big difference in terms of progression?

In WHO grade 3 glioma, 5-year OS and PFS were 59.2% and 34.1% for protons, and 83.9% and 79.1% for photons, respectively.

That's a lot of difference!

Do you think some of the "progression" could be necrosis or pseudoprogression they are calling progression?

We have a hard time differentiating that and even at a few huge regional academic centers I see them struggle with that as well in some cases, even with advanced imaging like MR perfusion or spec or amino acid pet.

 

[Gfunk6]

It's merely an abstract and not a detailed final analysis, but there's something very wrong happening here...

https://academic.oup.com/neuro-oncology/article/27/Supplement_5/v102/8318267

The NIFS (new treatment for either tumor progression or therapy effects) in the entire cohort had an HR of 3.07 (p<0.01), in favor of photons.

For WHO grade 2 glioma, no significant differences were seen in any of the outcomes.
For WHO grade 3 glioma results were: NIFS HR=5.0 (p<0.01), OS HR=5.0 (p<0.01), PFS HR=4.0 (p<0.01) and PsPFS HR=3.1 (p<0.01), all favoring photons. In WHO grade 3 glioma, 5-year OS and PFS were 59.2% and 34.1% for protons, and 83.9% and 79.1% for photons, respectively.

Median follow up is also rather short (44.2 months), which may make any PFS differences for grade 2 gliomas very hard to notice (all patients got chemotherapy too).

With treatment planning software modeling photons what you see is (mostly) what you get. For protons, the entire field is not a flat 1.1 RBE as proponents sometimes like to pretend. It can spike on the distal end of the target and in IDH-mutant grade 3 gliomas, this probably results in perivascular injury and overcooked margins to normal brain. Probably a combination of necrosis and/or pseudoprogression but the massive detriment in OS cannot be denied.

 

[Doctorer]

Do you think some of the "progression" could be necrosis or pseudoprogression they are calling progression?

We have a hard time differentiating that and even at a few huge regional academic centers I see them struggle with that as well in some cases, even with advanced imaging like MR perfusion or spec or amino acid pet.

That was my first thought too, but why the big OS difference?

 

[Gfunk6]

That was my first thought too, but why the big OS difference?

Probably because protons underdosed the tumor and overdosed the edges, injuring normal brain. Sub-therpaeutic dose to target plus more injury to surrounding brain = decreased OS.

 

[BobbyHeenan]

That was my first thought too, but why the big OS difference?

True. Probably treatment related patient decline - long term steroids or bev can take it's own toll.

Will be really curious to see a full text and someone break down this stuff.

Without randomization, selection bias may be at play as well (?bigger tumors, hard to reach areas with more STR?).

 

[Doctorer]

Probably because protons underdosed the tumor and overdosed the edges, injuring normal brain. Sub-therpaeutic dose to target plus more injury to surrounding brain = decreased OS.

Eh, not sure I buy that. Brain proton plans typically look "fine."

True. Probably treatment related patient decline - long term steroids or bev can take it's own toll.

Will be really curious to see a full text and someone break down this stuff.

Without randomization, selection bias may be at play as well (?bigger tumors, hard to reach areas with more STR?).

Yeah, I'm wondering if selection is a factor as well.

 

[Palex80]

ClinicalTrials.gov

www.clinicaltrials.gov

Patients with grade 2 glioma were treated with a 5mm CTV margin to compensate for microscopic invasion. Patients with grade 3 IDHmt tumors were treated with 10mm CTV margins.

Could it be that the tight margins caused more marginal failures in the proton arm?

 

[Palex80]

Yeah, I'm wondering if selection is a factor as well.

Could work both ways though.

A patient with a poor PS and/or in urgent need of treatment due to do a progressive/unresectable tumor will likely get … photons!

 

[Gfunk6]

Eh, not sure I buy that. Brain proton plans typically look "fine."

I'm sure they do, but it is misleading as most planning tools are not RBE/LET aware.

 

[Mandelin Rain]

ClinicalTrials.gov

www.clinicaltrials.gov

Patients with grade 2 glioma were treated with a 5mm CTV margin to compensate for microscopic invasion. Patients with grade 3 IDHmt tumors were treated with 10mm CTV margins.

Could it be that the tight margins caused more marginal failures in the proton arm?

Also, less low dose bath beyond those (tight) margins. The "too conformal 2.0" conundrum that the old heads used to talk about when IMRT became a thing.

 

[Neuronix]

I looked at our institutional experience of around 200 IDH-mutant glioma (~100) and meningioma (~100) patients treated about 50/50 with protons and photons retrospectively.

In the glioma patients we couldn't find any obvious differences in anything. Part of this is that it's hard to tell progression vs. pseudoprogression vs. RT necrosis in that cohort. One of the neuro-oncologists was quite vocal that their IDH-mutant oligodendroglioma cases had much worse outcomes with protons, though it just happened to be a selection bias in that doc's case (i.e. their patients had the problems, I believe out of coincidence). These were a few cases of impressive and symptomatic RT necrosis in young adults right at the beam edge particularly at the edge of the ventricles.

In the meningioma patients we could clearly separate RT induced intra-axial changes vs. extra-axial progression. It was obvious that the protons caused more imaging induced changes and earlier. They were also more symptomatic, though the p worked out to something like 0.08. The problem I have with measuring toxicities is that everyone cares about CTCAE v5, but a lot of serious neurologic toxicities (e.g. partial body weaknesses) are grade 2 and I believe are being under-recorded. We did our best to account for all that.

Despite being previously one of the largest users in the USA for adult CNS tumors, I've never been a believer in protons for anything outside peds or some very unusual adult conditions. The problem I always had is that the patients show up demanding protons, and if they don't get them they just go somewhere else with the protons.

The whole neuro-oncology field in the USA is weird like this. Patients come in demanding vaccine trials. Vaccines have failed repeatedly in glioblastoma and other CNS malignancies. Where else in the body do we use vaccines to treat an active cancer? On top of that, the CNS is particularly immunologically cold and the immune system is less understood, so it's the last place you'd want to use a vaccine. Immunotherapy actually worsens overall survival in primary glioblastoma. Meanwhile, there are a number of institutions actively marketing to patients and promoting single arm studies to come get their protons and/or vaccines, none of which do much of anything.

 

[BobbyHeenan]

I looked at our institutional experience of around 200 IDH-mutant glioma (~100) and meningioma (~100) patients treated about 50/50 with protons and photons retrospectively.

In the glioma patients we couldn't find any obvious differences in anything. Part of this is that it's hard to tell progression vs. pseudoprogression vs. RT necrosis in that cohort. One of the neuro-oncologists was quite vocal that their IDH-mutant oligodendroglioma cases had much worse outcomes with protons, though it just happened to be a selection bias in that doc's case (i.e. their patients had the problems, I believe out of coincidence). These were a few cases of impressive and symptomatic RT necrosis in young adults right at the beam edge particularly at the edge of the ventricles.

In the meningioma patients we could clearly separate RT induced intra-axial changes vs. extra-axial progression. It was obvious that the protons caused more imaging induced changes and earlier. They were also more symptomatic, though the p worked out to something like 0.08. The problem I have with measuring toxicities is that everyone cares about CTCAE v5, but a lot of serious neurologic toxicities (e.g. partial body weaknesses) are grade 2 and I believe are being under-recorded. We did our best to account for all that.

Despite being previously one of the largest users in the USA for adult CNS tumors, I've never been a believer in protons for anything outside peds or some very unusual adult conditions. The problem I always had is that the patients show up demanding protons, and if they don't get them they just go somewhere else with the protons.

The whole neuro-oncology field in the USA is weird like this. Patients come in demanding vaccine trials. Vaccines have failed repeatedly in glioblastoma and other CNS malignancies. Where else in the body do we use vaccines to treat an active cancer? On top of that, the CNS is particularly immunologically cold and the immune system is less understood, so it's the last place you'd want to use a vaccine. Immunotherapy actually worsens overall survival in primary glioblastoma. Meanwhile, there are a number of institutions actively marketing to patients and promoting single arm studies to come get their protons and/or vaccines, none of which do much of anything.

Great post.

I have definitely seen more necrosis right at ventricle edge with photons. I have a busy CNS practice and that is incredibly common to see in my experience with any grade gliomas. Soooo hard to tell progression versus necrosis but many patients I thought were progressing ending up having stable enhancement/necrosis years out in those locations.

===

Have had same experience with patients demanding protons too. Why as a busy rad onc would you spend an hour talking them out of that too if you have protons at your facility? It is a consequence of marketing, unfortunately. It is not fixable.

 

[RickyScott]

I looked at our institutional experience of around 200 IDH-mutant glioma (~100) and meningioma (~100) patients treated about 50/50 with protons and photons retrospectively.

In the glioma patients we couldn't find any obvious differences in anything. Part of this is that it's hard to tell progression vs. pseudoprogression vs. RT necrosis in that cohort. One of the neuro-oncologists was quite vocal that their IDH-mutant oligodendroglioma cases had much worse outcomes with protons, though it just happened to be a selection bias in that doc's case (i.e. their patients had the problems, I believe out of coincidence). These were a few cases of impressive and symptomatic RT necrosis in young adults right at the beam edge particularly at the edge of the ventricles.

In the meningioma patients we could clearly separate RT induced intra-axial changes vs. extra-axial progression. It was obvious that the protons caused more imaging induced changes and earlier. They were also more symptomatic, though the p worked out to something like 0.08. The problem I have with measuring toxicities is that everyone cares about CTCAE v5, but a lot of serious neurologic toxicities (e.g. partial body weaknesses) are grade 2 and I believe are being under-recorded. We did our best to account for all that.

Despite being previously one of the largest users in the USA for adult CNS tumors, I've never been a believer in protons for anything outside peds or some very unusual adult conditions. The problem I always had is that the patients show up demanding protons, and if they don't get them they just go somewhere else with the protons.

The whole neuro-oncology field in the USA is weird like this. Patients come in demanding vaccine trials. Vaccines have failed repeatedly in glioblastoma and other CNS malignancies. Where else in the body do we use vaccines to treat an active cancer? On top of that, the CNS is particularly immunologically cold and the immune system is less understood, so it's the last place you'd want to use a vaccine. Immunotherapy actually worsens overall survival in primary glioblastoma. Meanwhile, there are a number of institutions actively marketing to patients and promoting single arm studies to come get their protons and/or vaccines, none of which do much of anything.

I don’t have nearly the cns experience that you do, but I almost never see late cns radiation changes with conventional fractionation for meningiomas to 50 gy.

 

[Neuronix]

I don’t have nearly the cns experience that you do, but I almost never see late cns radiation changes with conventional fractionation for meningiomas to 50 gy.

Good point: there is a dependence on dose.

Where you see the toxicities more are in the 54-59.4 Gy range. You can certainly make the case that we were just too aggressive all along, but 54 Gy for benign meningioma and 59.4 Gy for atypical meningioma as well as 54 Gy for grade 2 IDH-mutant glioma is standard in academics in the US.

It may make sense to dose de-escalate protons for that reason. Some of my colleagues actually started doing that on their own--going on the higher dose range of photons and lower dose range of protons--since they were seeing these effects I'm describing.

 

[TheWallnerus]

Isn’t there this line in Casablanca where someone says at Rick’s cafe “Nobody is happy here but at least we’re all having a good time.” I feel like the proton centers could be this way with their clinical outcomes and reimbursement/physical plant.

 

[Palex80]

I hear all your points concerning necrosis and radiological changes, but the OS data in the Dutch cohort point out that something else beyond that, may be happening.

 

[Neuronix]

I hear all your points concerning necrosis and radiological changes, but the OS data in the Dutch cohort point out that something else beyond that, may be happening.

Need to see the paper. The abstract leaves too many methodological questions to draw conclusions.

Isn’t there this line in Casablanca where someone says at Rick’s cafe “Nobody is happy here but at least we’re all having a good time.”

Sounds like academics to me.