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update Management in two

and hello good morning all faral committees all faral and pastoral

attendees uh welcome to the 26 uh faral webinar uh my name is Dr a I will be a

moderator for this session first of all may I invite Professor

imar President elect of Faro to give a

greeting hello good morning from shangai Thailand I'm pleased to welcome you to

the 26 faral webinar which is organized By Thai Association of radiation orality

or testro this is part of a series of farro webinar which aims at providing

knowledge to our far member countries for the benefit of cancer patients in

Asia um the discovery of molecular analysis of idh mutation and one p19

cute Cil has led to uh a profile shift in the way that Goma grade 2 to three

are classified and how treatment decisions are made this webinar today will fulfill your knowledge by assistant

professor William briam from Department of radiation oncology mayor Clinic

Minnesota thank you very much for your contribution to Farrow um Dr Green and I

would like to thank pastro and also iros for the cooperation and make this webinar is international consistently

with the name and demand of the Farrow itself I thank you very much and I wish

you all a very successful webinar today thank you very

much thank you Dr in before I introduce our speaker I would like to remind all

attendees to mute your microphone uh if you have any question please type in the

Q&A box uh we would have time for Q&A at the end of the session If you experience

any uh technical difficulty please send a message in the chat box and please

note that uh a record of this session you post on the far website and now I'm

pleased to introduce our guest speaker assistant professor William Breen he's a

radiation oncologist from mayor Clinic Rochester Minnesota USA he graduated

from mayor Clinic uh school of medicine and pursue his residency training at

Mayo Clinic as well current he is a share of a CSS research group and a

principal investigator of many research he has more than 40 publication and

Abstract in uh focusing on CNS hematologic malignancy and toic

malignancy his publication included in the regional uh Journal of neurooncology

and neurooncology today he will give us a talk about update Management in Goma

wh get through to3 please welcome Dr Breen

thank you very much atah let me share my slides here and uh can you confirm with

me that you're able to see the slides do I need to switch it around here can you

see the slides yes okay please start okay well uh thanks again for the very

kind introduction my name is Will Reen I'm a radiation oncologist at Mayo Clinic in Rochester I'm really grateful

for the opportunity to join you all and talk to you today I haven't had the chance to U visit your beautiful part of

the world yet I hope I get to someday and maybe meet some of you in person and see the places where you and your

patients live and work um here's some of my disclosures um I'm employed by Mayo

Clinic and we do have a proton Center so as we get into some of the discussions and we talk about ongoing trials looking

at the value of protons which at least in North America is a fairly controversial thing um I think it's

important to know whether the person that's speaking has access to them or not and I do so that's a a bias that

exists I trained here and I work here um otherwise I did some Consulting with GE

Healthcare relating some related to some pet tracers used in the brain that aren't related to this talk at all and I

will briefly acknowledge I won't say support but off label use of idh

Inhibitors in lowra cleoma as we get to discussion of the Indigo trial towards the

end so here's a picture of Mayo Clinic in Rochester Minnesota um we got our first

snow here a couple weeks ago this year uh the snow is melted now but we have many months ahead of it looking like

this with uh with snow here so probably a little bit colder than where you guys

are currently in this talk today I'm gonna first of all as was mentioned earlier I'm going to go into a little

bit of the the background so that we can understand the modern classification of Goma and some of the changes that we've

um we've had with molecular testing and genetic testing and how that influences the way we think about treatment for

these patients uh we'll talk about the classic treatment paradigms in order to step the stage for how things are

changing what are the current directions we're looking at and also to contextualize some of the modern clinical

trials and then we will look at some uh very recent data and current trials that

will likely Define our practice moving forward and then uh posit some future directions at the the field may

go uh in this talk I'm going to talk about primarily grade 2 and three ID

mutant Gom so not going to get into some of the more rare things like brain stem Goma optic pathway Goma Etc that would

be another talk so first for the background uh as we all know brain and

central nervous system tumors are not the most common type of tumor that we see but um you know especially in

younger younger cohorts they're often very lethal and cause a great deal of morbidity and mortality so is the number

one uh cause of death at least in the United States birth to 19 years and second in the next highest uh the next

youngest cohort uh our brain and CNS Banes and so while they're less common they are lethal and they cause a great

deal of problems for our patients and we need to work on improving our

outcomes uh historically for these gomas have been classified by histology so by

a by a pathologist looking under the microphone under the microscope and we

need to contextualize that when we think about all these old clinical trials they all used Histology for inclusion and so

modern treatments and modern trials won't perfectly reflect the old trials um we use these four classic criteria

mitotic index endothelial proliferation nuclear atypia necrosis uh quite a bit easier to remember than the algorithms

use today for diagnos and overtime genetic and molecular characteristics have been integrated

alongside foscal histology so it's important that they haven't replaced U

classic histology they work together so right now we're kind of in a mixed picture between the old school

pathologic methods as well as the the newer School genetic and molecular characterization of

tumors so um sorry I'm just trying to move this out of the way I don't know if

see it so the modern classification of Goma

the first place to start is that oligodendrogliomas as were historically histologically classified are idh

mutated 1 p9q codeleted tumors and so they're now molecularly defined tumors

they can be either grade two or three and this is all according to the 2021 wh

classifications astrocytomas on the other hand are not 1 p19 Q Co deleted

and they would typically have loss of atrx there's some testing now where loss of atrx is seen 1 p19 Q doesn't even

need to be tested the diagnosis is over it's an astrocytoma with

atrx uh G blastoma are idh wild type and grade four so um idh wild type grade

four G blastoma is now the the diagnosis idh mutant tumors can be grade two grade

three or grade four four astrocytoma so there's now grade four astrocytoma idh

mutant that's not a GL blastoma these patients we know would have historically been treated on G blastoma trials but

have much better uh outcomes than than the idh wild type gleo blastomas they're

kind of an orphan right now in terms of how do we treat them do we treat them like Glo blastomas do we treat them like

idh mutant tumors and even within our our group in our department we have um

seven or eight people treat brain tumors in our department and within us there's variability on how to handle those grade

four idh mutant astrocytomas another very important factor is the

cdkn2ab deletion uh in idh mutant tumors that's the most important prognostic

factor and so if patients have homozygous deltion of that marker that automatically moves them up to a grade

four which we'll talk about a little bit more so this is a bit of a complicated

algorithm here but but I think it contains mostly all the information that I that I just mentioned and so I I show

it here and I'm happy to share these slides too through tharai if anybody was interested but essentially the first

thing we do when we have a a Goma of some type is we check the idh status if

it's idh wild type we're we're here and we have some histologic features it's a

GL blastoma that's the same tumors that have always been called glol blastoma if

there isn't those histologic features uh they can have these other molecular

features of GBM like egfr tur uh 710 uh to meet that diagnosis of G blastoma

versus some of these H3 diagnoses that we won't get into as much today on the other side on the idh mutant side if

they're 1 p9q codeleted they're oligos if they've lost atrx they're astrocytomas either of these can be

grade two or three astrocytoma idh mut can also be grade four and if they have

cdk and to 2ab deleted than their grade four so that's a lot of information really fast I have this uh piece of

paper printed out uh by my desk just to make sure that I'm I'm keeping it straight and I think you can't uh review

it enough times this paper here that I have the citation in the corner from neurooncology uh really describes how

they came to these diagnoses for the 2021 W classifications and again

summarizes um summarizes those things that we just disc that astrocytoma can be up to grade four idh mutant Le blasa

is always grade four oligos can be grade two or three there's been some conversations about whether there should

be a grade four oligo dendro Goma many of you in the audience have probably um

anecdotally seen these oligo dendro gomas that um act like a grade four

tumor that are very very aggressive locally recurrent and have shorter

survival and so you know I won't be surprised if eventually we do have a a grade four 1 p9q codal enity at some

point this what did the cdk n2a um marker come from uh it's it's a lot of

letters and hard to remember so um you know I hope it's an important one this

uh study here of over 2,000 idh mutant patients from nine different institutions showed that a little bit

over one fifth of them had homozygous cdk n2a uh deletions and those patients

with those deletions did worse and actually much much worse as you can see here progression free survival of 91

versus 31 months and overall survival of 154 months down to 61 months so getting

into the magnitude of of idh mutation itself how prognostic and predictive

that is so this is a a really important one and for us within the idh mutant

tumors before 2021 we had started to kind of use this as one of our decision

points on whether a patient could undergo observation after a gross to re section or not but now the who

classifications have caught up to reflect the importance of that marker and this is just to show that that it

appears to be a very important marker basically in all all groups and all studies and especially within idh mutant

tumors so which which markers should we look at here in a summary for grade two

and three we should look at the idh egfr tri promoter chomosome 710 basically

we're doing this to find out is this a g blastoma or not uh next we should look at 1 p19 q and atrx to find one or the

other to find if it's an oligodendroglioma versus an asterosoma and then finally is just discussed the

cdk n2a should be looked at as a very important prognostic factor to see

whether it's a grade four idh mutant tumor so what are the implications here

historical trials when we're looking at why we use a dose and fractionation for a given tumor those trials were based on

you know histologic rating without idh status and so um we have to give a little bit more thought to just doing

doses based on grades which is what we're still often doing in clinic but I think we'll be an evolving Target as we

move forward there are some unclear areas about how to treat them after the 2021 classification uh for idh mutant

tumors should we treat them all with 54 gray or less including a grade three or grade four I've never treated a grade

four um Goma with 54 gray but maybe we'll learn that if they idh mutant that

that's the that's the the right dose to use uh with time G blastoma idh wild type should we

take them all the 60 gray even the the ones that are histologically appearing lower grade the so-called molecular gbms

that previously would have got lower doses we are treating all these to to 60a at least in Rochester so beyond the

ular findings there's also quite a lot of potential for Imaging um all

pathologic diagnoses depends on um how much you've sampled and we know there can be quite a bit of heterogeneity

within tumors as there's different cell lines evolving and going different directions and so the power of radiomic

tools different Imaging methods to help us prognosticate patients and understand

the biology without uh pathology and without anything invasive will become

increasing important this is one of the most kind of basic for for this talk

grade two grade three Goma Imaging findings that many of you may be familiar with the t2 mismatch so this is

on a T2 MRI and um as many of the audience know uh so when you see this

this very characteristic finding where there's T2 hyper intense and T2 flare is

only bright at the edges of the tumor that's you know pretty much 100% chance that that's going to be an IDE mutant

asoma I've never seen that not hold and there's a number of papers including the one listed below that discussed this of

course it's not 100% sensitive there's going to be many idh mutant astrocytomas

that don't have this finding but once you see it this is the thing where our pathology colleagues will say you know

we're going to put them out of business because we don't need them to to diagnose what this tumor is going to

be um there's other Imaging that may help us with Target delineation and better understanding of biology ology uh

this is uh from a patient that we enrolled on a clinical trial of 18 EP Doopa which is an amino acid pet scan

and as you can see oligodendroglioma is just light up like a light bulb we'll be

submitting this to Astro this year but it seems to be a a very sensitive

Imaging uh method for this and what could that be used for why is that helpful well first of all to detect

multifocal disease and secondly if there's quite a large area of T2 abnormality and we think some of it's

edema and some of it is tumor the Pet Scan may help to um to know what's tumor

within there and what may need a higher dose or even no dose it was just edema but this is all still in the research

realm and finally spectroscopy um looking at the the ratio

of the choline to the NAA here is specific for tumors so you can see on this side where it's bright on the

spectroscopy you would have a higher ratio than you would over here and we don't do too much of this but um there

there have been circumstances where we've utilized it and other institutions certainly use it more so spectroscopy is

another another Imaging method that could potentially be used to help us um

identify where the tumor is in a given patient if there's biologic changing within a patient uh or

progression so getting into the standard standard treatment with some older and

more recent studies of grade two and grade three Gom uh the general treatment Paradigm as we

all know is maximal safe per section followed by Aden treatment with

radiation chemotherapy other systemic therapies a combination of those so

surgery for low grade Goma there the thought here is that we know it provides

us a diagnosis doing the reection and we strongly believe that it improves outcomes however there's never been a a

definitive randomized control trial asking exactly this question about um

reection for improving outcomes um there's a good bit of prospective and

and retrospective data though that strongly hints that having less tumor around is a good thing for patients so

the low risk arm of rtog 9802 uh they saw direct correlation between residual

disease with the risk of recurrence uh there's a systemic systematic review of 35 retrospective studies that looked at

the Rel relationship between reection and overall survival of those 35 26 of

them showed that increasing extent of reection directly correlated with improved overall survival whereas only

six showed no no correlation between resection and survival the remaining studies were a little more ambiguous in

their findings this is a study that that I really like here uh looking at the role of of surgery it was a

retrospective study of 228 patients they use semi automated software on the t2

sequences to define the the volume of residual disease um and then they saw

they looked to see if that correlated with overall survival uh especially in astrocytoma which it which it did um and

even very small amounts of post-operative tumor appear to impact overall survival so whenever your

surgeon if there was just a biopsy and you're kind of questioning should we go ahead with radiation or uh if if the

surgeon feels that they can safely reect more tumor especially in the case of astrocytoma we often encourage them to

do so so here is some of their survival curves uh based on the amount of

residual disease and here you can see um an overall oligodendroglioma astrocytoma

that the blue line no residual disease has the best outcomes which wouldn't surprise you I think the most striking

part of this is here in the astrocytoma curve at number panel number c here you

see that the blue line no residual disease is much better than even this one that has 0.1 to five cc's of tumor

so getting rid of all of the the detectable tumor on surgery seems to be

a very uh positive prognostic factor of course sometimes they can based on the anatomy or other patient factors this is

a difficult to look at set of um figures here but basically what it's getting at is it's using different cut points of

CC's um to split whether there's an improvement in overall survival so this

you know we just talked about if there's uh no disease left versus 0.1 or more

it's very clear there's better overall survival but the question this is getting at is well if you can't do a GTR

is it still worth debulking tumor and you can see here all the way up to 20 cc's of tumor um there's still a

significant overall survival benefit to having less than 20 CC's versus more than 20 CC's so what this tells me is

that if the choices between doing some debulking versus biopsy only we would uh

prefer there be debulking whatever can be safely reected um and then there was a

Norwegian study that looked at two different hospitals one who used biopsy only and one who used reection and they

treated all the patients in their area so it's not randomized but it's only dependent on residential address and

they had 153 patients they had significantly improved survival in the hospital that did reection rather than

bio so just another indication that you know we would support surgery in in these

patients as much as we can so classic adant treatment following reection we base treatment based on the risk and the

risk is based on either the rtog factors which is patients less than 40 years old

uh who have had a gross total reection and so if they have no neurologic symptoms no seizures those patients have

you know by some Bend safely observed and we'll get into that a little bit more or by the URC the European factors

if they have none or limited of the factors again 40 years old as for cytology a big tumor greater than six

centimeters crossing the midline or preoperative neurologic deficits these come from old studies from the 90s and

and 80s but some of these things can still be uh useful for us so the urtc

study they randomized patients between 54 gray and observation and patients

with low-grade Goma they were histologically defined and they saw that there was a significant difference in

progression free survival with radiation but no difference in overall survival

and so you know when we talk to patients that are in this group we talk to them there's about a two-year difference in

median progression free survival um by doing radiotherapy or not and maybe uh

more importantly some of the other differences that we see is that there's less seizures with radiation over time

um and also there's no increase in the rate of malignant transformation there was a time when a lot of neuro

oncologists including some of those at M Clinic were worried that radiation for lowgrade tumors was going to Spur their

um transformation into higher grade tumors and we know that you know TMZ there may be some concern for that but

with u with radiation we don't have evidence that it speeds malignant transformation so that's not a reason to

whip hold radiation and again there are less seizures the radiation are even in these most favorable

patients and we already mentioned the rtog 9802 group where they looked at low

Greg Goma patients they didn't randomize here there was 110 of them that they watch I like this I find this to be a

helpful number in clinic that five years after after surgery about half of them

were free of progression and you can see that in these graphs here that those

among that group with unfavorable risk factors had higher risks of progression or lower progression free survival and I

want everybody to make a mental note of this one so patients who have one cm of residual disease here they're the dotted

line so you see how poor they do in terms of progression free survival with a very very small amount free of

progression here and at two or three years and so some would say that that would make a standard arm in the

situation chemotherapy and radiation rather than uh observation but as we'll

get into later on uh on on modern studies some have have not have considered these patients with more than

a centimeter residual disease observation to be a standard of care arm

so what's the right radiation dose um the essentially the long and short of it here is that dose escalation does not

appear to help there's an ERC study looking at 59.4 versus 45 no difference

in overall survival or progression pre survival smack dab overlapping Lines no

improvement maybe a slight bit more radi acris with the higher dose as we might all expect uh similarly we recently

updated the um the ncctg trial that looked at dose escalation for low gray

Goma 64.8 gray versus 50.4 and again no difference whatsoever

between the two arms for progression three survival or overall survival um

here are these two curves from our snow presentation on this again getting out to even 20 years of followup uh for

these Pat and this is how long it takes to do lowgrade Goma studies it takes 15

20 years of followup which is inherently going to be a bigger problem as our

therapies Advance quicker and we're coming up with new things quicker we have to wait a long time to get

definitive results and by the time those results come the initial prow question may no longer be relevant but again no

benefit to dose escalation here the good news with this is that even with the higher dose uh later radiation effects

like radiation necrosis or serious toxicities were not seen so it does appear that treating gomas to Goma range

doses is is a safe thing in the long term for patients this was also an

encouraging H finding from this very longterm uh analysis out to 15 years uh

patients were stable on their mini mental state examination of course this is not the most sensitive neurocognitive

battery that we have or we could use now um and and that'd be another talk

talking about current advances in neurocognitive batteries for patients but stay focused on this with the with

the data we have it appears that they were neurocognitively stable and so getting radiation didn't appear to have

these drastic neurocognitive effects which again on Modern trials that we'll talk about later was used as the

justification for uh delaying and avoiding radiation therapy one more look at long-term

neurocognitive outcomes this was just published here a couple C months ago a German group looked at 71 Goma patients

that they did really nice serial neurocognitive testing on and they didn't see decline in any cognitive

domain from Baseline to followup in these patients and they didn't notice any difference between patients who got

radiation versus patients who were observed with watchful waiting and we know that that's you know if there was

worsening with radiation which there can be that seems to be washed away by the

the loss and progression free survival and as we all know tumor progression certainly has an impact neurocognitive

outcomes for a patient in terms of dosimetric correlates they noticed that

ipsilateral hippocampus dose did seem to matter so patients who are getting more than 50 Gray to the hippocampus on the

side of the tumor at worsening in half of the domains whereas if they had less than 10 gray uh to the the ipsilateral

hpoc campus then they had stability or even Improvement in all the domains so obviously the reason you have radiation

doses hippocampus is because there's tumor there and so um you know there's there's going to be some selection

issues here but to me this is also an indication that we should be cranking on our our radiation planning to minimize

dose of the hippocampi and other structures that are important for cognition and memory when we're doing our radiation planning for lowgrade Goma

so this is how we do it at Mayo right now for Goma generally speaking and of

course there's of course there's exceptions to this but our general approach to dose and fractionation for

grade two oligos we're doing 50.4 and 28 and typically it's the t2 to define the

GTV with a 1 cmet CTV and for all these we'll use a 3 millimeter PTV if we're using photons

grade two Asos we'll go to 54 and 30 if it's reasonably sized we'll use lower

doses for the more U for for larger more expansive lesions with 1 centimeter for

grade three gomas whether it's astrocytoma or good androma we're typically using 57 gray in 30 fractions

uh as an sib with a 51 gray in 30 volume uh to a 1.5 cimeter expansion the more

common dose you'll see for this is the Cooperative group doses of 5940 and 33

uh with a 50.4 and 28 lower dose to a sequential boost so of course these are both appropriate methods and for grade

four gomas whether they're idh mutant Toro blastoma we're doing 60 gray and 3 fractions typically for our younger

patients with good performance status and doing 2 centimeters of 51 and 30 if you've heard anybody from MD Anderson

talk about um radiation doses you'll see the same kind of 30 fraction pattern 54

57 60 from them and that's because we've both had Paul Brown at our institution

in the last 20 years he's kind of um LED uh the the rationale on those doses of

course we'll manually edit these ctvs where it makes sense so if there's T2

that's going more than 1.5 CM beyond the enhancement and it looks like tumor rather than edema of course we'll

include that in a CTV and then we anatomically constrain all ctvs uh these are General organs at risk

nothing here that I think is too Earth shattering to anybody um here we we look

at these and we try to really use our our beam angles as I'll get into a little bit later with protons to

minimize dose to the hippocampus by frontal loes and and other tissues wherever we can to try to avoid these

very typical acute and long-term side effects chemotherapy just to move very

quickly we know this rtog 9802 showed Improvement in overall survival with PCV

chemotherapy and oligos may benefit uh from that the most similarly and this

was this was true in the idh mutant patients when they looked at that because uh obviously idh mutation wasn't

available in 1998 when the trial was started um and a similar findings were

found in the ERC study so in in a plastic leas now that was grade two

which is the majority of these patients enoplastic leas which are more rare and a number of them historically have been

idh wild type tumors meaning that they're now categorized with Leo blastoma and not really in this category

so we'll move a little bit more quickly they're they're much more rare um we need to look at the molecular

characteristics to see which ones are GBM which ones are idh mutant um looking at

some of the older um older data with these you do have some some 15year

median survival in the the enoplastic oligodendrogliomas you know assuming these are idh mu one p19 Cube coded so

they're acting a lot like grade twos in some senses uh with all that being said there still does hold prognostic value

to grade two versus grade three which is why that still uh exists in the 2021 wh

class ation uh PCV here with 9402 does improve outcome significantly

similar to how 9802 did in the grade two patients um and this was done on both

rtog side and the eortc side to show that improved outcomes and so for us for

gomas for alod dendr gomas we're typically doing PCV um and you know for

astrocytomas we're often doing TMZ and it's sometimes that simple the the neuro

oncologists will have those conversations with patients um but I think there's a lot of Institutions

where they're doing TMZ for most everybody and of course we're awaiting the results of codell uh which is as of

the The Alliance meeting a couple weeks ago is is finally just about done AC crewing where we'll see the answer uh

for coded patients whether TMZ or PCV is the preferred

chemotherapy just to keep moving here so we have time um anaplastic astrocytomas are are also

poorly represented on a lot of these trials uh many will treat them like gleo

blastomas because they were included on the classic stoop trial and it's of course TMZ is easier to give than PCV

there are Trials of using um with that where they use concurrent enagement TMZ

with radiation like rtog 9813 where they compared it to bcnu and ccnu it worked

about the same in terms of survival that better toxicity than bcnu ccnu um a single arm trial by Mike babom

of just 47 patients where they did homide and Tel progression and then did homide and radiation seem to work okay

so again for the grade three astrocytomas we're often treating them with pomide and and

radiation then it gets to the to the current question of well are you giving concurrent temol amide with radiation

for grade threes are just adant and that's another topic where we have pretty significant variability within

our our group even and a lot of that is based on the Katon trial which is a

great trial of almost 750 non-coded anaplastic astrocytomas randomized

between between four arms radiation alone with 5940 radiation with

concurrent TMZ radiation with adant TMZ radiation with both concurrent and adant

TMZ and getting into some background on this the Assumption from the investigators and many others was that

that the concurrent TMZ may be the winner here that concurrent TMZ it's

really the radio sensitization of TMZ that matters the adant may not be adding much I think that that many thought that

this trial may eventually allow us to drop the adant TMZ for anaplastic astrocytomas and just use TMZ as a

concurrent drug and um you know the results of this Tri teach us why we do

randomized trials because even the smartest people's assumptions are are very often wrong even in things that

they've spent their career treating and learning about um and so the adant temozolomide is where the benefit was

that not concurrent temozolomide and there was no benefit to current current tasol mind regardless of them being idh

mut or idh wild type which brings out some maybe provocative thoughts about G blastoma whether we need the concurrent

t olomide or it's just the adant tamide that's important in our practice we still do give concurrent teide often

here are the curves for Katon showing with the adant temol amide in blue here significant overall survival benefit

compared to no adant teide whereas when we look at the concurrent IDE over here

no difference whatsoever between the concurrent or no concurrent T

olomide so in general for anaplastic gomas they get a maximal sa section with

neurologic preservation which is as much as they can safely get uh and then we'll

treat with adant radiation and chemotherapy we don't observe any grade three gomas even if they're younger than

40 and had a complete reection um there there're might be others particularly at

Stanford who have think that some of these can be observed that that hasn't been our our practice we typically treat

these to 57 gray and 30 fractions and then the chemotherapy you can go a lot of different directions with these with

PCV with just adant temozolomide with concurrent and adant temo olomide

there's a whole bunch of different directions you could go uh with a straight face with chemotherapy with

these recent data and future directions to continue with this so current trial that's going on right now and is

actually very close to closing I'm really um proud of the fact that this has been able to acre um so that we can

learn from this important question but this is a this is a phase two randomized study for

patients with idh mutant grade two or three Goma and that's protons versus photons uh so 54 gray either one with

vmat versus protons and the primary endpoint here is neurocognitive and end points there's a whole battery of

neurocognitive testing that's better than some of the older the older cognitive testing but maybe not the the

digital testing we would use in 2023 but still going to be helpful the CSR

protons really helping do the do the pretty color washes mean anything clinically and that's an unanswered

question at this point and of course they'll also look at secondary points like toxicity lymphopenia may end up

being different based on GL blastoma studies and others um Quality of Life

progression free survival Etc and as I mentioned this one is just about done AC crewing and uh a couple years afterwards

we'll have neurocognitive end points and be able to report that which is really exciting um thinking about the

difference between protons and photons this is a recent patient of mine where I made a a proton plan and an imrt plan

you can see I did use a controlateral beam here we'll talk about that later I'd be very interested in hearing what

some of those in the crowd that may have access to protons uh do with that but you can see here that the the benefit

isn't in the area where we're treating really with protons uh the benefit is the further away uninvolved brain

getting less low to moderate dose so this is the 12 gray at the edge of the blue here out here and so right

hippocampus is getting less dose less low to moderate dose does that matter for neurocognitive endpoints or other

endpoints we don't know that's why we're we're doing the trial to try to learn we know that it reduces dose we don't know

that that changes outcomes at all so case example here of another

recent patient 33-year-old guy presents with seizures found to have a T2

hyperintense left frontal lesion and has a subtotal resection performed this

shows a Grade Three astrocytoma idh mutant so you can all kind of think in your head um this patients come into

tumor board they've got a subtotal reection what are you going to offer in terms of uh radiation what are your

volumes going to be you want to do chemo what would you recommend and as I mentioned there can be a lot of right

answers here but I'll just talk to you about the way we did it um this red here

is the um is a a higher dose GTV that included some enhancement um after

surgery and the cavity that expansion on it this blue line here includes the t2

hyperintensity and then we have a margin on that out to CTV here so this is the area we're treating and for those who do

have access to protons you know think about would you do a contralateral beam or not for this one and what would be

the benefits of of doing it or not so this is how how I did this one um here's

our our high high do isodose line which of course looks pretty if you just look at that uh looking at the lower isoto

lines you can see we have one beam coming here and one beam coming here the benefit of this is that we spare any

dose from the other side of the brain and the frontal loopes the downside is that we have a higher biologic dose and

when I say biologic dose so that's the the end of range depositing of dose or

higher T dose essentially getting at the fact that the brag Peak at the end of

the proton's range it's going to have more than 1.1 times as much dose as the

photons at that point so it it deposits extra dose it packs an extra punch

biologically right there and so by doing it this way you are pouring out this hotter hotter biologic dose where the

end of range of these two beams come together and we have noticed that especially in the perventricular tissue

where you have this higher end of range dose they may be at more risk for at least two T2 changes maybe radiation

necrosis and so that would be a rationale for adding a controlateral beam and you just have to think of you

know is it worth it for this this tissue that you're completely sparing over here uh versus the higher biologic dose at

the end of range so uh for this patient I again like I showed before I did the

controlateral beam so that we wouldn't be end of ranging out in the the optic kayak you can see in the light blue

where my kaym Contour was here and we could keep the the biologic high do that

this is calculated by an in-house um model that we use but there's there's other ways to do this too but we keep

that end of range out of the optic structures you know out of the brain stem if we in that area so that's why I

used a controlateral beam except in some dose right here there's other cases where I've

decided not to so this is a manome a different type of tumor but just to show a case where you know this one we went

with with the the case without using the controlateral beam to spare the left tip of cample dose even though there was a

little more end of range biologic here with the without the contralateral beam

we're able to keep that out of the optics for the most part and so why did I think about in

that one well it seems that the left typ aample dose is particularly important um

and that's probably because for a lot of people in their brains that's where a lot of the language and speech uh

processing is and that's what helps them do well on the neurocognitive tests but that's also what helps them do well in

as a functioning member of society and so this was just a study of gasta so different population where they did

short course in Glo blastoma but they did um some dosimetric predictors of toxicity and of their cognitive outcomes

which is significant difference and cognitive

outcomes based on left tip of Campell dose and So based on that maybe shaky evidence uh I at least try to keep the

dose out of the left tip of Campus whenever I can and now to the uh

controversial recent thing I don't know how much you guys are talking about this in your daily practice but um we're

talking about it plenty so this is uh the Indigo trial it was published in the New England Journal of medison here um

just over two months ago this is a randomized uh phase three trial of the idh inhibitor or borid versus placebo in

residual recurrent grade 2 Goma so this pill is an idh uh idh1 and two inhibitor

idh1 is over 95% of cases but it also does idh2 and it's a pill that they take

once daily until progression or unacceptable toxicity and so you know as a drug company would love you you take

it in definitely um it's shown to decrease the

metabolite of idh of the actual enzyme which is two hydroxyglutarate and by by inhibiting

idh you get rid of this metabolite here and it changes some of the gene expression changes that happen in idh

mutant Theus so there was good basic science pre-clinical evidence that this might work and as you can tell uh it did

work and we got some uh you know a lot of hype in the L press at least in the United States about how excited people

were about this um inclusion criteria for this trial is pretty tight so 12

years or older they had to have residual recurrent grade 2 Goma not grade three

could be asoma or oligos no brain stem involvement uh at least one prior

surgery within one to five years and they can't have had prior radiation before um they had to have at least one

centimeter of measurable non-enhancing disease but no enhancing disease had to be asymptomatic and a candidate for

watch and wait now based on some of the previous data I showed you there'd be some that would say well this doesn't make sense

if they have a cc of non-enhancing disease that means they should get radiation they shouldn't be a candidate

for watch and wait and so the you know the control arms from this trial shouldn't have been observation it

should have been standard chemotherapy and radiation that that would be one one argument that people make but these are

the findings and this is why this is in the New England Journal medicine uh VOR sidb improved progression free survival

quite a bit bit here 11 months to 27 months though you see the curve just kind of hangs on there for us for about

nine months before dipping below but still very significant Hazard ratio um

and P value this is not overall survival this is a receipt of next Intervention which of course is pretty well

correlated with progression free survival and they hadn't reached that yet with Boris s niip here the reason

they don't show overall survival is because no patients had died yet and that's because there's only 14 months of

median followup on the study which you know we look at low-grade Goma studies

they take 10 15 20 years to to often tell us what we need to know and so just

over a year of median followup it is awesome that we're seeing this progression three survival benefit but

it's not giving us enough information I would say to to totally uh change things it did seem to help in all subgroups

looking at Adverse Events here very important um so there is a non-trivial

increase in liver tox toxicity so more than 10% of patients are going to have grade three liver toxicity on this

patients also can't be um having children during this time these are often young patients who have this

window available and so we don't know that it improves survival which matters to patients we don't know if it improves

quality of life or you know longer term outcomes functional outcomes for patients which matter to patients and so

you know there's reason to be cautious all that being said of course the bottom line is that it's great that we have

another treatment that seems to work for um for low GRE leas for AG mutant gomas

now we need to know when to use it are we going to follow the specific inclusion criteria on the trial uh that

didn't include uh grade three they can't have had prior chemo radiation they can't have any symptoms um you know we

talked about the short followup here that there's no deaths and we don't have neurocognitive data

um and again the the other concern that I've heard from some is that we don't know that once patients develop

resistance to these idh Inhibitors how they'll be changed biologically and how they'll then respond to standard

radiation and chemotherapy and so whether there'll be any negative long-term biologic effects of this uh

for us in the United States we're waiting approval of this drug and our neuro oncologists have been um some of

them have been pretty eager to use other idh in Inhibitors that are improved for things like leukemia um there's some for

clango to uh which wasn't the drug that was tested and also being used in

situations that it wasn't necessarily used in the trial and I think as radiation oncologist but we have a tool

that we know works and so we I think really need to Advocate uh caution in

getting carried away with this exciting new drug um and using it when it might

help but not uh [Music] in place of of treatments that we know increase survival and progression free

survival decrease seizures and maintain function for patients uh of course

there's future trials looking at this uh in other settings with grade three with idh mutant grade four there's a trial

coming through Alliance in combination with radiation and chemotherapy these are all things that we're going to learn

in the coming years and if you guys ever invite me to talk again hopefully we'll be talking about some of those

things here's a busy slide that just shows one way to think about how to guide adant treatment

for grade two Goma um if they're symptomatic or asymptomatic they can get maximal safe reection if they're classic

low risk by the Rog category here they can go to Observation or bidnip but if

they're higher risk for any of these things uh symptoms greater than 40 subtotal resection you know then we

would recommend doing radiation therapy with Cho theapy the chemotherapy can be PCV or TMZ as we learn about that

radiation can be protons or photons we don't need a dose escalate and so I went over a little bit

past what I think I was supposed to talk very happy to take any questions again

I'm really grateful for the opportunity to talk to you all and hope I get a chance to meet you in person someday thank you very

much thank you Dr B for Your Excellence and informative lectures uh now it's

time for Q&A for the onsite attendee if you have any question please come to the microphone uh for the online attendees

please type the question in the Q&A box uh there are some question uh the first

question is do you routinely cor down your target volume at Mayo

Clinic sorry do do we do what at M Clinic do you routinely conduct

down the target volume yeah we we typically don't so um our our approach

is typically using a a simultaneous integrated boost um there I don't think

one way is wrong and the other way is right but for example if we're going to um the 57 gray is what we'll use in 30

fraction for grade three we have our low do volume is 51 and 30 and so we'll have

the bigger volume going to 51 gray and 30 and the smaller volume going to 57

Grand 30 and the reasoning behind that is that you're making it in just one plan the the do symetris and the

optimizer is doing it all together and so then inherently you know you're going to hopefully do the best job of

accounting for all the objectives within the optimizer to the oars and the targets that being said you can have

great sequential plans and I still have used sequential plans and in in many

situations but typically we're not doing a con down we're doing a simultaneous integrated

boost thanks for the

question about the criteria of the maximal subtotal restriction yeah yep so

um the the the paper that I I showed to me so you know a lot of the older data

it's like when we think about medel Blasta they talk about 2D measurements of residual tumor and now a lot of the

modern studies use radiomic methods to give us volumetric numbers and I think

it's a different question for astrocytoma and oligodendroglioma how much reection we want to get for

astrocytoma some of those curves showed that any bit of residual disease seems

to confer a worse prognosis and so if you can get that last CC out of there

for astrocytoma a complete gross total reection even in the non-enhancing disase disease that seems to be worth it

and so going for re-resections I think is not wrong when it can be safely done whereas with allos you know it seems

like resecting more is better but they do so well with radiation and chemotherapy there seems to be less of a

benefit of being super aggressive with surgery so I think you know in those cases we're maybe a little more lenient

with the subtotal resections and less eager to go back in for a re-resection even if it might be safe so uh uh for

the because Mo molecular testing may take uh weeks to the we have to wait for

the results so the question is how long can we wait uh after the surgery to the

radiation or aan chemotherapy based on the interim result of Katon you are you

are asking me a question that makes me very frustrated every week because uh

even at a place where I think our lab does a great job in in their un molecular testing uh porge is my my

pathologist friend and he he may not think of me as his friend because I am always harassing him for when is the

when are the molecular tests going to be done especially when it's a a GBM and you want to get going relatively quickly

or a higher Greg Leoma and especially when you're trying to enroll the patient on a trial and they need to meet inclusion criteria and so you know

ideally all these things as the assays get better will get to us quicker and we'll come with diagnosis or within a

few days but it's sometimes two three weeks that we're waiting for all the information that we need for this

molecular classification and we have in some cases I have in some cases started treating with 1.8 gray per day knowing

that I might adjust my final dose based on molecular markers that come in when I

you know don't feel like we should wait and so uh you you touch the nerve there I totally agree we need to get faster

results on these things so and how how about your opinion about the malignant

transformation for both uh either osami or the radiation

group there uh because some study said that uh the malignan transformation is

uh maybe higher in the chemotherapy alone group yes yeah yeah so I I agree

that there there does not appear to be compelling data for malignant transformation with radiation I think

that has been um you know of course we don't know and in some cases could that happen sure it doesn't appear from some

of the watch and weight data comparing observation to radiation they have the same rate of high-grade recurrence in

malignant transformation doesn't appear that radiation caused it however there does appear to be a subset where

teide um causes you know these hyper mutation profiles and does cause malignant transformation of course on

average it doesn't because temol improves outcomes on average for our population hopefully we'll know which

patients are at risk of that and you know when we shouldn't do it but for us that's a reason why we we never at least

in our group we never do just radiation or just chemo if we're going to do adant

treatment we do radiation and chemo we don't just do chemo and wait a while for radiation with the temozolomide you know

for some of those concerns and so it's you know they go together from from our perspective uh I saw there's a question

about what dose uh for the sib what's the the dose per fraction for the high and low dose so for a gleo blastoma

where we're going 60 and 30 that's two gray uh and then 1.7 gray for the um for

the Loos volume the 51 gray for uh grade three Goma where we do 57 gray it's 1.9

gray 1.7 gray and then if if we're doing an sib for grade two then it'll be 54

and 51 so 1 .8 gray and 1.7 gray so it just goes up 0.1 gray per fraction as

the grade goes up by one that's a question is there any subgroup that we

use a 12 month of atanos solami good question the TW when when

are we doing 12 months of um Taz olamine um that that is really neuroon driven

but for us right now we're really mostly doing six months of agement t

I I haven't seen a patient in any subgroup get 12 months of adant tasol

amide in a little while but um you know and some of the I don't think it's

unreasonable to do it and I I've seen it done plenty but we right now we're we're

doing six months in the far room and we are

running out of time I have to choose some question okay uh

uh are you routinely give oral steroid during the radiation to minimize the

side effect yeah uh great question so we don't do oral steroids unless we have to

is the short answer if if there's a reason to do it symptomatically of course we'll we'll give them some

dexamethazone but um we don't if we don't have to if there if it um you know

if the symptoms haven't told us we have to for a couple reason one as we all know long-term corticosteroids is really

rough on people's quality of life their sleep their mood their blood sugar their weight um uh and then also I don't think

that there's a huge immune component to the treatment of lowr Goma but just like

we think of in other cancers that were becoming more and more trained dexamethazone suppresses the immune

system if the immune system's helping us at all uh we'd like to avoid doing that

so so we're only doing dexamethazone when patients have symptomatic

swelling okay this probably the last question in case that uh the asosa grade

three after receive uh surgery and radiation two or three year later they

developed the transformation to gr four what about your recommendation uh

treatment recommendation in this case do you consider re radiation and what do

yes yep yep reiation unfortunately is a situation um that we're in for almost

all these patients because we're we're not curing patients and and um you know

unfortunately and so if it's infield if it's an infield recurrence a high grade

infield recurrence we use 35 gray in 10 fractions so the rtog 125 recurrent Cleo

blastoma dose uh we will use that we don't reer radiate until basically all

the systemic therapy and uh surgical options have been exhausted so we have the biggest duration between radiation

courses if there's an out of field recurrence if they recur not within the prior radiation field but somewhere out

of field then we're often taking a hypo fractionated 15 fraction course so 40

4.05 gray and 15 fractions for an out of field recurrence versus 35 gray and 10

for an in field recurrence okay as we are running out of time I would like to conclude this

session Dr be thank thank you very much for your excellent and informative lecture and thank you for our

participant to join this session have a good day and enjoy your weekend thank

you y thank you very much thanks everybody and please feel free to email me my last name. firstname Atma with any

questions thank you very much thank you okay

bye

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