CNS E06: Low-Grade Gliomas: Foundations, Risk, and Timing

This is Episode 6, and we are kicking off our new mini-series on Low-Grade Gliomas. Today's episode is titled: "LGG P1: Foundations, Risk Stratification & The Timing Debate."For years, the management of WHO Grade II gliomas has been one of the most debated topics in neuro-oncology. These tumors often occur in young, otherwise healthy individuals and have a long natural history, making the decision of when to intervene complex. Today, we will lay the foundation for managing these tumors by first establishing their modern molecular definition, then learning how to use the Pignatti risk factors to stratify patients, and finally, we will dissect the landmark evidence that answers the central, controversial question: Should we treat now, or can we safely watch and wait?

Episode Transcript

(00:00):
Welcome to the Radon Smart Review CNS Cancer series.
Glad to be here today. We're really going to get into
low grade gliomas. Yeah.
We want to cover the foundations, how we stratify
risk and that big question that's been around forever.
Yeah. When's the best time to treat?
Exactly. It's a complex area.
So let's paint a picture. Imagine you know a pretty

(00:20):
typical case. A 35 year old guy shows up after
his first seizure, A tonic clonic one.
His brain MRI shows a non enhancing T2 hyperintense mass,
right insula. He gets a navigation guided
surgery. A gross total resection does
really well. KPS is 100.
Fantastic outcome initially. And the final path report comes

(00:42):
back WHO Grade 2 oligodendroglioma and the
moleculars confirm it IDH mutantand 1P19 Q go deleted.
So the classic oligo picture molecularly defines.
Right, so he's in clinic feelinggreat, asking you.
OK, doc, what's next? And that's the $1,000,000
question, isn't it? The answer is, well, it's
complicated. It really boils down to figuring

(01:03):
out his risk of the tumor comingback.
That's what we need to unpack. OK, let's start with the
pathology itself. What makes a grade 2 glioma a
true grade 2 glioma today? Well, the absolute starting
point the modern definition is it must be ideh mutant.
That's nonnegotiable now. And what if it looks like grade
2 histologically but it's ideh wild type?

(01:23):
That's a critical distinction. If it's IDH wild type, even if
the Histology looks low grade, we now consider it a molecular
glioblastoma. Wow.
OK, so treated completely. Different completely
differently, aggressively, like a GBM.
It's a huge paradigm shift basedon the molecular.
So back to our IDH mutant patient.
Once we know that, what's next, molecularly?
Then we look at 1P19 Q status. If it's Co deleted like in our

(01:47):
case patient, that defines it asan oligodendro glioma.
And if 1P and 19 Q are intact? If there, which often goes along
with ATRX loss, that defines an astrocytoma.
Different biology, different implications.
Got it. Olego versus Astro based on
1P19Q. Precisely.
And remember by definition thesegrade 2 tumors also lack high
grade features. So no necrosis, no homozygous

(02:08):
CDK and two AB deletion, those are signs of higher grade
transformation, OK. Clear on the pathology now,
before we even get to what's next after surgery, What's the
absolute first step in treatment?
Maximal safer section No question that initial surgery is
crucial. And there's good evidence for
that, right? That's not just intuition.
Oh absolutely. Tons of retrospective data,

(02:29):
multiple series all pointing thesame way.
More extensive resection leads to better survival.
It's really solid I. Remember reading that Jicola
study in JAMA? That was pretty striking.
Yeah, Jicola was compelling. They compared resection versus
just biopsy. And the difference was huge,
wasn't? It massive median survival
difference was nearly 10 year, like 14.4 years with resection

(02:50):
versus only 5.8 with biopsy. Wow, And didn't it also reduce
the chance of the tumor turning nasty later?
Malignant transformation. It did almost a 20% reduction in
malignant transformation rate. It really highlights that
surgery is our first and maybe best chance to significantly
impact the disease. OK.
So surgery is key. Now the patients have the

(03:11):
resection. We know the path.
What now? Treat or watch?
And that decision that hinges entirely on risk stratification.
We need to figure out if the patient is low risk or high
risk. How do we do that?
Is there a standard system? Yes.
The most widely used factors come from an EORTC analysis by
Pignotti and his group. These are the Pignotti risk

(03:33):
factors. They're fundamental.
OK. Pignotti factors.
How many are there? What are they?
There are five, and there's actually a pretty memorable
mnemonic for them. Satan.
Satan. Seriously.
OK, I'll remember that. What does it stand for?
OK. So S is for size tumor diameters
6 centimeters or more. A is for age 40 years or older.

(03:53):
Got. It SAT is for tumor crossing the
midline, A is for astrocytoma Histology.
Remember, oligo is generally better prognosis OK, TA and N is
for neurologic deficits present before surgery and that
specifically excludes well controlled seizures.
SAT AM size, age, tumor crossing, midline astrocytoma,
neurologic deficits. OK, how do we use these?

(04:15):
Simple grouping zero to two factors means low risk.
Three to five factors means highrisk.
All right, let's go back to our case. 35 year old guy DTR not
crossing midline oligo. Yeah, no pre op deficits.
OK, let's take them off. Age under 40, yes.
So no a size, probably under 6 centimeters if it was a DTR in

(04:36):
the insula and not mentioned as huge, but let's assume under 6.
No S crossing midline No No T Histology illegal Not Astro No A
neurologic deficits No No N. So zero factors.
Zero factors. He is firmly in the low risk.
Category makes his what's next question lean towards.
Observation generally, but this whole low risk versus high risk

(04:57):
thing brings us to that huge historical debate in low grade
gliomas. The timing question when do we
treat? Exactly.
For decades it's split the community.
You have the the believers and the non believers.
Kind of a fun way to think aboutit.
OK. Tell me about the believers.
What was their argument? Well supported by trials like
ertc 22844, they argued for hitting it hard and early.
You know these tumors are infiltrative.

(05:18):
They do eventually progress, often fatally.
So the logic was treat early, treat aggressively, improve the
outcome. Like putting out a fire early.
Makes sense. What about the non believers?
Their view, supported by the other big your ATC trial 22845
was different. They pointed out these are often
slow growing tumors in young people.
Right? And radiation has significant

(05:40):
long term side effects, cognitive issues, endocrine
problems. So they questioned if the
potential toxicity of early treatment was worth it,
especially if survival wasn't clearly improved by hitting it
early. Maybe wait until you absolutely
have to treat. So 2 competing philosophies.
Which trial gave us the best answer, especially for the high
risk group? ERTC 22845 really tackled that

(06:02):
head on for high risk patients. That was a design.
They took high risk grade 2 patients, mostly people with
subtotal resections and randomized them.
One arm got immediate post op radiation, 54 grey standard dose
and the other. Arm.
Observation. They just watched them closely
with MRI's and only gave radiation if or when the tumor
progressed. OK.
So immediate RT versus delayed RT at progression, what

(06:25):
happened? Here's the fascinating kind of
paradoxical part for progressionfree survival PFS.
How long until the tumor grew back?
Early radiation one. By how much?
Pretty significantly. Median PFS went from 3.4 years
in the observation arm up to 5.3years with early RT, so
definitely delayed progression. OK, so early RT keeps the tumor

(06:46):
quiet for longer. That sounds like a win.
You'd think so, but when they looked at overall survival OS
how long people actually live, there was absolutely zero
difference between the arms. Wait, really?
Zero difference? How is that possible?
Median OS was around 7.2 years in both groups exactly the same.
So delaying progression didn't translate to living longer.

(07:07):
How do you explain that? The key was that salvage
radiation, the radiation given later when the observation group
progressed, was highly effective.
It worked just as well when given later.
OK, so waiting didn't hurt them in the long run because the
treatment still worked when theyeventually needed.
It precisely. And that has huge implications
for practice, right? Yeah, it means for these high
risk patients, you can actually defer radiation without

(07:30):
compromising their ultimate survival.
Exactly. It forms the bedrock of sharing
decision making. You can sit down with a high
risk patient and say look OptionA radiation now it'll likely
keep the tumor controlled longer.
Option B we watch closely. Use radiation.
If it grows, your overall long term survival outcome looks the
same either way. That's a powerful conversation

(07:51):
to be able to have. Gives patients real choice.
It really does. Was there anything else from
that trial that might tip the balance for a patient deciding
between early or delayed RT? Yes, one important quality of
life finding seizures early RT significantly reduced seizures
at the one year mark. Oh interesting, how much of a

(08:11):
difference? It went from 41% of patients
having seizures in the observation arm down to 25% in
the early RT arm at one year. For someone struggling with
seizures, that could be a major deciding factor.
Absolutely. OK.
So that's high risk. What about the low risk patients
like our initial case? What's the evidence say for
them? For low risk, the evidence
really points towards observation being the standard

(08:33):
approach. And where does that evidence
come from? A key piece is from the RTG
98-O2 trial. They had a specific cohort of
low risk patients younger than 40 gross total resection who
were just observed. And what was their outcome like?
Their five year progression freesurvival was about 50 percent,
50%. Yeah.
So half of them had progressed within five years even though

(08:54):
they were low risk. Exactly.
So when you're counseling that young low risk patient with
AGPR, you can say observation issafe, it's standard, but you
have to be upfront. There's roughly A50 nifty chance
your tumor might start growing again within the next five
years. It emphasizes the need for
ongoing surveillance. Right, watchful waiting
definitely means watchful. OK, that's a lot of crucial

(09:15):
info. Let's try and boil it down.
Time for some clinical pearls. All right, let's lock these in
Pearl #1. Pearl 1A true WHO grade 2 glioma
definition wise is IDH mutant Andy lacks high grade features
like necrosis or that homozygousCDK into AB deletion.
Molecular definition is key. For all #2 risk stratification,

(09:36):
it's guided by the Pinati criteria.
Remember Satan? Satan size 6 centimeters age O
40 tumor crossing midline astrocytoma Histology,
Neurologic deficits pre op Got it.
Pearl #3 for the low risk patients think younger than 40
with a GTR observation is standard, but counsel them about
that 50% five year PFS based on RTOG 98-O2.

(10:01):
Pearl #4 high risk patients. The landmark timing trial is EOR
TC-22845. Key finding early RT improves
PFS. Right 5.3 versus 3.4 years.
Median PFS. But does not improve overall
survival. OS was about 7.2 years in both
arms. Deferred RT is a safe option
regarding survival. And Pearl #5 don't forget the
quality of life aspect. Early RT does offer better

(10:23):
seizure control at one year thatcan be important.
OK, great pearls. So, thinking about treatment
techniques, how does knowing allthis about when to treat
influence how we approach radiation when we do decide to
give it, well, it? Reinforces that radiation is a
powerful tool, but EOR TC-22845 gives us license to really think
about the long term toxicities, especially in these young
patients. Neurocognitive effects,
endocrine issues. They're real.

(10:45):
So allows for a more nuanced discussion weighing that PFS
benefit against potential a longterm harm.
Exactly. It's not just if or when, but
also carefully considering the Longview for the patient's
overall life quality. And that seizure control point
comes back again, doesn't it? Yeah.
It's a tangible benefit of earlyRT that needs to be part of that
individualized decision. Absolutely.
It's about optimizing the whole picture for the patient.

(11:07):
All right. I think we're ready.
How about a quick board? Let's put this into practice.
Let's do it. Fire away.
OK, case 132 year old GTR of a three centimeter grade 2 all ego
KPS, 100 normal neuro exam. What's the most appropriate next
step? A immediate RT to 54 GGI, B
immediate chemo, RT with PCV, C observation with serial Mris or

(11:29):
D biopsy the other side of the brain.
OK, let's see 32, So under 40 GTR oligo, small tumor, normal
exam sounds pretty low risk. How many SCTAN factors?
Looks like 0 again. H40 size 6 not crossing midline,
implied by GTR of small tumor oligo.
No deficits, 0 factors. So the answer is.
Observation with serial MRI's standard for low risk based on

(11:51):
RTOG 98-O2 data. Perfect case 250 year old
subtotal resection of a 7 centimeter grade 2 astrocytoma
that crosses the midline. He has mild left weakness.
How do you I am using Pinati A low risk observed B low risk
early RTC high risk discuss early versus delayed RT or D
high risk immediate committee required.

(12:13):
All right, let's run Satan. Age 50.
That's one factor. By 7 centimeters.
That's two. SAT astrocytoma.
That's 4A. Neurologic deficit weakness.
That's five. Wow.
He hits all 5. Definitely high risk then.
So what's the approach? He's high risk based on ertc
22845. We know early or delayed RT have
equivalent OS, so the answer hasto be C high risk and you

(12:34):
discuss the options only versus delayed RT.
It's exactly discuss the pros and cons, PFS versus OS, seizure
control, toxicity, shared decision making.
OK, last one, case 3, you're counseling that same high risk
patient from case 2. He's leaning towards not having
radiation right away. You tell him based on EORTC
22845, deferring RT until progression will likely result

(12:56):
in what? A Worse OSB, shorter PFS but
equivalent OSC or seizure control.
Andy, Worse OS or D higher rate of malignant transformation.
OK, this is the core finding of 22845.
Deferring RT means the tumor will likely grow back sooner, so
shorter PFS, right? But salvage RT works well, so
overall survival is the same equivalent OS.
So the answer is. B Shorter time to progression,

(13:18):
but equivalent overall survival.That's the key paradox and
counseling point. Excellent.
You know, it really feels like ERTC 20 to 845 fundamentally
changed how we approach these high risk patients didn't.
It absolutely. It empowered us and patients to
have these nuanced conversationsabout timing and quality of life
versus just focusing solely on delaying progression at all
costs. True shared decision making.

(13:39):
And this whole discussion about timing really sets this up
perfectly for our next session, doesn't it?
It does, because while 22845 established the timing debate
for RT alone, the field kept moving.
Next time we'll dive into the evidence that actually shifted
the standard for high risk disease towards combined
treatment, radiation plus chemotherapy looking.
Forward to that. OK, so let's quickly summarize

(14:00):
today's key points on WHO Grade 2 gliomas.
We started with the definition. Got to be IDH mutant.
No high grade features. Molecular is paramount.
Then we covered risk stratification using the Pagati
criteria. Remember Satan to sort patients
into low and high risk. For low risk patients
observation is standard backed by RTG 98-O2, but keeping in

(14:21):
mind that roughly 50% five year PFS.
And for high risk, the big take away from EOR TC-2 and 2845.
Early RT improves PFS but not OS, making deferred RT a safe
option from a survival standpoint, though early RT
might help with seizures. A complex field, but hopefully
that provides a solid framework.Definitely bleep.

(14:41):
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