CNS E02: High-Grade Glioma Part 2: Anaplastic Astrocytoma and the Rise of Molecular Grade 4

In our last episode, we established the modern molecular framework for diagnosing high-grade gliomas and detailed the management of anaplastic oligodendroglioma. Today, we explore the other side of that coin. We will master the management of anaplastic astrocytoma by dissecting the pivotal CATNON trial, and we’ll tackle a challenging new entity introduced in the 2021 WHO classification: the IDH-mutant astrocytoma, Grade 4, a tumor that looks lower-grade under the microscope but carries a much graver prognosis based on its genetics.

Episode Transcript

(00:00):
Welcome to the Radox Smart Review CNS Cancer series.
Today we're diving into, well, areally crucial area of CNS
radiation oncology, high grade Leoma Part 2.
Our focus for this deep dive is specifically on anaplastic
astrocytoma and the really big shift towards what we now call
molecular grade 4 tumors. This field, honestly, it's

(00:20):
incredibly dynamic, isn't it? It's constantly changing how we
think about cancer way beyond just what we see under a
microscope. It's really where genomics is
redefining everything Diagnosis,prognosis, treatment.
That's a perfect way to put it. Yeah.
In our last session, we kind of laid the groundwork, right.
We set up the modern molecular framework for diagnosing these
high grade glyomas and we went into detail and managing
anaplastic oligodendroglyoma. So today, yeah, we're looking at

(00:44):
the other side of that molecularcoin.
Building on that essential foundation, we established our
mission for this discussion. It's pretty ambitious.
We really want you to master themanagement of anaplastic
astrocytoma. We'll do that by dissecting a
really key practice changing trial, the CATNON trial CATNON.
And then we're going to tackle well a challenging but

(01:06):
incredibly important new player introduced in the 2021 WHO
classification, the IDH mutant atrocytoma grade 4.
Now, this isn't just a new name.It's a tumor that might, you
know, look lower grade under themicroscope, maybe even seem
deceptively less aggressive histologically.
But it carries a much, much graver prognosis and absolutely
demands a different treatment strategy based entirely on its

(01:27):
genetics. It really embodies this whole
precision oncology revolution we're seeing.
OK, perfect. Let's let's ground this with a
case, then make these concepts abit more concrete, more relevant
for everyone listening. So imagine you're in clinic and
you're seeing a 38 year old woman.
She initially came in with, you know, pretty common symptoms for
a brain lesion, persistent headaches, and some noticeable

(01:49):
trouble finding her words. These symptoms, while often
benign, were well concerning enough in her case to trigger a
full work up. Exactly, and her MRIMRI confirm
those suspicions. It showed an irregularly shaped
mass in her left parietal lobe. Importantly, it was non
enhancing and T2 and FLAI are hyper intense.

(02:09):
Now, that non enhancing feature on the MRI is actually a really
crucial detail here, because historically that finding might
have led clinicians to lean towards suspecting a lower grade
lesion, maybe even thinking grade two initially, which just
highlights precisely why this comprehensive molecular workup
has become so absolutely vital. So she underwent A subtotal
resection, meaning not all the tumor could be removed safely.

(02:31):
And the preliminary pathology report just came back saying
anaplastic glioma grade 3. And right there, you know, for
us as radiation oncologist, thatinitial diagnosis, it's helpful,
sure, but it's just not enough anymore, is it?
It's a start, definitely, but itdoesn't give us the detailed
road map we absolutely need for modern practice to really
formulate A precise evidence based and effective treatment

(02:54):
plan today. You absolutely, unequivocally
need to know which specific molecular pathway this tumor
belongs to. You need that detail from the
modern classification algorithm.So what happens next?
What's the critical piece of information we're really waiting
on to make those definitive treatment calls?
Because without it, we're kind of flying blind.
You're absolutely right. That initial path report is just

(03:14):
well the opening scene, the realstory, the definitive
fingerprint that guides our entire strategy that comes with
the final integrated report. And for our patient, that
crucial report revealed her tumors precise molecular
signature. It was isocitrate dehydrogenase
or IDH mutant. It was 1P and 19 Q non Co
deleted and it showed loss of ATRX expression ATRX this exact

(03:38):
combination IDH mutant 119 Q intact ATRX loss.
That's the core definition of our topic today, anaplastic
astrocytoma. It lets us move way beyond those
older, broader, sometimes ambiguous categories and really
tailor our approach with much greater specificity and,
importantly, with solid evidencebacking us up.
OK, so let's just lock that diagnosis down for everyone

(04:00):
listening. Let's walk through The Who
algorithm quickly just to make sure we're all clear on how we
arrived here. For this patient following the
World Health Organization or WHOalgorithm, the first big
decision point for diffuse gliomas is IDH status.
And for our patient, it's clearly IDH movement.
That's the critical first step, yeah.
Once we know it's IDH mutant, the next crucial question in
that algorithm is about the 1P and 19 Q status.

(04:23):
Because her tumor is non Co deleted or as we often say
intact, that immediately tells us we are dealing with an
astrocytic tumor. Just to refresh from our last
discussion, if it were Co deleted that would point
straight towards an oligodendroglioma.
Right, a completely different entity.
Exactly different management, different prognosis.
So non Co deleted means astrocytoma lineage then the

(04:45):
characteristic loss of the ATRX protein further concerns this.
For those wondering, ATRX is a protein involved in chromatin
remodeling, basically organizingDNA in the nucleus.
Its loss often leads to genomic instability, which is a hallmark
of these specific astrocytomas and it strongly points to their
astrocytic lineage and helps separate them from oligos.
So putting all together IDH mutant 119 Q intact ATRX loss,

(05:08):
our patient definitively has an anaplastic astrocytoma WHO grade
3A little Monica that might helpyou remember the key features
for Anaplas astrocytoma think IDHAT RX1P19Q intact.
I like that IDHAT RX1P19Q intact.
Exactly. Cover to the bases.
And this precise molecular diagnosis, it really sets her

(05:29):
apart in a major way, not just slightly from the patients we
discussed last time, like those with anaplastic oligodon
druglioma. It's a fundamental difference
that completely changes how we see the disease.
The prognosis are totally different and crucially, the
evidence guiding our treatment is also different.
This molecular guided precision,it's not just academic jargon.
It is absolutely key to giving the most effective personalized

(05:53):
care possible in modern neuro oncology.
It moves us way beyond those oldbroad classifications.
You've nailed the core principlethere.
Yeah. And for anaplastic astrocytoma
specifically, the central piece of evidence, the landmark study
that truly revolutionized our practice and set the current
standard of care, that's the CATNON trial.
CATNON, this is a study that every single radiation

(06:15):
oncologist treating brain tumors, frankly, every neuro
oncologist needs to know inside and out because it answered a
critical question that honestly,we struggled with for years.
OK. Tell us more about CATNON then.
What was its main goal? What was the overall design?
What specific clinical questionswas it trying to resolve for
this particular group of patients, especially given the
uncertainty that existed before the trial?

(06:37):
Well, before CATNON, clinicians often had to to make, you know,
educated guesses or maybe even worse, sometimes they'd apply
treatment paradigms from glioblastoma to these anaplastic
glioma patients, which potentially expose them to
unnecessary toxicity. It created a lot of deviation
and practice. So the CATNON trial, which is
led by the European Organizationfor Research and Treatment of

(06:58):
Cancer, the EORTCAO. RTC, right?
It was designed specifically to answer that fundamental
treatment question for this population, the 1P and 19 Q non
Co deleted anaplastic gliomus. The core question was
essentially what's the best way to sequence and combine
radiation and the chemotherapy drug temazolamide, KMZ?

(07:22):
Should TMZ be given concurrentlywith radiation, should be given
as adjuvant therapy after radiation, or maybe both?
This is so important because TMZhad already shown effectiveness
and other gliomas, especially GBM, so figuring out its optimal
role here was absolutely critical for truly personalizing
treatment. And how did they actually go
about answering that? Well, pretty complex question.

(07:42):
What did the trial structure look like?
It sounds like it needed to be pretty sophisticated to tease
out the best approach among several possibilities.
It was, yeah, it was an ambitious and it really
elegantly designed study. They used A2 by two factorial
design, which is a clever setup.It allowed them to independently
test the impact of concurrent TMZ and adjuvant TMZ all within
the same trial. It's a very efficient way to

(08:05):
answer multiple questions at once.
They randomized over 750 patients into four distinct
treatment arms. First arm radiation therapy
alone delivered to 59.4 grey. This is the baseline control,
kind of the historical standard without TMZ.
OK, Standard, are you? Second Arm Radiation Therapy, or
RT, followed by adjuvant TMZ. So TMZ given after radiation,

(08:27):
typically for 12 cycles. This tested the benefit of TMZ
as like a maintenance therapy. Host RT Chemo. 3rd arm RT with
concurrent TMZ, so TMZ given daily during the radiation
course. This mirrored the standard GBM
approach at the time. Testing if that.
Concurrent chemo help here too. The step like approach.
And the fourth arm RT with both concurrent and adjuvant TMZ.

(08:49):
This combined the previous two the most intensive chemo
regimen. Testing if you know more is
better. OK, let's unpack those results
then because you said they're truly practice defining.
They've really reshaped how we approach these specific tumors.
What did the interim analysis and maybe more importantly, the
final 2021 analysis, show, especially regarding the role of

(09:10):
the adjuvant TMZ? Right.
So first, focusing on adjuvant TMZ, the trial delivered a
really clear, total, unequivocaland profoundly positive result.
This was a huge win for patients.
A key finding is that adding those 12 cycles of adjuvant TMZ
after radiation significantly improved the five year overall

(09:30):
survival. It jumped from 44% in the RT
Alone group to 56% in the RT Plus adjuvant TMZ group.
Wow, 44 to 56%, that's a 12% absolute improvement at five
years. That's substantial.
It's a really substantial improvement, yes.
It translates directly into significantly more patients
living longer, living better. This finding fundamentally and

(09:52):
without question, established a new standard of care for this
specific patient population. It wasn't just, you know, a
marginal gain. It was a robust, clinically
meaningful difference that really demanded widespread
adoption. OK, that's a definite win, a
clear step forward, offering a real increase in survival.
But now what about the concurrent TMZ?

(10:14):
You know, the role of giving chemo during radiation is so
deeply ingrained in our thinkingfor other high grade brain
tumors, especially GBM, it was almost assumed it would be
beneficial here too. What did CATNON tell us about
that? Were there any surprises?
This is really where things get fascinating, and it provided A
crucial, maybe even surprising, distinction that definitely
challenged some prior assumptions.

(10:35):
The final analysis published in 2021, it clearly showed that
adding concurrent TMZ to radiation provided no overall
survival benefit at all for thisspecific patient population.
No benefit. Seriously.
Zero benefit in terms of overallsurvival.
The five year overall survival rates were remarkably similar,
around 50 to 53%. Whether concurrent TMZ was given

(10:58):
or not. This is a critical negative
finding. It fundamentally showed that
unlike in glioblastoma where concurrent TMZ is absolutely
essential and provides a survival advantage, for
anaplastic gastrocytoma, this specific group, the concurrent
part of the therapy just isn't beneficial, which is great news
in a way because it allows us toavoid potentially significant

(11:21):
toxicity without compromising the outcome.
That's a huge win for patient quality of life.
So for these patients, giving TMZ during radiation just add
side effects, you know, things like nausea, fatigue, low blood
counts, infection risks without actually helping them live
longer. That's a super important
distinction for clinical practice.
It saves patients from those side effects while still

(11:42):
ensuring they get the best outcome.
Now, you mentioned earlier the profound power of molecular
classification. What about the molecular sub
analysis within CATNON? This is often where the real
magic of personalized medicine reveals itself, isn't it?
Absolutely. This is precisely where the
story gets even more compelling and truly cemented.
Why molecular classification is paramount in guiding therapy.

(12:03):
When the investigators did a careful sub analysis breaking
down the outcomes based on IDH status, well, a clear,
unmistakable and profoundly important pattern just jumped
out. The survival benefit from adding
adjuvant TMZ. It was seen only in the IDH
mutant population. Only in the IDH mutant group
only. For these patients, adding

(12:24):
adjuvant TMZ was nothing short of transformative.
It extended the median overall survival from about 47 months in
the RT Alone group to a remarkable 82 months.
That's nearly seven years for those getting RT Plus adjuvant
TMZ. Wow.
From roughly 4 years to almost seven years.
Median survival. Exactly.
Think about that nearly doublingthe median survival time for a

(12:45):
patient. And the updated 2021 results
push this even further. The median overall survival
reached an astounding 98 months for IDH mutant patients who
received adjuvant PMZ. 98 months.
That's over eight years. Just over 8 years median
survival. It's an incredible testament to
the power of targeted therapy based on these specific

(13:05):
molecular markers. OK wow, pushing close to 8 years
median survival is truly significant.
A huge improvement, profoundly highlighting how molecular
classification doesn't just predict but actually dictates
response to therapy. It really changes what was once
a much bleaker outlook. So what about the IDH Wild type
group within CATNON? Did they see any similar

(13:28):
benefits from getting that adjuvant TMZ?
Unfortunately, no. And this is equally important in
the relatively small subset of patients in CATNON who had IDH
wild type anaplastic astrocytoma.
And remember, according to the updated WHO guidelines, we would
now molecularly classify these tumors as GBM glioblastoma
regardless of their histologic grades, simply because they are

(13:50):
IDH wild type. Right, that's a key point from
the new classification. Yes, for that group, adjuvant
TMZ provided absolutely no benefit whatsoever.
Their median survival remained depressingly poor, stuck at
around 20 months, regardless of which treatment arm they were
in. This stark difference just
underscores how absolutely critical molecular subtyping is.

(14:11):
It's essential for accurate prognosis and for making
informed, evidence based treatment choices.
It stops us from giving patientstoxic therapies that won't help
them, while making sure those who will benefit get the right
life extending treatment. It's truly about the right
treatment for the right patient.So OK, bringing it back to our
38 year old patient, she has theIDH mutant anaplastic
astrocytoma. The CATNON trial gives us a

(14:34):
crystal clear unambiguous answerfor her standard of care.
There's really no guesswork involved here, is there?
You're absolutely right. The standard of care based
squarely on the robust evidence from CATNON is radiation therapy
to 59.4 grey, typically delivered over about six weeks
followed by up to 12 cycles of adjuvant TMZ, usually given in

(14:55):
that five days on 23 days off schedule.
For our patient, deciding to emit adjuvant chemotherapy would
be a significant and honestly anindefensible deviation from the
established standard of care. It would undeniably compromise
her long term outcome. It's not just a matter of
clinical preference, it's about applying powerful evidence based
oncology that we know extends lives.

(15:17):
OK, that's very clear for the Grade 3 anaplastic astrocytoma.
Now let's pivot slightly and address this new and well
challenging entity that really highlights how fast glioma
grading is evolving and the increasing power of molecular
markers. I'm talking about the atrocytoma
IDH meeting WHO grade 4. What exactly defines this
molecular grade 4? Especially since, as you
mentioned, it might not actuallylook like a grade 4 under the

(15:40):
microscope, which sounds pretty counterintuitive.
This is a really crucial concept.
It may be the most significant conceptual shift in the entire
2021 WHO classification. It truly embodies this massive
paradigm shift towards moleculargrading.
What it fundamentally means is that a tumor might
histologically look like a grade2 or maybe a grade 3 astrocytoma

(16:02):
under the microscope. It might lack those classic high
grade features we traditionally associate with GBM, like
necrosis or microvascular proliferation, but crucially, it
harbors a specific high risk molecular feature that
automatically gives it the prognosis and the biological
behavior of a true grade 4 tumor.
Think of it like this. Maybe an analogy helps.

(16:23):
Imagine a car that looks like a standard family sedan on the
outside, maybe even kind of quiet and unassuming, but under
the hood it's got a souped up, high performance racing engine.
I see. That engine, regardless of the
car's outward appearance, dictates its true speed and
power. That's exactly what an IDH
Mutant Astrocytoma Grade 4 is like.
It's microscopic appearance can be misleading, but that specific

(16:46):
molecular alteration is its highperformance engine driving
aggressive grade 4 behavior and prognosis.
This isn't just slapping on a new label.
It's a profound statement. What a tumor is molecularly now
outweighs what it looks like microscopically.
It forces us to embrace genomicsas the ultimate arbiter of
prognosis and treatment. So it's truly about the deep

(17:07):
down biology, the genetic drivers, not just the
superficial cellular appearance.That's a huge shift from
traditional pathology. What is that key molecular
feature then? What's the specific genetic
engine as you put it that automatically upgrades a
seemingly lower grade astrocytoma to AWHO grade 4?
The defining alteration. The specific high risk molecular
particular feature we're lookingfor is a homozygous deletion of

(17:29):
the CDK and 2A and B gene, CDK and 2A and B.
OK, CDK and two AB homozygous deletion.
Exactly. Now for context, CDK and 2A and
B are crucial tumor suppressor genes.
They basically act as the brakeson uncontrolled cell division.
When you have a homozygous deletion, it means both copies
of these critical brake genes are completely gone, completely

(17:51):
lost. This basically removes the
brakes unleashing uncontrolled cell growth.
It fundamentally transforms a seemingly lower grade tumor into
a highly aggressive one. Regardless of how it looks under
the microscope, the diagnostic implication is paramount.
It's automatic if you have an IDH mutant astrocytoma of any
histologic grade. Could look like grade two.
Could look like grade three. That also has a homozygous CDK

(18:13):
in 2A and B deletion. It is automatically upgraded to
WHO Grade 4, full stop. Non negotiable.
Non negotiable in the new classification system and that
has immediate critical implications for how we think
about prognosis and how we approach treatment.
That's a massive shift in classification with really
profound implications for how weview these tumors and more
importantly, how we treat them. So given that we might be

(18:36):
dealing with a tumor that looks lower grade histologically but
molecularly is screaming grade 4, how aggressive are these
molecular grade 4 tumors in reality and what are the current
ways we approach treating them, especially given they lack those
classic histological grade 4 features?
This sounds like it could be a tricky conversation to have with
a patient. It absolutely can be a

(18:57):
challenging conversation yet, but it's a vital one.
Well, these specific tumors as newly defined molecular grade 4
category are relatively rare. They are indeed significantly
more aggressive than their gradetwo or three counterparts that
don't have the deletion. Retrospective data clearly shows
they behave much more like glioblastoma in terms of how

(19:17):
quickly they progress and patient survival.
Now, As for treatment, this is currently a point of
considerable controversy, largely because, well, it's such
a newly defined entity. There's a critical lack of
direct perspective evidence froma dedicated clinical trial to
guide us. The NCCN guidelines, the NCCN
guidelines, they acknowledge this uncertainty and reflecting

(19:38):
this ongoing debate, they suggest these tumors can be
treated either like grade 3 astrocytomas following the
CATNON approach. So RT followed by adjuvant TMZ.
Right. Or more aggressively, like
glioblastoma. Meaning RT with concurrent and
adjuvant TMZ. Exactly.
However, given their definitively poor prognosis.

(20:01):
Which is already clear from the observational data we have.
Most experts would argue for taking a more aggressive
approach right from the beginning.
Imagine explaining to a patient that what looks like a
relatively less aggressive tumorunder the microscope is actually
behaving like the most aggressive type of brain cancer
because of one specific genetic deletion.
It's a tough message. Yeah.
That's a heavy conversation and it.

(20:22):
Forces a very different discussion about the intensity
of treatment needed. So when you say more aggressive
approach, what does that usuallymean in practice for these
molecular grade for IDH mutant astrocytomas, especially since
as you said, we don't have a dedicated landmark trial like
CATNON specifically for them yet?
Are we basically borrowing from other paradigms and how

(20:43):
comfortable are we doing that? Yes, exactly.
It is reasonable and it's actually common practice now
among neuro oncology experts to extrapolate from the
glioblastoma paradigm. We do that because of the shared
aggressive biology and the uniformly poor prognosis these
tumors show, despite their sometimes misleading Histology.
Therefore, many, probably most experts would treat these

(21:04):
patients with the full step protocol.
OK, the full step. Which means 60 greys radiation,
usually over 30 fractions given with both concurrent TMZ during
radiation and then followed by 6, maybe up to 12 cycles of
adjuvant TMZ. This approach aims to maximize
the therapeutic punch against a tumor that we know is inherently
aggressive. However, and this is a big

(21:26):
issue, however, it's vital to remember this is an area of very
active investigation. The huge unanswered question is
do these IDH mutant molecular grade 4 tumors truly benefit
from the concurrent part of the TMZ like IDH wild type GBM does
right? Or would adjuvant TMZ alone
after radiation be sufficient, similar to their grade 3

(21:46):
counterparts defined at CATNON? That's a key question because of
the added toxicity. Precisely concurrent TMZ adds
toxicity, so these patients are truly ideal candidates for
enrollment and dedicated clinical trials.
We desperately need more direct perspective evidence to
definitively figure out and optimize their treatment.
Understanding their distinct biology is really paving the way
for those critical future trials.

(22:07):
All right, that makes sense. Let's shift gears slightly and
distill this down into some clinical pearls.
These are the concise, high yield takeaways that everyone
listening can carry right into their clinic or maybe into their
board exams. These are the absolute must
knows. Sounds good.
Yeah, here are the absolute key takeaways for Anaplastic
Astrocytoma in this crucial concept of molecular grade four.

(22:28):
First, an anaplastic astrocytomais defined A molecularly it's an
IDH mutant 1P19Q non codelated glioma, remember 1P19Q intact.
It also almost always shows ATRXloss, which helps confirm its
astrocytic lineage and signals that genomic instability.
Got it. IDH mutant 1P19Q intact ATRX

(22:49):
loss. Second, the CATNON trial.
That is the landmark study for this disease.
It showed without a doubt that adjuvant TMZ significantly
improves survival, but crucially, concurrent TMZ does
not add further overall survivalbenefit, only toxicity.
Adjuvant yes. Concurrent No.
Clear Third, the numbers from CATNON are important.
Five year overall survival improved significantly from 44%

(23:12):
to 56% just by adding adjuvant TMZ.
And importantly, this benefit was limited entirely to the IDH
mutant population. Their median overall survival is
now approaching that impressive 8 year mark.
Eight years for IDH mutant with adjuvant TMZ.
OK. And finally #4 astrocytoma IDH
mutant WHO grade 4. This is a newly defined

(23:36):
molecular entity. It's an IDH mutant glioma that
has a homozygous deletion of CDKN 2A and B.
This deletion confers a significantly worse prognosis
regardless of how it looks underthe microscope, and therefore
strongly justifies a more aggressive treatment approach,
often borrowing from GBM protocols for now.
Excellent synthesis. Really clear pearls.

(23:57):
Now Are you ready for a quick board blitz?
Let's test these concepts and lock them in.
These are exactly the kinds of questions and scenarios you
might face in exams or just thinking through cases in
clinic. Absolutely.
Let's do it. Let's put it all together and
see how these concepts apply in practice.
OK, case 1. You have a 40 year old woman.
She undergoes A subtotal research of a grade 3 glioma.
The final pathology report comesback IDH mutant and 1P and 19 Q

(24:20):
non code deleted. Based on the practice changing
CATNON trial, which adjuvant regimen provides a proven
overall survival benefit for this patient?
Is it a none radiation alone is sufficient, B concurrent TMZ
given daily during radiation, C adjuvant TMZ for 12 cycles after
radiation, or D both concurrent and adjuvant TMZ?

(24:41):
OK, the best answer here clearlyis C adjuvant TMZ for 12 cycles
after radiation. The clinical reasoning comes
straight from the CATNON trials main finding.
The primary result was that significant overall survival
benefit came from adding adjuvant TMZ after radiation.
The trial specifically found that adding concurrent TMZ
during radiation was futile. It didn't improve survival for

(25:01):
these patients, only added toxicity.
So for an IDH mutant 119 Q non Co deleted anaplastic
astrocytoma adjuvant TMZ post RTis the standard.
Perfect case 2, same 4 year old patient.
She now asks you about her prognosis.
Understandably, you explained that based on the CATNON data
specifically for IDH mutant tumors treated with radiation

(25:22):
and adjuvant TMZ, her expected median overall survival is
approximately what, a two years,B4 years, C eight years, or D /
15 years? The best answer here reflecting
that huge impact of molecularly guided therapy is C
approximately 8 years. The CATNON trial, especially
with those updated 2021 results,showed that robust median

(25:45):
overall survival of 82 to 98 months, which translates
directly to around 7 to 8 years.And that's specifically for the
IDH mutant subgroup who receivedradiation followed by adjuvant
TMZ. It really highlights how
important that molecular information is for prognosis and
treatment. Excellent case 3 Now 35 year old
man undergoes resection of a tumor.

(26:05):
When the pathologist first looksat it under the microscope,
histologically it's classified as a grade 2 astrocytoma, looks
lower grade. However, the full molecular port
comes back and definitively shows an IDH mutation and
critically, A homozygous deletion of CDK N2A.
Based on the 2021 WHO interview classification, what is the
correct definitive diagnosis forthis patient?

(26:26):
A astrocytoma IDH mute in grade 2B.
Astrocytoma IDH mute in grade 3C.
Astrocytoma IDH mute in grade 4 or D Glioblastoma IDH wild type
grade 4. The correct answer which really
captures that core principle of modern molecular grading is C
astrocytoma IDH mutant grade 4. The presence of that homozygous

(26:47):
deletion of CDKN 2A and B in an IDH mutant astrocycoma
automatically definitively upgrades the tumor to WHO grade
4. It doesn't matter what the
initial Histology look like, That molecular finding
supersedes the Histology in determining the tumors true
biological grade and its prognosis.
It's a key principle of the 2021WHO system.

(27:09):
We look beyond the appearance tounderstand the underlying
biology. OK, that concept of molecular
grade 4 definitely adds a new important layer of complexity to
managing gliomas. It really pushes us to rethink
traditional greeting systems. What are some of the ongoing
discussions or maybe active areas of research in this space?
Especially given how relatively new this specific classification

(27:30):
is? It sounds like there's still
quite a bit to figure out. You're absolutely right.
This is really where the cuttingedge of neuro oncology meets.
While clinical uncertainty as we've discussed the optimal
treatment for astrocytoma IDH mutant WHO grade 4, it's
currently a point of significantdiscussion, even controversy
among experts and that's primarily because we lack that

(27:52):
direct perspective evidence froma dedicated trial to really
guide us. Now extrapolating from the
glioblastoma paradigm, treating them aggressively with
concurrent and adjuvant TMZ, that's common practice for most
experts. Now given the clear poor
prognosis seen in retrospective data, but it is an area very
active investigation. The big unanswered question

(28:12):
remains, do these tumors truly need the concurrent TMZ
component like IDH wild type GBMdoes or would adjuvant TMZ alone
after radiation be enough similar to the grade 3 tumors in
CATNOM? Right, avoiding that extra
toxicity if possible. Exactly so these patients are
truly ideal candidates for enrollment and dedicated
clinical trials. We desperately need that direct

(28:34):
evidence to solidify the optimal, most personalized
treatment for this newly definedmolecular entity.
Understanding their distinct biology isn't just academic,
it's absolutely essential for designing the future trials that
will ultimately resolve this crucial controversy.
OK, great. So to summarize today's deep
dive them, we've effectively wrapped up our comprehensive

(28:54):
look at WHO Grade 3 Gleamas. We've carefully separated the
management of oligodendrogliomas, which we
covered last time from anaplastic astrocytomas and we
based that separation squarely on their distinct molecular
profiles and the landmark trialslike CATNON that now rigorously
guide our practice. And maybe most importantly, we
introduced and really explored this powerful game changing

(29:17):
concept of molecularly defined Grade 4 astrocytomas,
highlighting how specific genetic changes can completely
redefine A tumor's behavior, itsprognosis, and how we need to
treat it. Precisely, we defined anaplastic
astrocytoma IDH mutant 119 Q nonCo deleted often with ATRX loss.
We thoroughly analyzed the pivotal CATNON trial, which

(29:38):
established unequivocally that for these tumors, adjuvant TMZ
after radiation significantly improves 5 year survival from
44% to 56%. And that benefit was driven
almost entirely by the IDH mutant group, where median
overall survival is now impressively approaching 8
years. And we clearly defined that new
clinically vital entity astrocytoma IDH mutant grade 4,

(30:02):
which gets automatically upgraded to the highest grade
based on that homozygous deletion of CDKN 2 ABA critical
molecular marker. That signals a much worse
prognosis and therefore warrantsa more aggressive treatment
approach, often borrowing from GBM protocols until we get more
specific evidence. Exactly.
So in our next deep dive, we're going to shift our focus
entirely to the most common and arguably still the most

(30:22):
challenging high grade glioma, GBM glioblastoma, IDH wild type.
We'll do an in depth explorationof the STEP protocol, why it
remains our cornerstone therapy even after all these years, and
we'll critically review the many, many negative trials that
have unfortunately only reinforced its standing.
It really illustrates just how difficult it is to make progress

(30:43):
in GBM treatment that will bringour High grade glioma series to
a powerful conclusion. Sounds great.
Don't miss our next episode. And remember, you can complete
practice oral boards and find more learning resources at RAD
on smartlearn.com. That's RAD on smartlearn.com.
Thanks for tuning into this deemed dive on anaplastic
astrocytomas and molecular grading.

(31:03):
We really hope this conversationhas given you a clearer, more
nuanced understanding of these complex tumors and how molecular
classification does fundamentally reshaping
everything we do.