July 6, 2025 • 21 mins
Welcome back to Rad Onc Smart Review, CNS Edition.T his is Episode 1 of our new series on CNS oncology, titled: Modern Classification & Anaplastic Oligodendroglioma Evidence. For decades, we treated high-grade gliomas based on what a pathologist saw under a microscope. But in the last ten years, a molecular revolution has completely rewritten the textbook. You cannot treat what you can't accurately diagnose, and the modern diagnosis of glioma is now an integrated, molecular one. Today, we will establish this critical diagnostic framework. Then, we will apply it by taking a deep dive into the management of anaplastic oligodendroglioma, synthesizing the two landmark trials that define its standard of care.
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(00:00):
Welcome everyone to the Radon smart Review CNS Cancer series
great to. Be here.
Today we're jumping into a really crucial tutoring session,
looking at something that's, well, completely changed the
landscape for brain tumors. We're calling it modern
classification and anaplastic oligodendrogolioma.
Evidence sounds good, and our mission really is twofold.
(00:20):
First, we want to lay out the essential the modern diagnostic
framework for gliomas. How do we even think about these
tumors now? Which is critical because it's
totally different than it was, say, 1015 years ago.
Exactly. And then right after
establishing that framework, we'll immediately apply it.
We're going to detail the evidence based management for a
(00:41):
specific type anaplastic. All good under glioma.
Right digging into the two big landmark trials that define how
we treat it. Because there's been this
molecular revolution, hasn't there?
Yeah, completely rewritten how we understand high grade
gliomas. Accurate diagnosis.
Now, is molecular diagnosis integrated with Histology?
Couldn't agree more. It's moved beyond just looking
(01:04):
at slides. We're understanding the, you
know, the fundamental biology now.
It dictates everything. And to make this really
concrete, let's maybe start witha quick case, something pretty
typical you might see. OK, sounds good.
Anchor us. All right, imagine a 42 year old
man. He presents with about a six
month history of seizures. Focal seizures getting worse.
(01:25):
OK, six months. Focal seizures.
Classic signs. Yep.
So he gets a brain MRI. It shows a pretty large mass in
his left frontal lobe. It's non enhancing which is
interesting and it has calcifications.
Non enhancing calcifications already given some clues, maybe
pointing away from the most aggressive types initially.
Potentially. And those calcifications, you
(01:47):
know, tiny calcium deposits, they're often seen in certain
glioma types, like oligodendrochliomas, though not
exclusively. Got it.
And location left frontal lobe could be tricky.
Very tricky. Let's say it's right up against
the motor cortex. So the neurosurgeon
understandably performs a subtotal resection.
They get out as much as they safely can, right?
Makes sense. Balancing tumor removal with
(02:09):
function. A common scenario.
Exactly. So surgery is done, pathology is
pending, and your neuro oncologyPolly calls you asks for your
initial thoughts. The classic What you think call
while waiting for the path report.
Precisely. And this is where it all hinges.
It looks like a high grade glioma presentation, but what
you do next, your entire management plan is completely
(02:31):
dependent on that final integrated pathology.
Without it, you're really just guessing.
Yeah, you can't make a plan without knowing exactly what
you're dealing with, especially now.
That's the core. Point.
OK, so let's unpack that. This paradigm shift in
diagnosis. You mentioned, it's not just
Histology anymore. For years we had these names
based on looks, anaplastic astrocytoma, anaplastic oligotin
(02:53):
drug Leon, ileoblastoma, and I, I remember seeing anaplastic
oligoasterocytoma all the time. That diagnosis caused so much
confusion. Oh.
Definitely a real headache. Thankfully, it's pretty much
obsolete now. Because The Who, the World
Health Organization came out with new classifications in
2016, updated again in 2021. They mandate this integrated
(03:16):
approach, right? Combining the Histology with key
molecular markers. That's it exactly.
It's Histology plus molecular genetics.
So when that path report finallyarrives for our patient or any
glioma patient, what are the absolute first most critical
molecular questions we need answered?
What's step one and Step 2? OK.
Excellent question. This is the foundation.
Now the very first thing you look for the absolute key
(03:37):
question #1 is what is the IDH status?
IDH, isocitrate dehydrogenase. Correct.
Is that gene mutated or is it wild type meaning normal?
This single piece of informationfundamentally splits gliomas
into two completely different diseases.
It's not subtle, it's a profoundbiological divide.
Two different diseases entirely based on one gene status.
(03:59):
Essentially, yes. It changes cellular metabolism,
how the tumor behaves, prognosis, treatment response,
everything. OK, so.
Tell us about those two pathways.
What happens if it's IDH mutant versus IDH wild type?
Right. So if the tumor is IDH mutant,
these are what we now consider the kind of true diffuse
gliomas. They tend to show up in younger
patients, 30s forties like our case example.
(04:21):
And crucially, they carry a significantly better prognosis.
They generally grow slower, respond better to therapy.
It's just a different Natural History.
OK, better prognosis with IDH mutant.
What about IDH wild type? Now if it's IDH wild type, no
mutation, things are different even if the Histology looks
lower grade like A grade two or three under the microscope.
(04:42):
Yeah, clinically and biologically, these tumors
behave like glioblastoma, full stop.
Wow. Even if it doesn't look like a
GBM pathologically. Exactly.
We now call these molecular GBMSand unfortunately their
prognosis is poor mirroring conventional glioblastoma.
We'll actually dive deep into those IDH file type tumors and
there's specific management, thestar protocol and all that in
(05:03):
Episode 3. OK, important distinction.
So IDH status is the first majorbranch point crucial.
What's the second key? Molecular question, assuming
we've gone down the IDH mutant path.
Good clarification. This second question only
applies if the tumor is IDH mutant.
If it's wild type, you're already heading towards the
molecular GBM category. But if it is IDH mutant then you
(05:24):
need to know what is the 1P and 19 Q status. 119 Q That refers
to chromosome arms, right? Correct.
Specifically, the code deletion of the short arm of chromosome
11P and the long arm of chromosome 1919 Q.
This specific combination, this code deletion, is the definitive
molecular signature of an oligodendroglioma within the IDH
(05:47):
mutant family AH. So this is how we finally
separate the IDH mutant astrocytomas from the IDH mutant
oligodendrogliomas cleanly. It's the 1P19Q status.
Precisely, it cuts through all that old ambiguity if you have
an IDH mutant tumor and it's 119Q code deleted.
Then it's an oligodendroglioma. Ingo oligodendroglioma.
Now if you have an IDH mutant tumor but the 1P and 19 Q are
(06:08):
intact, no code deletion. Then it has to be an
astrocytoma. Astrocytoma simple as that.
IDH mutant 1P19Q intact equals astrocytoma.
It provides such clear diagnostic bins which is
essential for picking the right treatment path.
That really clarifies things. It feels much more objective
than just relying on how fried egg their cells looked under the
scope. Exactly.
(06:29):
Though Histology still matters for grading.
These molecular markers are the defining features for the type
of glioma. OK.
Now you often hear ATRX mentioned alongside these.
Is there a quick clinical Pearl or maybe a nonic to tie IDH
1P19Q and ATRX together? Something easy to recall in
clinic? Yes, absolutely.
(06:49):
There's a very useful relationship here.
A 119 Q code deletion and loss of ATRX expression typically
detected by immunohistochemistryshowing the protein is missing
are almost always mutually exclusive.
It's. Mutually exclusive, meaning if
you have one, you don't have theother.
Pretty much yes. It's a very strong inverse
correlation, and loss of ATRX expression is a key hallmark of
IDH mutant astrocytomas. OK, so the Perl is.
(07:12):
The Perl is if you see on the path report that the tumor is
IDH mutant and it shows loss of ATRX, you can be very confident
it's an astrocytoma. And because it's an astrocytoma
marked by ATRX loss, you alreadyknow it won't have the 1P19Q
code deletion. It's a quick way to confirm the
astrocytoma lineage. That's it's a great shortcut.
So IDH mutant plus ATRX loss points strongly to astrocytoma
(07:33):
and intact 1P19 Q. You got it.
OK, maybe a mnemonic then to remember the sequence.
IDH first, then 1P19Q for the oligo Ostro split.
Maybe think about ATRX confirming the Astro path.
How about IDHONEIDH first, then O for oligo defined by the 118 Q
code deletion? Maybe any for not expressed atrx
(07:54):
and astrocytoma or just IDH then1P19Q and remember ETRXATRX goes
with the astrocytoma. I like IDHONE, it emphasizes the
key markers in order IDH then the 1P19 Q status and you just
have to remember atrx loss pairswith the other one, the
astrocytoma. Whatever works to make it stick.
Perfect. IDHONE it is.
(08:14):
OK, so armed with this, let's goback to our 42 year old man
frontal lobe mass subtotal resection.
The final path report lands on your desk.
It reads histologic grade 3 IDH mutant and 119 Q code deleted.
OK Grade 3 IDH mutant 1P19Q Codedeleted.
So, using our shiny new integrated diagnosis framework,
what is this and what's the nextstep?
(08:35):
All right. Piece by piece, IDH mutant 1P19Q
code deleted that tells us it's an oligoden druglioma.
Histologic grade 3 tells us it'sanaplastic.
So the integrated diagnosis is anaplastic oligoden druglioma
WHO grade 3. Got it.
Anaplastic oligo grade 3. Now we know exactly what we're
treating. Precisely and now that we have
that specific diagnosis, we can look at the high level evidence
(08:57):
for this specific tumor. Grade 3 IDH mutant 1P19Q code
deleted all ago. The standard of care is defined
by two absolutely pivotal phase three trials.
The ones you mentioned earlier. Yes, URTC 26951 and RTOG 9402
both basically asked for these patients.
Does adding PCV chemotherapy to radiation therapy improve
survival? PCV can you quickly remind us
(09:19):
what's in that chemo cocktail? It sounds pretty heavy duty.
It is a potent regimen. PCV stands for Procarbazine CCNU
which is lomestine and vincristine.
Procarbazine lomestine vincristine.
OK. Yeah, procarbazine and lomestine
are oral alkylating agents. They damage DNA.
Vincristine is the fantidy and messes with cell division.
(09:39):
It's effective, but it definitely comes with side
effects, especially hematologic toxicity impacting blood counts.
Right, not a walk in the park. So let's run the ERTC 26951
first. How is that trial set up?
OK ERTC randomized patients who had at the time what was called
anaplastic oligodendroglioma or anaplastic oligoastrocytoma.
(10:01):
That old mixed diagnosis again. Right, they randomized them to
get either radiation therapy alone or radiation therapy
followed by 6 cycles of adjuvantPCV chemo after radiation.
And the radiation. Does standard dose 29.4 grey and
33 fractions OK? What were the key findings,
especially when they went back and looked with the molecular
data? That's where it got really
interesting. The long term update
(10:23):
incorporating the molecular subtypes showed a clear overall
survival benefit for adding PCV.But the kicker was this benefit
was driven entirely by the patients whose tumors had the
119 Q code deletion. Entirely so no benefit for the
intact group in that trial. Essentially, yes.
The benefit was concentrated in the code deleted subgroup.
(10:45):
For those patients, adding PCV was a game changer.
How much of A game changer quantify that massive benefit
for us? OK, get this for the code
deleted group, adding adjuvant PCV boosted the medium
progression free survival time without the tumor growing from
about 4.2 years to 13.1 years. Wow, from 4 to 13 years PFS,
(11:06):
that's huge. Incredible difference and median
overall survival jumped from 9.3years with radiation alone to
14.2 years with the combination 9. .3 to 14.2 years median
survival, nearly five extra years, yeah.
In brain tumors, that kind of survival improvement is, well,
massive. Truly redefined the standard for
these patients. Unbelievable data.
Okay, that's EO RTC adjuvant PCVworks for code deleted oligos.
(11:31):
What about the other big one? RTOG 9402?
Did it ask the same question? Similar patient population,
again mostly anaplastic oligo and oligo astrocytomas, but RTOG
94-O2 tested a different sequence.
They compared radiation alone versus neoadjuvant PCV, giving
the PCV before the radiation. OK, chemo first, then radiation.
(11:51):
How did that one pan out initially before they had the
molecular data? Well, this is a fascinating
story in clinical trial evolution.
When RTOG 94-O2 was first published back in 2006, it was
considered a negative trial. Negative.
How so? It showed no significant
difference in overall survival between the arms.
Median survival was something like 4.7 years versus 4.6 years
(12:12):
basically identical. So the initial conclusion was,
well, maybe adding PCV doesn't really help this group overall.
Huh. So initially one trial positive
EORTC, long term one negative RTOG initial.
That must have been confusing. It was, but then came the
molecular reanalysis years later, applying the IDH and 1P19
Q status retrospectively to the patient samples.
(12:33):
And this is where the picture flips completely, right?
Like cleaning off an old painting, you said.
Exactly that analogy. The reanalysis results were
profound. They looked specifically at the
119 Q Co deleted subgroup withinRTOG 94-O2, and in that
subgroup, adding the neoadjuvantPCV almost doubled the median
overall survival. It went from 7.3 years in the
(12:55):
radiation alone arm to an incredible 14.7 years in the PCV
plus radiation arm. 14.7 years, so almost identical long term
survival benefit as seen in ERTCjust achieved with a different
sequence. Precisely 7.3 years up to 14.7.
What was initially a negative trial became incredibly positive
(13:16):
once they could identify the right patient population using
molecular markers. It was just hidden by the mix of
patients in the original analysis.
So the message from both EORTC 26951 and RTOG 9402 viewed to
this modern molecular lens is crystal clear.
Undeniable for patients with anaplastic oligon druglioma
defined now is IDH mutant 1P9 10Q Co deleted.
(13:37):
Adding PCV chemotherapy to radiation dramatically improves
survival. Whether you give the PCV before
radiation or after radiation, that combined modality
approaches the standard of care,yielding median survivals over
14 years. That's the bottom line.
Robust benefit. Established standard.
OK. So the evidence supports chemo
radiation, but clinically you have to choose neoadjuvant PCV
(14:02):
first like RTOG or adjuvant PCV after radiation like EORTC.
Which way do most centers lean and why?
That's the practical question. Most centers, and the NCCN
guidelines reflect this, tend tofavor the adjuvant approach from
the ertc trial. Radiation first, then PCV.
And the reasoning behind that preference, is it efficacy or
(14:25):
something else? It mostly comes down to
tolerability and feasibility. That dose intensive neoadjuvant
PCV used in RTOG 9402. It caused a lot of hematologic
toxicity. Right, The blood count issues
you mentioned. Yeah, significant
myelosuppression. A substantial number of patients
actually couldn't complete all the planned cycles of chemo
before radiation because the side effects were too severe.
(14:45):
So giving it upfront was just too tough for many patients.
Exactly. Giving the PCV after radiation
in the adjuvant setting seems tobe generally better tolerated.
Patients have recovered from surgery and RT, their marrow
reserve might be a bit better, and more people tend to complete
the planned treatment. So it's about delivering the
effect of therapy in a way most patients can actually receive
(15:05):
it. Makes sense, Maximize the chance
of getting the full treatment in.
OK, one more clinical point here.
The PCV toxicity is still a concern, even adjuvantly.
What about substituting temazonamide?
TMZ. It's oral, generally much easier
to take. Is that a reasonable swap for
PCV in these patients? That is the big question right
now now and a source of debate. It's being formally tested head
(15:27):
to head against PCV with radiation and the ongoing Codell
trial. We're eagerly awaiting those
results. So no definitive answer yet from
a phase three trial specificallyasking that question.
Not from Codell yet. However we do have some clues
from other studies. The German NOAO 4 trial, for
instance, compared RT, PCV and TMZ in anaplastic lamas.
(15:50):
And what did it suggest for the oligos?
It suggested that for the 119 Q Co deleted tumor specifically
PCV seem to be superior to TMZ in terms of progression free
survival. Interesting.
So preliminary signals favor PCV's efficacy in this specific
group? That's the current
interpretation of the available data.
So while TMZ is appealing for its better side effect profile,
(16:12):
PCV currently remains the evidence based standard chemo
backbone for anaplastive oligodendroglioma based on
proven survival benefit from ERTC and RTG, and hints of
superiority over TMZ from Noazer4.
We need Codell to really settle it.
OK, so PCV is still the champ for now evidence wise.
Got it. And just to reiterate, the
radiation part, you mentioned the dose used in ERTC was 59.4
(16:36):
Gray and 33 fractions. That specific dose remains the
standard we aim for. Absolutely.
That's the dose proven in in combination with PCV in the
trial that showed the survival benefit.
We stick to that dose in fractionation 1.8 grey per day
to ensure we're replicating the conditions under which that
benefit was demonstrated. Precision and radiation delivery
matching the trial parameters iskey.
(16:58):
Great. OK.
I think we've covered the diagnosis in the evidence really
well. Should we try putting it into
practice with a few quick cases?Time for our board blitz?
Let's do it. Always good to apply the
knowledge. All right case 145 year old
woman Subtotal resection of a frontal lobe.
Tumor pathology is back. Anaplastic oligodendroglioma.
IDH mutant 119 Q code deleted. What's the most appropriate
(17:19):
management? A observation with serial MRISB
radiation to 59.4 Gray alone. C radiation to 59.4 Gray
followed by adjuvant PCV chemotherapy or DTMZ
monotherapy. OK, Grade 3 oligo IDH Mutant
1P19Q Code deleted. Based on everything we've
discussed, the clear answer is. CC radiation followed by
(17:41):
adjuvant? Absolutely.
This is the classic high risk grade 3 oligodendrogliomo
profile. EORTC 26951 and RTOG 9402
established combined modality with RT and PCV as the standard,
showing that major survival benefit observation.
R2 alone or TMZ alone would be under treating this patient
based on level 1 evidence. Perfect.
(18:02):
Standard of care is chemo radiation.
OK. Case 2.
Testing the diagnostic algorithm. 52 year old diagnosed
with an anaplastic glioma. Molecular report shows IDH
mutation 119 Q intact and loss of ATRX exression.
Which statement is most accurate?
A. It's an an plastic oligo treat
with RT plus CVB. It's an anaplastic Astro treat
(18:24):
with RT plus CVC. It's an anaplastic astrocytoma
and treatment should be based onthe cat on trial or D.
It's a molecular GBM treat per step.
Protocol. OK, let's use our algorithm.
IDH mutant Yes 119 Q status intact.
OK, so that rules out oligo. Right, IDH mutant plus 1P19Q
intact astrocytoma. The loss of ATRX confirms this.
(18:44):
So we know it's an anaplastic astrocytoma.
IDH mutant. Therefore treatment isn't guided
by the oligo trials. Your TCR TOGA, the GBM protocol
stuck because it's IDH mutant. It's guided by trials specific
to anaplastic astrocytoma, the main one being the catnon trial.
So the answer is C. Excellent breakdown.
C is correct, it's an anaplasticastrocytoma and catnon guides
treatment. OK, last one, case 3, you're
(19:06):
discussing RTOG 94-AO2. What's a key finding from that
trial specifically for anaplastic oligodendrolioma?
ATMZ was superior to PCVB. The trial was positive initially
in 2006. C neoadjuvant PCV plus route
imroved median O to 147 years inthe code deleted subgroup or D
route dose escalation to 70 Grayimroved local control.
(19:29):
OK, thinking about R2G94-O2 and its impact on all it goes.
Option A is wrong. TMZ wasn't tested in that trial.
Option B is wrong. It was initially published as
negative. Option D is wrong.
Dose escalation wasn't part of 94-O2.
That leaves CC. Neo adjuvant PCV followed by RT
improved median OS to 14.7 yearsin the code deleted group.
And that is absolutely the key finding the molecular reanalysis
(19:51):
revealing that dramatic survivalbenefit from 7.3 to 14.7 years
in the chemo RT arm for code deleted tumors is the lasting
legacy of RTOG 9/2. Fantastic.
Great job working through those.So let's try to quickly
summarize today's session. We really built that essential
molecular framework for high grade gliomas.
Focusing on IDH status first, then 1P19 Q status for the IDH
(20:12):
mutants. Right.
And we saw how that framework directly applies to defining and
treating anaplastic oligodendroglioma.
The key take away has to be thatmodern diagnosis is molecular.
Absolutely, and anaplastic oligen druglioma is specifically
IDH mutant and 1P19Q code deleted.
That's the definition. And for treatment.
The standard is clear based on those two huge trials, EOR
(20:35):
TC-26951 and RTOG 9402. Radiation plus PCV chemotherapy
provides a major survival benefit, pushing median survival
over 14 years. An incredible outcome really,
for a primary brain tumor established by understanding the
underlying molecular biology. It truly highlights the power of
precision oncology. Definitely.
(20:56):
So as we finish up, this naturally leads to our next
questions, doesn't it? We've covered the grade 3
oligos. What about the grade 3
astrocytomas? The IDH mutant 1P19Q intact
ones? How does that Canon trial
pronounced Catanon right? How does that guide their
management? Yes, Catanon is key there.
And there's another layer now too, which the newer WHO
classification recognizes. IDH mutant grade 4 astrocytomas.
(21:19):
That's a relatively new entity based on specific molecular
features like CDKN 2 AB deletion.
Even if the Histology looks grade two or three, how do we
treat those? So even more complexity
emerging. Lots to cover next time then.
Anaplastic astrocytomas, katnolin and these new grade 4
IDH mutant Astros. Plenty to discuss.
The field keeps moving fast. It certainly does.
(21:42):
Well, for more practice, remember to complete practice
oral boards at radonksmartlearn.com.
That's rad ONC smartlearn.com. And subscribe to Radonk Smart
Review for our next episode diving into those astrocytomas.
Thanks for tuning. In thanks everyone.
Welcome everyone to the Radon smart Review CNS Cancer series
great to. Be here.
Today we're jumping into a really crucial tutoring session,
looking at something that's, well, completely changed the
landscape for brain tumors. We're calling it modern
classification and anaplastic oligodendrogolioma.
Evidence sounds good, and our mission really is twofold.
(00:20):
First, we want to lay out the essential the modern diagnostic
framework for gliomas. How do we even think about these
tumors now? Which is critical because it's
totally different than it was, say, 1015 years ago.
Exactly. And then right after
establishing that framework, we'll immediately apply it.
We're going to detail the evidence based management for a
(00:41):
specific type anaplastic. All good under glioma.
Right digging into the two big landmark trials that define how
we treat it. Because there's been this
molecular revolution, hasn't there?
Yeah, completely rewritten how we understand high grade
gliomas. Accurate diagnosis.
Now, is molecular diagnosis integrated with Histology?
Couldn't agree more. It's moved beyond just looking
(01:04):
at slides. We're understanding the, you
know, the fundamental biology now.
It dictates everything. And to make this really
concrete, let's maybe start witha quick case, something pretty
typical you might see. OK, sounds good.
Anchor us. All right, imagine a 42 year old
man. He presents with about a six
month history of seizures. Focal seizures getting worse.
(01:25):
OK, six months. Focal seizures.
Classic signs. Yep.
So he gets a brain MRI. It shows a pretty large mass in
his left frontal lobe. It's non enhancing which is
interesting and it has calcifications.
Non enhancing calcifications already given some clues, maybe
pointing away from the most aggressive types initially.
Potentially. And those calcifications, you
(01:47):
know, tiny calcium deposits, they're often seen in certain
glioma types, like oligodendrochliomas, though not
exclusively. Got it.
And location left frontal lobe could be tricky.
Very tricky. Let's say it's right up against
the motor cortex. So the neurosurgeon
understandably performs a subtotal resection.
They get out as much as they safely can, right?
Makes sense. Balancing tumor removal with
(02:09):
function. A common scenario.
Exactly. So surgery is done, pathology is
pending, and your neuro oncologyPolly calls you asks for your
initial thoughts. The classic What you think call
while waiting for the path report.
Precisely. And this is where it all hinges.
It looks like a high grade glioma presentation, but what
you do next, your entire management plan is completely
(02:31):
dependent on that final integrated pathology.
Without it, you're really just guessing.
Yeah, you can't make a plan without knowing exactly what
you're dealing with, especially now.
That's the core. Point.
OK, so let's unpack that. This paradigm shift in
diagnosis. You mentioned, it's not just
Histology anymore. For years we had these names
based on looks, anaplastic astrocytoma, anaplastic oligotin
(02:53):
drug Leon, ileoblastoma, and I, I remember seeing anaplastic
oligoasterocytoma all the time. That diagnosis caused so much
confusion. Oh.
Definitely a real headache. Thankfully, it's pretty much
obsolete now. Because The Who, the World
Health Organization came out with new classifications in
2016, updated again in 2021. They mandate this integrated
(03:16):
approach, right? Combining the Histology with key
molecular markers. That's it exactly.
It's Histology plus molecular genetics.
So when that path report finallyarrives for our patient or any
glioma patient, what are the absolute first most critical
molecular questions we need answered?
What's step one and Step 2? OK.
Excellent question. This is the foundation.
Now the very first thing you look for the absolute key
(03:37):
question #1 is what is the IDH status?
IDH, isocitrate dehydrogenase. Correct.
Is that gene mutated or is it wild type meaning normal?
This single piece of informationfundamentally splits gliomas
into two completely different diseases.
It's not subtle, it's a profoundbiological divide.
Two different diseases entirely based on one gene status.
(03:59):
Essentially, yes. It changes cellular metabolism,
how the tumor behaves, prognosis, treatment response,
everything. OK, so.
Tell us about those two pathways.
What happens if it's IDH mutant versus IDH wild type?
Right. So if the tumor is IDH mutant,
these are what we now consider the kind of true diffuse
gliomas. They tend to show up in younger
patients, 30s forties like our case example.
(04:21):
And crucially, they carry a significantly better prognosis.
They generally grow slower, respond better to therapy.
It's just a different Natural History.
OK, better prognosis with IDH mutant.
What about IDH wild type? Now if it's IDH wild type, no
mutation, things are different even if the Histology looks
lower grade like A grade two or three under the microscope.
(04:42):
Yeah, clinically and biologically, these tumors
behave like glioblastoma, full stop.
Wow. Even if it doesn't look like a
GBM pathologically. Exactly.
We now call these molecular GBMSand unfortunately their
prognosis is poor mirroring conventional glioblastoma.
We'll actually dive deep into those IDH file type tumors and
there's specific management, thestar protocol and all that in
(05:03):
Episode 3. OK, important distinction.
So IDH status is the first majorbranch point crucial.
What's the second key? Molecular question, assuming
we've gone down the IDH mutant path.
Good clarification. This second question only
applies if the tumor is IDH mutant.
If it's wild type, you're already heading towards the
molecular GBM category. But if it is IDH mutant then you
(05:24):
need to know what is the 1P and 19 Q status. 119 Q That refers
to chromosome arms, right? Correct.
Specifically, the code deletion of the short arm of chromosome
11P and the long arm of chromosome 1919 Q.
This specific combination, this code deletion, is the definitive
molecular signature of an oligodendroglioma within the IDH
(05:47):
mutant family AH. So this is how we finally
separate the IDH mutant astrocytomas from the IDH mutant
oligodendrogliomas cleanly. It's the 1P19Q status.
Precisely, it cuts through all that old ambiguity if you have
an IDH mutant tumor and it's 119Q code deleted.
Then it's an oligodendroglioma. Ingo oligodendroglioma.
Now if you have an IDH mutant tumor but the 1P and 19 Q are
(06:08):
intact, no code deletion. Then it has to be an
astrocytoma. Astrocytoma simple as that.
IDH mutant 1P19Q intact equals astrocytoma.
It provides such clear diagnostic bins which is
essential for picking the right treatment path.
That really clarifies things. It feels much more objective
than just relying on how fried egg their cells looked under the
scope. Exactly.
(06:29):
Though Histology still matters for grading.
These molecular markers are the defining features for the type
of glioma. OK.
Now you often hear ATRX mentioned alongside these.
Is there a quick clinical Pearl or maybe a nonic to tie IDH
1P19Q and ATRX together? Something easy to recall in
clinic? Yes, absolutely.
(06:49):
There's a very useful relationship here.
A 119 Q code deletion and loss of ATRX expression typically
detected by immunohistochemistryshowing the protein is missing
are almost always mutually exclusive.
It's. Mutually exclusive, meaning if
you have one, you don't have theother.
Pretty much yes. It's a very strong inverse
correlation, and loss of ATRX expression is a key hallmark of
IDH mutant astrocytomas. OK, so the Perl is.
(07:12):
The Perl is if you see on the path report that the tumor is
IDH mutant and it shows loss of ATRX, you can be very confident
it's an astrocytoma. And because it's an astrocytoma
marked by ATRX loss, you alreadyknow it won't have the 1P19Q
code deletion. It's a quick way to confirm the
astrocytoma lineage. That's it's a great shortcut.
So IDH mutant plus ATRX loss points strongly to astrocytoma
(07:33):
and intact 1P19 Q. You got it.
OK, maybe a mnemonic then to remember the sequence.
IDH first, then 1P19Q for the oligo Ostro split.
Maybe think about ATRX confirming the Astro path.
How about IDHONEIDH first, then O for oligo defined by the 118 Q
code deletion? Maybe any for not expressed atrx
(07:54):
and astrocytoma or just IDH then1P19Q and remember ETRXATRX goes
with the astrocytoma. I like IDHONE, it emphasizes the
key markers in order IDH then the 1P19 Q status and you just
have to remember atrx loss pairswith the other one, the
astrocytoma. Whatever works to make it stick.
Perfect. IDHONE it is.
(08:14):
OK, so armed with this, let's goback to our 42 year old man
frontal lobe mass subtotal resection.
The final path report lands on your desk.
It reads histologic grade 3 IDH mutant and 119 Q code deleted.
OK Grade 3 IDH mutant 1P19Q Codedeleted.
So, using our shiny new integrated diagnosis framework,
what is this and what's the nextstep?
(08:35):
All right. Piece by piece, IDH mutant 1P19Q
code deleted that tells us it's an oligoden druglioma.
Histologic grade 3 tells us it'sanaplastic.
So the integrated diagnosis is anaplastic oligoden druglioma
WHO grade 3. Got it.
Anaplastic oligo grade 3. Now we know exactly what we're
treating. Precisely and now that we have
that specific diagnosis, we can look at the high level evidence
(08:57):
for this specific tumor. Grade 3 IDH mutant 1P19Q code
deleted all ago. The standard of care is defined
by two absolutely pivotal phase three trials.
The ones you mentioned earlier. Yes, URTC 26951 and RTOG 9402
both basically asked for these patients.
Does adding PCV chemotherapy to radiation therapy improve
survival? PCV can you quickly remind us
(09:19):
what's in that chemo cocktail? It sounds pretty heavy duty.
It is a potent regimen. PCV stands for Procarbazine CCNU
which is lomestine and vincristine.
Procarbazine lomestine vincristine.
OK. Yeah, procarbazine and lomestine
are oral alkylating agents. They damage DNA.
Vincristine is the fantidy and messes with cell division.
(09:39):
It's effective, but it definitely comes with side
effects, especially hematologic toxicity impacting blood counts.
Right, not a walk in the park. So let's run the ERTC 26951
first. How is that trial set up?
OK ERTC randomized patients who had at the time what was called
anaplastic oligodendroglioma or anaplastic oligoastrocytoma.
(10:01):
That old mixed diagnosis again. Right, they randomized them to
get either radiation therapy alone or radiation therapy
followed by 6 cycles of adjuvantPCV chemo after radiation.
And the radiation. Does standard dose 29.4 grey and
33 fractions OK? What were the key findings,
especially when they went back and looked with the molecular
data? That's where it got really
interesting. The long term update
(10:23):
incorporating the molecular subtypes showed a clear overall
survival benefit for adding PCV.But the kicker was this benefit
was driven entirely by the patients whose tumors had the
119 Q code deletion. Entirely so no benefit for the
intact group in that trial. Essentially, yes.
The benefit was concentrated in the code deleted subgroup.
(10:45):
For those patients, adding PCV was a game changer.
How much of A game changer quantify that massive benefit
for us? OK, get this for the code
deleted group, adding adjuvant PCV boosted the medium
progression free survival time without the tumor growing from
about 4.2 years to 13.1 years. Wow, from 4 to 13 years PFS,
(11:06):
that's huge. Incredible difference and median
overall survival jumped from 9.3years with radiation alone to
14.2 years with the combination 9. .3 to 14.2 years median
survival, nearly five extra years, yeah.
In brain tumors, that kind of survival improvement is, well,
massive. Truly redefined the standard for
these patients. Unbelievable data.
Okay, that's EO RTC adjuvant PCVworks for code deleted oligos.
(11:31):
What about the other big one? RTOG 9402?
Did it ask the same question? Similar patient population,
again mostly anaplastic oligo and oligo astrocytomas, but RTOG
94-O2 tested a different sequence.
They compared radiation alone versus neoadjuvant PCV, giving
the PCV before the radiation. OK, chemo first, then radiation.
(11:51):
How did that one pan out initially before they had the
molecular data? Well, this is a fascinating
story in clinical trial evolution.
When RTOG 94-O2 was first published back in 2006, it was
considered a negative trial. Negative.
How so? It showed no significant
difference in overall survival between the arms.
Median survival was something like 4.7 years versus 4.6 years
(12:12):
basically identical. So the initial conclusion was,
well, maybe adding PCV doesn't really help this group overall.
Huh. So initially one trial positive
EORTC, long term one negative RTOG initial.
That must have been confusing. It was, but then came the
molecular reanalysis years later, applying the IDH and 1P19
Q status retrospectively to the patient samples.
(12:33):
And this is where the picture flips completely, right?
Like cleaning off an old painting, you said.
Exactly that analogy. The reanalysis results were
profound. They looked specifically at the
119 Q Co deleted subgroup withinRTOG 94-O2, and in that
subgroup, adding the neoadjuvantPCV almost doubled the median
overall survival. It went from 7.3 years in the
(12:55):
radiation alone arm to an incredible 14.7 years in the PCV
plus radiation arm. 14.7 years, so almost identical long term
survival benefit as seen in ERTCjust achieved with a different
sequence. Precisely 7.3 years up to 14.7.
What was initially a negative trial became incredibly positive
(13:16):
once they could identify the right patient population using
molecular markers. It was just hidden by the mix of
patients in the original analysis.
So the message from both EORTC 26951 and RTOG 9402 viewed to
this modern molecular lens is crystal clear.
Undeniable for patients with anaplastic oligon druglioma
defined now is IDH mutant 1P9 10Q Co deleted.
(13:37):
Adding PCV chemotherapy to radiation dramatically improves
survival. Whether you give the PCV before
radiation or after radiation, that combined modality
approaches the standard of care,yielding median survivals over
14 years. That's the bottom line.
Robust benefit. Established standard.
OK. So the evidence supports chemo
radiation, but clinically you have to choose neoadjuvant PCV
(14:02):
first like RTOG or adjuvant PCV after radiation like EORTC.
Which way do most centers lean and why?
That's the practical question. Most centers, and the NCCN
guidelines reflect this, tend tofavor the adjuvant approach from
the ertc trial. Radiation first, then PCV.
And the reasoning behind that preference, is it efficacy or
(14:25):
something else? It mostly comes down to
tolerability and feasibility. That dose intensive neoadjuvant
PCV used in RTOG 9402. It caused a lot of hematologic
toxicity. Right, The blood count issues
you mentioned. Yeah, significant
myelosuppression. A substantial number of patients
actually couldn't complete all the planned cycles of chemo
before radiation because the side effects were too severe.
(14:45):
So giving it upfront was just too tough for many patients.
Exactly. Giving the PCV after radiation
in the adjuvant setting seems tobe generally better tolerated.
Patients have recovered from surgery and RT, their marrow
reserve might be a bit better, and more people tend to complete
the planned treatment. So it's about delivering the
effect of therapy in a way most patients can actually receive
(15:05):
it. Makes sense, Maximize the chance
of getting the full treatment in.
OK, one more clinical point here.
The PCV toxicity is still a concern, even adjuvantly.
What about substituting temazonamide?
TMZ. It's oral, generally much easier
to take. Is that a reasonable swap for
PCV in these patients? That is the big question right
now now and a source of debate. It's being formally tested head
(15:27):
to head against PCV with radiation and the ongoing Codell
trial. We're eagerly awaiting those
results. So no definitive answer yet from
a phase three trial specificallyasking that question.
Not from Codell yet. However we do have some clues
from other studies. The German NOAO 4 trial, for
instance, compared RT, PCV and TMZ in anaplastic lamas.
(15:50):
And what did it suggest for the oligos?
It suggested that for the 119 Q Co deleted tumor specifically
PCV seem to be superior to TMZ in terms of progression free
survival. Interesting.
So preliminary signals favor PCV's efficacy in this specific
group? That's the current
interpretation of the available data.
So while TMZ is appealing for its better side effect profile,
(16:12):
PCV currently remains the evidence based standard chemo
backbone for anaplastive oligodendroglioma based on
proven survival benefit from ERTC and RTG, and hints of
superiority over TMZ from Noazer4.
We need Codell to really settle it.
OK, so PCV is still the champ for now evidence wise.
Got it. And just to reiterate, the
radiation part, you mentioned the dose used in ERTC was 59.4
(16:36):
Gray and 33 fractions. That specific dose remains the
standard we aim for. Absolutely.
That's the dose proven in in combination with PCV in the
trial that showed the survival benefit.
We stick to that dose in fractionation 1.8 grey per day
to ensure we're replicating the conditions under which that
benefit was demonstrated. Precision and radiation delivery
matching the trial parameters iskey.
(16:58):
Great. OK.
I think we've covered the diagnosis in the evidence really
well. Should we try putting it into
practice with a few quick cases?Time for our board blitz?
Let's do it. Always good to apply the
knowledge. All right case 145 year old
woman Subtotal resection of a frontal lobe.
Tumor pathology is back. Anaplastic oligodendroglioma.
IDH mutant 119 Q code deleted. What's the most appropriate
(17:19):
management? A observation with serial MRISB
radiation to 59.4 Gray alone. C radiation to 59.4 Gray
followed by adjuvant PCV chemotherapy or DTMZ
monotherapy. OK, Grade 3 oligo IDH Mutant
1P19Q Code deleted. Based on everything we've
discussed, the clear answer is. CC radiation followed by
(17:41):
adjuvant? Absolutely.
This is the classic high risk grade 3 oligodendrogliomo
profile. EORTC 26951 and RTOG 9402
established combined modality with RT and PCV as the standard,
showing that major survival benefit observation.
R2 alone or TMZ alone would be under treating this patient
based on level 1 evidence. Perfect.
(18:02):
Standard of care is chemo radiation.
OK. Case 2.
Testing the diagnostic algorithm. 52 year old diagnosed
with an anaplastic glioma. Molecular report shows IDH
mutation 119 Q intact and loss of ATRX exression.
Which statement is most accurate?
A. It's an an plastic oligo treat
with RT plus CVB. It's an anaplastic Astro treat
(18:24):
with RT plus CVC. It's an anaplastic astrocytoma
and treatment should be based onthe cat on trial or D.
It's a molecular GBM treat per step.
Protocol. OK, let's use our algorithm.
IDH mutant Yes 119 Q status intact.
OK, so that rules out oligo. Right, IDH mutant plus 1P19Q
intact astrocytoma. The loss of ATRX confirms this.
(18:44):
So we know it's an anaplastic astrocytoma.
IDH mutant. Therefore treatment isn't guided
by the oligo trials. Your TCR TOGA, the GBM protocol
stuck because it's IDH mutant. It's guided by trials specific
to anaplastic astrocytoma, the main one being the catnon trial.
So the answer is C. Excellent breakdown.
C is correct, it's an anaplasticastrocytoma and catnon guides
treatment. OK, last one, case 3, you're
(19:06):
discussing RTOG 94-AO2. What's a key finding from that
trial specifically for anaplastic oligodendrolioma?
ATMZ was superior to PCVB. The trial was positive initially
in 2006. C neoadjuvant PCV plus route
imroved median O to 147 years inthe code deleted subgroup or D
route dose escalation to 70 Grayimroved local control.
(19:29):
OK, thinking about R2G94-O2 and its impact on all it goes.
Option A is wrong. TMZ wasn't tested in that trial.
Option B is wrong. It was initially published as
negative. Option D is wrong.
Dose escalation wasn't part of 94-O2.
That leaves CC. Neo adjuvant PCV followed by RT
improved median OS to 14.7 yearsin the code deleted group.
And that is absolutely the key finding the molecular reanalysis
(19:51):
revealing that dramatic survivalbenefit from 7.3 to 14.7 years
in the chemo RT arm for code deleted tumors is the lasting
legacy of RTOG 9/2. Fantastic.
Great job working through those.So let's try to quickly
summarize today's session. We really built that essential
molecular framework for high grade gliomas.
Focusing on IDH status first, then 1P19 Q status for the IDH
(20:12):
mutants. Right.
And we saw how that framework directly applies to defining and
treating anaplastic oligodendroglioma.
The key take away has to be thatmodern diagnosis is molecular.
Absolutely, and anaplastic oligen druglioma is specifically
IDH mutant and 1P19Q code deleted.
That's the definition. And for treatment.
The standard is clear based on those two huge trials, EOR
(20:35):
TC-26951 and RTOG 9402. Radiation plus PCV chemotherapy
provides a major survival benefit, pushing median survival
over 14 years. An incredible outcome really,
for a primary brain tumor established by understanding the
underlying molecular biology. It truly highlights the power of
precision oncology. Definitely.
(20:56):
So as we finish up, this naturally leads to our next
questions, doesn't it? We've covered the grade 3
oligos. What about the grade 3
astrocytomas? The IDH mutant 1P19Q intact
ones? How does that Canon trial
pronounced Catanon right? How does that guide their
management? Yes, Catanon is key there.
And there's another layer now too, which the newer WHO
classification recognizes. IDH mutant grade 4 astrocytomas.
(21:19):
That's a relatively new entity based on specific molecular
features like CDKN 2 AB deletion.
Even if the Histology looks grade two or three, how do we
treat those? So even more complexity
emerging. Lots to cover next time then.
Anaplastic astrocytomas, katnolin and these new grade 4
IDH mutant Astros. Plenty to discuss.
The field keeps moving fast. It certainly does.
(21:42):
Well, for more practice, remember to complete practice
oral boards at radonksmartlearn.com.
That's rad ONC smartlearn.com. And subscribe to Radonk Smart
Review for our next episode diving into those astrocytomas.
Thanks for tuning. In thanks everyone.
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