July 6, 2025 • 20 mins
In our first two episodes, we built the modern diagnostic framework for high-grade gliomas, focusing on anaplastic oligodendrogliomas and astrocytomas. Today, we turn our attention to the most common and most formidable of these tumors: glioblastoma, IDH-wildtype. For years, this diagnosis came with a grim prognosis. But in 2005, one trial created a paradigm shift, establishing the bedrock of modern neuro-oncology. We will do a deep dive into the Stupp protocol and explore why, despite nearly two decades of research, it remains our standard of care.
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(00:00):
Welcome back to the Radong SmartReview CNS Cancer series.
Really glad you could join us today.
Yes, welcome. Today we're jumping into episode
3 of our high Grade Glioma series.
That's right. And the focus today is
glioblastoma foundations and specifically the STEP protocol.
Exactly a really crucial topic. In our last couple of sessions,
(00:20):
we sort of set the stage right. We talked about the modern
diagnostics for high grade gliomas, looked at anaplastic
oligodendrogliomas. I have the 1P19Q code, deleted
ones. Precisely.
And astrocytomas too. But today we're tackling well
the big one, glioblastoma, IDH, wild type.
It's the most common and honestly the toughest of these
(00:40):
tumors. It really is.
For years, I mean years, this diagnosis was just devastatingly
grim. Yeah, the prognosis was
incredibly poor. But then back in 2005, this
pivotal trial came along. It wasn't just a small step.
It was, you know, a real paradigm shift.
It laid the groundwork for modern neuro oncology, didn't
it? Absolutely.
So today we'll really unpack theStoke protocol and importantly
(01:02):
we need to understand and why even after almost 20 years of
research trying to beat it, it'sstill our standard of care.
That's fascinating in itself. OK, so to make this really
practical, let's use a case. A classic scenario you're likely
to see. Good idea, helps frame the
discussion. All right, picture this.
A 64 year old man comes in presented with a seizure, his
(01:22):
first one. OK, a common presentation.
Imaging finds a right frontal lobe mass.
He undergoes A maximal safe resection.
Critical first step getting as much tumor out as safely
possible. Exactly and the pathology comes
back. Final integrated path confirms
glioblastoma IDH, wild type WHO grade 4.
The classic, most aggressive type.
(01:43):
And the molecular workup, it shows an unmethylated MGMT
promoter. We'll definitely need to dig
into what that means. Crucial piece of information
that MGMT status. Performance wise, he's doing
well. KPS is 90, so he's ready to talk
about what comes next. The adjuvant therapy.
OK, perfect. A very typical, albeit
challenging case. It sets the stage nicely for
discussing the evidence. Right.
(02:05):
But before we dive into the Stoop trial itself, let's just
make sure we're crystal clear onthe terminology.
It matters especially with The Who updates.
Absolutely essential precision is key here.
So according to the 2021 WHO classification, a classic GBM
glioblastoma needs two things. OK, what are they?
First it has to be an IDH wild type astrocytic glioma.
(02:28):
That molecular definition is fundamental.
Right separates it from the IDH mutant types.
Exactly. And second, under the microscope
you need to see those histologichallmarks of high grade
malignancy. That means either microvascular
proliferation. Abnormal blood vessel growth.
Or necrosis many areas of dead tumors tissue.
Seeing either of those confirms it's grade 4.
(02:49):
And that IDH wild type piece is so critical, isn't it?
Because those IDH mutant gliomas, they behave very
differently. Totally different biology, much
better prognosis generally. You absolutely have to make that
distinction for treatment and counseling.
It changes everything. OK, so with that definition
clear, let's get to the trial that changed the game.
Right. The single most important trial,
(03:09):
no question, is that 2005 ERETC and CIC study.
That one just calls it the Snooptrial.
The one that established radiation plus TMZ chemotherapy
as the standard. That's the one before soup.
It was usually just surgery, then radiation, and outcomes
were, well, dismal. This combination was the
breakthrough. So how was the trial design?
(03:31):
They took patients with newly diagnosed GBM.
Yep, 573 patients. They were randomized into two
groups. Group One got radiation alone.
Radiation alone standard, 60 Gray and 30 fractions.
That was the control arm representing the previous
standard. OK.
And group 2. Group 2 got the same radiation,
60 Gray and 30 fractions, but with temazolamide or TMZ given
(03:51):
concurrently during radiation and then as adjuvant therapy
afterward. So chemotherapy during an after
radiation, that was the key difference.
Precisely that combined approach.
And the specific regimen stoop, How does it actually work
day-to-day for a patient? OK, so it's got 2 phases.
First, is the concurrent phase happening at the same time as
the radiation? Right, the six weeks of
(04:12):
radiation. During those six weeks, patients
take TMZ orally every single day, including weekends.
The dose is 75 milligrams per meter squared.
Relatively low dose daily. Right, the idea is radius
sensitization, making the radiation work better by
impairing DNA repair in the tumor cells.
OK, so six weeks of daily TMZ alongside radiation, then what?
(04:37):
Then there's a break, usually about four weeks.
Let's the patient recover a bit from the initial treatment side
effects like fatigue or low blood counts.
Makes sense. And after the break?
After the break, the adjuvant phase starts.
This involves 6 cycles of maintenance.
TMZ. 6 cycles? How often are those?
He's given for five days straight every 28 days, so five
days on, 23 days off, repeated 6times.
(04:58):
And the dose is higher here. Yes.
The dose goes up in the adjuvantphase, typically 150 to 200
milligrams per meter squared forthose five days.
The goal here is to tackle any residual microscopic disease.
Got it concurrent daily low dose, then a break, then six
cycles of higher dose maintenance.
TMZ for five days a month. That's the Stoke regimen in a
(05:21):
nutshell. And the results, you said it was
a landmark achievement. Absolutely landmark.
Look at the primary endpoint median overall survival.
With radiation alone it was only12.1 months, right?
But with the chemo radiation arm, the soup protocol, it
improved to 14.6 months. OK.
About 2 1/2 months improvement in the medium, which in GBM is
(05:43):
significant. Hugely significant statistically
and clinically, it offered real,tangible hope.
And the longer term survival, that's often where you see the
real difference. Exactly.
The two year overall survival numbers were striking.
It went from just 10% with radiation alone.
Only one 10 patients alive at two years.
To 27% with chemo radiation, more than double the chance of
(06:04):
reaching that two year mark. Wow, OK, that is a big
difference. And maybe even more profoundly,
look at five years with radiation alone.
Survival was practically non existent, just 2%.
Almost unheard of. But with the STIP regimen, it
climbed to nearly 10 percent, 9.8% to be exact.
So nearly one in 10 patients surviving five years that tail
(06:25):
on the curve you mentioned? That's it exactly.
That tail signifies that a smallbut real subset of patients
could achieve truly long term survival, something unimaginable
before it changed the entire conversation.
OK, So significant survival benefit overall, but the trial
also shed light on something else crucial, right, the MGMT
promoter status? Yes, absolutely critical
(06:45):
finding. It confirmed MGMT methylation as
a powerful predictive biomarker for TMZ benefit.
Can you quickly remind us what MGMT does?
Sure. MGMT is a DNA repair enzyme.
Its job is to fix the kind of damage caused by alkylating
agents like TMZTMZ adds a metal group to DNA, which is toxic to
(07:06):
the cell. So MGMT protects the cell by
removing that damage. Exactly.
But if the promoter region of the MGMT gene is methylated,
essentially switched off, the tumor cell can't produce the
MGMT enzyme effectively. Meaning it can't repair the TMZ
damage, right? The tumor becomes much more
vulnerable to the chemo. So what did the stop trial show
(07:26):
for patients with this MGMT meselation?
For those patients, the benefit of adding TMZ was huge.
Their median overall survival jumped dramatically from 15.3
months with radiation alone to 23.4 months with chemo
radiation. Wow, over 23 months median
survival. That's a massive difference
(07:47):
compared to the overall median of 14.6.
Massive. An 8 month improvement just
within that subgroup and their two years survival nearly
doubled too, from 24% to 49%. Almost half were alive at two
years if their tumor was methylated and they got stuck,
OK. So MGMT Methylation clearly
identifies the patients who get the biggest bang for the buck
from TMZ. No question but.
(08:08):
What about the patients without methylation?
The unmethylated group like our case patient.
Right, that's the tougher group.Since their MGMT enzyme is
active, it can repair the TMZ damage more effectively, making
the drug less potent. So the benefit was smaller for
them. Much more modest test.
Yes. Their median overall survival
was around 12 months whether they got TMZ or not.
(08:29):
Didn't see that big jump in the median.
So why give TMZ to them at all, then?
That's the question patients ask.
It's a very fair question, and the key lies in looking beyond
the median at the survival curves.
Again, even in the unmethylated group of the chemo, radiation
arm still had that persistent tail.
Meaning more long term survivors.
(08:49):
Exactly. While the median wasn't greatly
improved, the two year survival for unmethylated patients
getting chemo radiation was 15%.Compare that to just 2% for
those getting radiation alone inthat same unmethylated group.
OK, so even if the average benefit is small, there's still
a significantly better chance, albeit small overall, of longer
(09:09):
term survival with TMZ even if you're unmethylated.
Precisely that small but real chance of long term benefit in
the unmethylated group, plus thesignificant overall survival
benefit seen in the entire trialpopulation when you pool
everyone together. That's why Stoop is the standard
for everyone eligible, regardless of MGMTC status.
That's exactly why the NCCN Category One recommendation
(09:32):
holds for all eligible patients,because on balance, the
potential benefit outweighs the risks.
Even for the unmethylated group,it's still our best shot
upfront. Makes perfect sense.
OK, so steps at the standard in 2005, but you mentioned earlier
that almost everything tried since then to improve upon it
has, well, failed. It's quite remarkable and
(09:55):
humbling. A huge amount of research went
into trying to build on STOP, but subsequent large phase three
trials testing various additionsor modifications have largely
been negative. So understanding what doesn't
work is almost as important. Absolutely critical.
You need to know the history to avoid repeating mistakes or
using treatments that add toxicity without benefit.
(10:16):
OK. So what's the first big category
of things that didn't work? You mentioned dose escalation
earlier. Right.
The idea of just giving more radiation seems intuitive for
cancer, doesn't it? Yeah.
Hit it harder. But for GBM it just hasn't
panned out. Early RTOG trials like 7 four O
1 looked at a conventional boostfrom 60 grey up to 70 grey.
No benefit, no improvement in survival or control.
(10:37):
OK, so just adding more Gray didn't help.
What about different ways of delivering the dose like hyper
fractionation? Also tested, RTOG 906 compared
standard 60 Gray to 72 Gray, delivered in smaller twice daily
fractions. The idea being maybe better
tumor kill, less normal tissue damage.
That was the hope, but again, nosurvival benefit didn't move the
(10:57):
needle. Wow, even with a higher total
dose? What about a really focused high
dose like an SRS boost? Stereotactic radiosurgery boost
was also investigated in RTOG 9305.
They added an SRS boost to the tumor bed or residual tumor
after standard chemo radiation and the outcome.
Same story, No improvement in overall survival, no improvement
(11:18):
in quality of life, just added complexity and potential
toxicity. So the message regarding
radiation dose is crystal clear though.
Absolutely definitive for GBM. The standard evidence based dose
is 60 Grays and 30 fractions going higher through any method
tested so far. Conventional Boost Hyper
Fractionation SRS Boost offers no proven survival benefit and
only increases risks. Stick to 60 and 30.
(11:40):
OK. Message received.
What's the second major strategythat failed upfront?
You mentioned bevacizumab or Avastin, right?
Bevacizumab as AVEGF inhibitor. It targets tumor blood vessel
growth. There was enormous hope for it
in GBM, which is so reliant on abnormal vasculature.
Seemed like a perfect target. It did, but two huge
(12:02):
international trials, Avalio andRTOG 0825, put it to the test,
adding bivisizumab to the standard step regimen.
And what did they find? They both found the same thing.
Adding bivisizumab did significantly improve
progression free survival, or PFS, by about four months.
OK. So the tumors look like they
were controlled for longer on scans.
Exactly. BFS improved from around six
(12:24):
months to over 10 months in Avalio, for example.
That looked good initially, but native trials showed any
improvement in overall survival.Median OS was identical around
16 or 17 months whether patientsgot bevicizumab or not.
So longer time until the scan showed progression but patients
didn't actually live any longer.How does that happen?
It's that concept of pseudo response.
(12:44):
Bivacizumab is great at fixing leaky blood vessels in the
tumor. This reduces brain swelling or
edema and makes the tumor enhance less on MRI scans.
So the. Scans look better, much better.
Sometimes it makes it look like the tumor is shrinking or stable
for longer, hence the improved PFS, but it's not actually
killing more tumor cells or stopping the underlying
(13:05):
progression effectively enough to make people live longer.
It's masking. The progression almost in a way.
Yes, it controls the radio graphic signs without
necessarily controlling the tumor long term and it comes
with its own side effects hypertension, risk of bleeding,
blood clots, so. The bottom line for upfront
vivacizumab. The bottom.
Line is clear, adding it to upfront scup therapy does not
(13:27):
improve overall survival, increases toxicity, and is not
recommended outside of a clinical trial.
It does have a role in recurrentdisease, but that's a different
discussion. OK dose.
Escalation is out upfront. Vivacizumab is out with the
third category immunotherapy, right?
Immunotherapy, specifically checkpoint inhibitors given
their success in Melanoma, lung cancer, etcetera.
(13:48):
Hopes were sky high for GBM. Makes sense?
Unleash the immune system against the tumor, but the.
Checkmate 498 trial was a major disappointment.
It tested radiation plus nivolumab versus the standard
step protocol specifically in unmethylated patients where
maybe immunotherapy could offer more and the.
Result. Surprisingly, the STEP protocol
(14:09):
actually performed better. Median OS was 14.9 months with
STEP versus only 13.4 months with nivolumab plus radiation.
Wow. Actually worse with the
immunotherapy in that setting. Why is GBM so resistant?
It highlights. That unique immunologically cold
environment of GBM we touched onUnlike hot tumors infiltrated
(14:29):
with T cells, GBM is often surrounded by immunosuppressive
factors in cells. So the immune.
System isn't really primed for the checkpoint inhibitors to
work effectively. Exactly.
Current checkpoint inhibitors often rely on an existing anti
tumor immune response that they can unleash.
In GBMS COAL environment that response is often weak or
absent. Overcoming that remains a huge
challenge. OK, so.
(14:50):
That's a lot of negative trials reinforcing the STEP protocol.
How do we synthesize all this for making decisions with our
patients? Well, the.
Synthesis is actually quite straightforward thanks to all
this data. The overwhelming evidence
confirms that the stoke protocol, 60 grey and 30
fractions with concurrent and adjuvant TMZ remains the
undisputed standard of care for eligible IDH wild type GBM
(15:13):
patients. It's the.
Foundation. It's the.
Foundation and we know not to deviate by escalating the
radiation dose, right? 60 and 30 is the optimal dose
and we know. Not to add Basismab upfront
because it doesn't improve survival and adds toxicity.
Got it. And current immunotherapy hasn't
shown a benefit upfront either, correct?
So knowing what not to do is just as vital.
(15:33):
It allows you to confidently recommend the standard STEP
protocol as the best proven therapy, manage expectations,
and avoid ineffective, potentially harmful
interventions. Excellent.
Summary. OK, let's pivot to some quick
takeaways. Clinical pearls, right?
Clinical. Pearls.
The absolute must remember points.
Pearl number. One stoop.
Protocol is the standard for IDHwild type, GBM 60, grey plus
(15:56):
concurrent and adjuvant. TMZ significantly improved
survival over radiation alone. It's the benchmark tool number.
2. MGMT methylation status is your
critical predictive biomarker. It tells you who gets the
biggest benefit. MTMC.
Remember those methylated patients hitting nearly two
years median survival and curl number?
Three know what? Failed dose escalation beyond 60
(16:17):
grey upfront vivacism AB and current checkpoint inhibitors
have not shown an overall survival benefit in phase three
trials for newly diagnosed GBM. Stick to the evidence.
Perfect. Ready for a board blitz?
Let's test the application. Let's do it quick.
Cases OK Case. 158 year old newly diagnosed GBM MGMT
methylated. He asked about getting more
aggressive radiation, maybe an SRS boost.
(16:38):
What do you say? A yes 70 D Gray improves local
control B yes, SRS boost improved OS and RTOG 93O5C No.
Multiple trials show no survivalbenefit beyond 60 Gray or D No.
But maybe add bevacizumab. OK, the.
Clearance has to be C. This directly hits those
negative dose escalation trials.RTOG 740-190-0693 OO 5.
(17:00):
None showed a survival benefit for going above 60 Grays,
regardless of how it was delivered.
A is wrong, B is contradicted by9 three O 5, and D is wrong
because upfront Bev has no OS benefits.
Standard is 60 grey. Exactly.
Case 262 year old woman IDH wildtype GBM.
Read about Avastin online, askedif it should be part of her
initial treatment. What's the advice?
(17:21):
A Yes, it improves OS by four months.
B Yes, it's standard for all newly diagnosed GBMC.
No Improves PFS but not OS and adds toxicity or D No, only use
for IDH mutant tumors right? Another common question.
The answer is C reflects the save aglio and RTOG 02/5 results
perfectly. It improves progression free
survival, that radiographic endpoint of absolutely no
(17:42):
overall survival benefit upfrontand it does add toxicity.
A is wrong on OSB is wrong aboutit being standard upfront, and D
is incorrect about its use context.
So C is the correct counsel. Perfect.
Last one case 3 patient with newly diagnosed MGMT methylated
GBM receiving standard step. What's the approximate expected
median overall survival? A 12 months, B 15 months, C 23
(18:07):
months, or D 48 months? This.
Tests the specific step subgroupdata for MGMT methylated
patients getting chemo RT. The median OS was significantly
longer. The answer is C, approximately
23 months. Remember it was 23.4 months in
the trial, much better than the UN methylated group 12 months or
the overall population 15 months.
(18:28):
Excellent. Nails down those key numbers.
So reflecting on all this, it really is remarkable how stuff
has remained the standard for solong, isn't it?
Despite all the effort, it truly.
Is it speaks volumes about the profound initial impact of that
trial, but also, frankly, about the incredible biological
challenges that glioblastoma presents.
Trying to improve on stuff has proven exceptionally difficult,
yeah. That immunologically cold and
(18:48):
environment, the heterogeneity, the blood brain barrier, it's a
tough nut to crack. Exactly and while research is
incredibly active looking at novel immunotherapies targeted
agents on coletic viruses T he fields, which we'll discuss next
time, none have yet managed to displace stoop as the
foundational upfront therapy andlarge phase three trials, which
really. Underscores why for an eligible
(19:09):
patient, adhering to the STOOP protocol remains absolutely
critical. It's our most effective evidence
based starting point. Couldn't agree more.
Understanding its nuances, the MGMT implications, and why
alternatives have failed is coreknowledge for managing this
disease. OK, let's.
Summarize today's deep dive thenright so.
Today we really cemented our understanding of classic IDH
(19:31):
wild type glioblastoma. We defined it molecularly and
histologically. We spent significant time on the
landmark stoop trials 60 Gray radiation with concurrent and
adjuvant TMZ establishing it as the standard yielding that 14.6
month median survival overall wedetailed.
The huge predictive power of MG and T methylation, identifying
patients who get the most benefit from TMZ, pushing Widian
(19:54):
survival towards two years in that group.
And crucially, we reinforce Step's place by reviewing the
major negative trials showing nobenefit for dose escalation
beyond 60 Grays adding upfront. Zoomab or using initial
immunotherapy. Well put.
So in our next session, we'll tackle what happens beyond stuff
eligibility or after initial treatment.
(20:14):
We'll get into Part 4 special cases, managing elderly or frail
patients, tackling recurrent disease and digging into the
role of tumor treating fields sounds.
Great. Remember, you can find complete
practice oral boards and other resources over at
radonsmartlearn.com. That's pronounced
radonsmartlearn.com. And please subscribe to Radon
Smart Reviews so you don't miss our next session.
(20:35):
Thanks very. Much for tuning in.
Welcome back to the Radong SmartReview CNS Cancer series.
Really glad you could join us today.
Yes, welcome. Today we're jumping into episode
3 of our high Grade Glioma series.
That's right. And the focus today is
glioblastoma foundations and specifically the STEP protocol.
Exactly a really crucial topic. In our last couple of sessions,
(00:20):
we sort of set the stage right. We talked about the modern
diagnostics for high grade gliomas, looked at anaplastic
oligodendrogliomas. I have the 1P19Q code, deleted
ones. Precisely.
And astrocytomas too. But today we're tackling well
the big one, glioblastoma, IDH, wild type.
It's the most common and honestly the toughest of these
(00:40):
tumors. It really is.
For years, I mean years, this diagnosis was just devastatingly
grim. Yeah, the prognosis was
incredibly poor. But then back in 2005, this
pivotal trial came along. It wasn't just a small step.
It was, you know, a real paradigm shift.
It laid the groundwork for modern neuro oncology, didn't
it? Absolutely.
So today we'll really unpack theStoke protocol and importantly
(01:02):
we need to understand and why even after almost 20 years of
research trying to beat it, it'sstill our standard of care.
That's fascinating in itself. OK, so to make this really
practical, let's use a case. A classic scenario you're likely
to see. Good idea, helps frame the
discussion. All right, picture this.
A 64 year old man comes in presented with a seizure, his
(01:22):
first one. OK, a common presentation.
Imaging finds a right frontal lobe mass.
He undergoes A maximal safe resection.
Critical first step getting as much tumor out as safely
possible. Exactly and the pathology comes
back. Final integrated path confirms
glioblastoma IDH, wild type WHO grade 4.
The classic, most aggressive type.
(01:43):
And the molecular workup, it shows an unmethylated MGMT
promoter. We'll definitely need to dig
into what that means. Crucial piece of information
that MGMT status. Performance wise, he's doing
well. KPS is 90, so he's ready to talk
about what comes next. The adjuvant therapy.
OK, perfect. A very typical, albeit
challenging case. It sets the stage nicely for
discussing the evidence. Right.
(02:05):
But before we dive into the Stoop trial itself, let's just
make sure we're crystal clear onthe terminology.
It matters especially with The Who updates.
Absolutely essential precision is key here.
So according to the 2021 WHO classification, a classic GBM
glioblastoma needs two things. OK, what are they?
First it has to be an IDH wild type astrocytic glioma.
(02:28):
That molecular definition is fundamental.
Right separates it from the IDH mutant types.
Exactly. And second, under the microscope
you need to see those histologichallmarks of high grade
malignancy. That means either microvascular
proliferation. Abnormal blood vessel growth.
Or necrosis many areas of dead tumors tissue.
Seeing either of those confirms it's grade 4.
(02:49):
And that IDH wild type piece is so critical, isn't it?
Because those IDH mutant gliomas, they behave very
differently. Totally different biology, much
better prognosis generally. You absolutely have to make that
distinction for treatment and counseling.
It changes everything. OK, so with that definition
clear, let's get to the trial that changed the game.
Right. The single most important trial,
(03:09):
no question, is that 2005 ERETC and CIC study.
That one just calls it the Snooptrial.
The one that established radiation plus TMZ chemotherapy
as the standard. That's the one before soup.
It was usually just surgery, then radiation, and outcomes
were, well, dismal. This combination was the
breakthrough. So how was the trial design?
(03:31):
They took patients with newly diagnosed GBM.
Yep, 573 patients. They were randomized into two
groups. Group One got radiation alone.
Radiation alone standard, 60 Gray and 30 fractions.
That was the control arm representing the previous
standard. OK.
And group 2. Group 2 got the same radiation,
60 Gray and 30 fractions, but with temazolamide or TMZ given
(03:51):
concurrently during radiation and then as adjuvant therapy
afterward. So chemotherapy during an after
radiation, that was the key difference.
Precisely that combined approach.
And the specific regimen stoop, How does it actually work
day-to-day for a patient? OK, so it's got 2 phases.
First, is the concurrent phase happening at the same time as
the radiation? Right, the six weeks of
(04:12):
radiation. During those six weeks, patients
take TMZ orally every single day, including weekends.
The dose is 75 milligrams per meter squared.
Relatively low dose daily. Right, the idea is radius
sensitization, making the radiation work better by
impairing DNA repair in the tumor cells.
OK, so six weeks of daily TMZ alongside radiation, then what?
(04:37):
Then there's a break, usually about four weeks.
Let's the patient recover a bit from the initial treatment side
effects like fatigue or low blood counts.
Makes sense. And after the break?
After the break, the adjuvant phase starts.
This involves 6 cycles of maintenance.
TMZ. 6 cycles? How often are those?
He's given for five days straight every 28 days, so five
days on, 23 days off, repeated 6times.
(04:58):
And the dose is higher here. Yes.
The dose goes up in the adjuvantphase, typically 150 to 200
milligrams per meter squared forthose five days.
The goal here is to tackle any residual microscopic disease.
Got it concurrent daily low dose, then a break, then six
cycles of higher dose maintenance.
TMZ for five days a month. That's the Stoke regimen in a
(05:21):
nutshell. And the results, you said it was
a landmark achievement. Absolutely landmark.
Look at the primary endpoint median overall survival.
With radiation alone it was only12.1 months, right?
But with the chemo radiation arm, the soup protocol, it
improved to 14.6 months. OK.
About 2 1/2 months improvement in the medium, which in GBM is
(05:43):
significant. Hugely significant statistically
and clinically, it offered real,tangible hope.
And the longer term survival, that's often where you see the
real difference. Exactly.
The two year overall survival numbers were striking.
It went from just 10% with radiation alone.
Only one 10 patients alive at two years.
To 27% with chemo radiation, more than double the chance of
(06:04):
reaching that two year mark. Wow, OK, that is a big
difference. And maybe even more profoundly,
look at five years with radiation alone.
Survival was practically non existent, just 2%.
Almost unheard of. But with the STIP regimen, it
climbed to nearly 10 percent, 9.8% to be exact.
So nearly one in 10 patients surviving five years that tail
(06:25):
on the curve you mentioned? That's it exactly.
That tail signifies that a smallbut real subset of patients
could achieve truly long term survival, something unimaginable
before it changed the entire conversation.
OK, So significant survival benefit overall, but the trial
also shed light on something else crucial, right, the MGMT
promoter status? Yes, absolutely critical
(06:45):
finding. It confirmed MGMT methylation as
a powerful predictive biomarker for TMZ benefit.
Can you quickly remind us what MGMT does?
Sure. MGMT is a DNA repair enzyme.
Its job is to fix the kind of damage caused by alkylating
agents like TMZTMZ adds a metal group to DNA, which is toxic to
(07:06):
the cell. So MGMT protects the cell by
removing that damage. Exactly.
But if the promoter region of the MGMT gene is methylated,
essentially switched off, the tumor cell can't produce the
MGMT enzyme effectively. Meaning it can't repair the TMZ
damage, right? The tumor becomes much more
vulnerable to the chemo. So what did the stop trial show
(07:26):
for patients with this MGMT meselation?
For those patients, the benefit of adding TMZ was huge.
Their median overall survival jumped dramatically from 15.3
months with radiation alone to 23.4 months with chemo
radiation. Wow, over 23 months median
survival. That's a massive difference
(07:47):
compared to the overall median of 14.6.
Massive. An 8 month improvement just
within that subgroup and their two years survival nearly
doubled too, from 24% to 49%. Almost half were alive at two
years if their tumor was methylated and they got stuck,
OK. So MGMT Methylation clearly
identifies the patients who get the biggest bang for the buck
from TMZ. No question but.
(08:08):
What about the patients without methylation?
The unmethylated group like our case patient.
Right, that's the tougher group.Since their MGMT enzyme is
active, it can repair the TMZ damage more effectively, making
the drug less potent. So the benefit was smaller for
them. Much more modest test.
Yes. Their median overall survival
was around 12 months whether they got TMZ or not.
(08:29):
Didn't see that big jump in the median.
So why give TMZ to them at all, then?
That's the question patients ask.
It's a very fair question, and the key lies in looking beyond
the median at the survival curves.
Again, even in the unmethylated group of the chemo, radiation
arm still had that persistent tail.
Meaning more long term survivors.
(08:49):
Exactly. While the median wasn't greatly
improved, the two year survival for unmethylated patients
getting chemo radiation was 15%.Compare that to just 2% for
those getting radiation alone inthat same unmethylated group.
OK, so even if the average benefit is small, there's still
a significantly better chance, albeit small overall, of longer
(09:09):
term survival with TMZ even if you're unmethylated.
Precisely that small but real chance of long term benefit in
the unmethylated group, plus thesignificant overall survival
benefit seen in the entire trialpopulation when you pool
everyone together. That's why Stoop is the standard
for everyone eligible, regardless of MGMTC status.
That's exactly why the NCCN Category One recommendation
(09:32):
holds for all eligible patients,because on balance, the
potential benefit outweighs the risks.
Even for the unmethylated group,it's still our best shot
upfront. Makes perfect sense.
OK, so steps at the standard in 2005, but you mentioned earlier
that almost everything tried since then to improve upon it
has, well, failed. It's quite remarkable and
(09:55):
humbling. A huge amount of research went
into trying to build on STOP, but subsequent large phase three
trials testing various additionsor modifications have largely
been negative. So understanding what doesn't
work is almost as important. Absolutely critical.
You need to know the history to avoid repeating mistakes or
using treatments that add toxicity without benefit.
(10:16):
OK. So what's the first big category
of things that didn't work? You mentioned dose escalation
earlier. Right.
The idea of just giving more radiation seems intuitive for
cancer, doesn't it? Yeah.
Hit it harder. But for GBM it just hasn't
panned out. Early RTOG trials like 7 four O
1 looked at a conventional boostfrom 60 grey up to 70 grey.
No benefit, no improvement in survival or control.
(10:37):
OK, so just adding more Gray didn't help.
What about different ways of delivering the dose like hyper
fractionation? Also tested, RTOG 906 compared
standard 60 Gray to 72 Gray, delivered in smaller twice daily
fractions. The idea being maybe better
tumor kill, less normal tissue damage.
That was the hope, but again, nosurvival benefit didn't move the
(10:57):
needle. Wow, even with a higher total
dose? What about a really focused high
dose like an SRS boost? Stereotactic radiosurgery boost
was also investigated in RTOG 9305.
They added an SRS boost to the tumor bed or residual tumor
after standard chemo radiation and the outcome.
Same story, No improvement in overall survival, no improvement
(11:18):
in quality of life, just added complexity and potential
toxicity. So the message regarding
radiation dose is crystal clear though.
Absolutely definitive for GBM. The standard evidence based dose
is 60 Grays and 30 fractions going higher through any method
tested so far. Conventional Boost Hyper
Fractionation SRS Boost offers no proven survival benefit and
only increases risks. Stick to 60 and 30.
(11:40):
OK. Message received.
What's the second major strategythat failed upfront?
You mentioned bevacizumab or Avastin, right?
Bevacizumab as AVEGF inhibitor. It targets tumor blood vessel
growth. There was enormous hope for it
in GBM, which is so reliant on abnormal vasculature.
Seemed like a perfect target. It did, but two huge
(12:02):
international trials, Avalio andRTOG 0825, put it to the test,
adding bivisizumab to the standard step regimen.
And what did they find? They both found the same thing.
Adding bivisizumab did significantly improve
progression free survival, or PFS, by about four months.
OK. So the tumors look like they
were controlled for longer on scans.
Exactly. BFS improved from around six
(12:24):
months to over 10 months in Avalio, for example.
That looked good initially, but native trials showed any
improvement in overall survival.Median OS was identical around
16 or 17 months whether patientsgot bevicizumab or not.
So longer time until the scan showed progression but patients
didn't actually live any longer.How does that happen?
It's that concept of pseudo response.
(12:44):
Bivacizumab is great at fixing leaky blood vessels in the
tumor. This reduces brain swelling or
edema and makes the tumor enhance less on MRI scans.
So the. Scans look better, much better.
Sometimes it makes it look like the tumor is shrinking or stable
for longer, hence the improved PFS, but it's not actually
killing more tumor cells or stopping the underlying
(13:05):
progression effectively enough to make people live longer.
It's masking. The progression almost in a way.
Yes, it controls the radio graphic signs without
necessarily controlling the tumor long term and it comes
with its own side effects hypertension, risk of bleeding,
blood clots, so. The bottom line for upfront
vivacizumab. The bottom.
Line is clear, adding it to upfront scup therapy does not
(13:27):
improve overall survival, increases toxicity, and is not
recommended outside of a clinical trial.
It does have a role in recurrentdisease, but that's a different
discussion. OK dose.
Escalation is out upfront. Vivacizumab is out with the
third category immunotherapy, right?
Immunotherapy, specifically checkpoint inhibitors given
their success in Melanoma, lung cancer, etcetera.
(13:48):
Hopes were sky high for GBM. Makes sense?
Unleash the immune system against the tumor, but the.
Checkmate 498 trial was a major disappointment.
It tested radiation plus nivolumab versus the standard
step protocol specifically in unmethylated patients where
maybe immunotherapy could offer more and the.
Result. Surprisingly, the STEP protocol
(14:09):
actually performed better. Median OS was 14.9 months with
STEP versus only 13.4 months with nivolumab plus radiation.
Wow. Actually worse with the
immunotherapy in that setting. Why is GBM so resistant?
It highlights. That unique immunologically cold
environment of GBM we touched onUnlike hot tumors infiltrated
(14:29):
with T cells, GBM is often surrounded by immunosuppressive
factors in cells. So the immune.
System isn't really primed for the checkpoint inhibitors to
work effectively. Exactly.
Current checkpoint inhibitors often rely on an existing anti
tumor immune response that they can unleash.
In GBMS COAL environment that response is often weak or
absent. Overcoming that remains a huge
challenge. OK, so.
(14:50):
That's a lot of negative trials reinforcing the STEP protocol.
How do we synthesize all this for making decisions with our
patients? Well, the.
Synthesis is actually quite straightforward thanks to all
this data. The overwhelming evidence
confirms that the stoke protocol, 60 grey and 30
fractions with concurrent and adjuvant TMZ remains the
undisputed standard of care for eligible IDH wild type GBM
(15:13):
patients. It's the.
Foundation. It's the.
Foundation and we know not to deviate by escalating the
radiation dose, right? 60 and 30 is the optimal dose
and we know. Not to add Basismab upfront
because it doesn't improve survival and adds toxicity.
Got it. And current immunotherapy hasn't
shown a benefit upfront either, correct?
So knowing what not to do is just as vital.
(15:33):
It allows you to confidently recommend the standard STEP
protocol as the best proven therapy, manage expectations,
and avoid ineffective, potentially harmful
interventions. Excellent.
Summary. OK, let's pivot to some quick
takeaways. Clinical pearls, right?
Clinical. Pearls.
The absolute must remember points.
Pearl number. One stoop.
Protocol is the standard for IDHwild type, GBM 60, grey plus
(15:56):
concurrent and adjuvant. TMZ significantly improved
survival over radiation alone. It's the benchmark tool number.
2. MGMT methylation status is your
critical predictive biomarker. It tells you who gets the
biggest benefit. MTMC.
Remember those methylated patients hitting nearly two
years median survival and curl number?
Three know what? Failed dose escalation beyond 60
(16:17):
grey upfront vivacism AB and current checkpoint inhibitors
have not shown an overall survival benefit in phase three
trials for newly diagnosed GBM. Stick to the evidence.
Perfect. Ready for a board blitz?
Let's test the application. Let's do it quick.
Cases OK Case. 158 year old newly diagnosed GBM MGMT
methylated. He asked about getting more
aggressive radiation, maybe an SRS boost.
(16:38):
What do you say? A yes 70 D Gray improves local
control B yes, SRS boost improved OS and RTOG 93O5C No.
Multiple trials show no survivalbenefit beyond 60 Gray or D No.
But maybe add bevacizumab. OK, the.
Clearance has to be C. This directly hits those
negative dose escalation trials.RTOG 740-190-0693 OO 5.
(17:00):
None showed a survival benefit for going above 60 Grays,
regardless of how it was delivered.
A is wrong, B is contradicted by9 three O 5, and D is wrong
because upfront Bev has no OS benefits.
Standard is 60 grey. Exactly.
Case 262 year old woman IDH wildtype GBM.
Read about Avastin online, askedif it should be part of her
initial treatment. What's the advice?
(17:21):
A Yes, it improves OS by four months.
B Yes, it's standard for all newly diagnosed GBMC.
No Improves PFS but not OS and adds toxicity or D No, only use
for IDH mutant tumors right? Another common question.
The answer is C reflects the save aglio and RTOG 02/5 results
perfectly. It improves progression free
survival, that radiographic endpoint of absolutely no
(17:42):
overall survival benefit upfrontand it does add toxicity.
A is wrong on OSB is wrong aboutit being standard upfront, and D
is incorrect about its use context.
So C is the correct counsel. Perfect.
Last one case 3 patient with newly diagnosed MGMT methylated
GBM receiving standard step. What's the approximate expected
median overall survival? A 12 months, B 15 months, C 23
(18:07):
months, or D 48 months? This.
Tests the specific step subgroupdata for MGMT methylated
patients getting chemo RT. The median OS was significantly
longer. The answer is C, approximately
23 months. Remember it was 23.4 months in
the trial, much better than the UN methylated group 12 months or
the overall population 15 months.
(18:28):
Excellent. Nails down those key numbers.
So reflecting on all this, it really is remarkable how stuff
has remained the standard for solong, isn't it?
Despite all the effort, it truly.
Is it speaks volumes about the profound initial impact of that
trial, but also, frankly, about the incredible biological
challenges that glioblastoma presents.
Trying to improve on stuff has proven exceptionally difficult,
yeah. That immunologically cold and
(18:48):
environment, the heterogeneity, the blood brain barrier, it's a
tough nut to crack. Exactly and while research is
incredibly active looking at novel immunotherapies targeted
agents on coletic viruses T he fields, which we'll discuss next
time, none have yet managed to displace stoop as the
foundational upfront therapy andlarge phase three trials, which
really. Underscores why for an eligible
(19:09):
patient, adhering to the STOOP protocol remains absolutely
critical. It's our most effective evidence
based starting point. Couldn't agree more.
Understanding its nuances, the MGMT implications, and why
alternatives have failed is coreknowledge for managing this
disease. OK, let's.
Summarize today's deep dive thenright so.
Today we really cemented our understanding of classic IDH
(19:31):
wild type glioblastoma. We defined it molecularly and
histologically. We spent significant time on the
landmark stoop trials 60 Gray radiation with concurrent and
adjuvant TMZ establishing it as the standard yielding that 14.6
month median survival overall wedetailed.
The huge predictive power of MG and T methylation, identifying
patients who get the most benefit from TMZ, pushing Widian
(19:54):
survival towards two years in that group.
And crucially, we reinforce Step's place by reviewing the
major negative trials showing nobenefit for dose escalation
beyond 60 Grays adding upfront. Zoomab or using initial
immunotherapy. Well put.
So in our next session, we'll tackle what happens beyond stuff
eligibility or after initial treatment.
(20:14):
We'll get into Part 4 special cases, managing elderly or frail
patients, tackling recurrent disease and digging into the
role of tumor treating fields sounds.
Great. Remember, you can find complete
practice oral boards and other resources over at
radonsmartlearn.com. That's pronounced
radonsmartlearn.com. And please subscribe to Radon
Smart Reviews so you don't miss our next session.
(20:35):
Thanks very. Much for tuning in.
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