CNS 04: HGG: Special Cases and Advanced Treatments

In our first three episodes, we mastered the standard approach for a "Stupp-eligible" patient with glioblastoma. But as you know, many of our patients do not fit this mold. They are older, have a lower performance status, or present with the formidable challenge of recurrent disease. Today, we address these special cases head-on. We'll build a framework for treating elderly and frail patients, review the evidence for re-irradiation, and discuss the role of the novel technology, Tumor-Treating Fields.

Episode Transcript

(00:00):
Welcome back to the rat on SmartReview CNS cancer series.
Glad to be here today. We're really getting into some
important nuances in episode 4 of our high grade glioma series.
We're kind of moving past the standard stop eligible patient
that you know, everyone learns first.
Exactly. We're tackling the special
cases, the ones you actually seea lot in clinic, focusing on

(00:22):
elderly patients, how we handle recurrence, which is always
tough, and the role of tumor treating fields.
Right, because we've all, you know, worked hard to master that
standard step protocol for glioblastoma.
It's foundational. Absolutely, it's the
cornerstone. But the reality is many patients
just don't fit that mold. Do they?
They're older, Maybe their KPS Karnosky performance status is

(00:43):
lower, meaning they're less functional.
Where they face recurrence. That's a big.
One, a really big one. So our mission today really is
to build a practical framework. How do you approach these these
challenging scenarios? You know, older folks, frail
patients, recurrent disease. We want you to feel confident
tailoring the treatment. Yeah, it's about adding tools to
your toolkit, isn't it? Because of that standard

(01:04):
approach, the six weeks of chemoRT, it works wonders for the
right patient, but it's just notalways suitable.
Or even possible? Precisely.
You see these patients constantly older, maybe at KPS
of 60 or 70, or the disease has unfortunately come back after
initial treatment. These situations, they really
demand more than just following a flow chart.

(01:25):
You need a deeper understanding of the evidence.
And the clinical judgement to apply.
It exactly it's judgement. So to make this really
practical, let's use a couple oftypical cases cases you'll
definitely encounter. Good idea.
OK, first imagine an 82 year oldwoman, let's call her Missus
Thompson. She comes in after a fall, gets
an MRI. Standard work up.
Standard work up. Yep, and it shows a ring

(01:46):
enhancing mass left temporal lobe.
Clinically, she's well, she's frail.
Her KPS is 60. So requires considerable
assistance, but not completely dependent.
That's right, needs help with daily activities.
Biopsy confirms glioblastoma andimportantly, it's IDH wild type.
OK. So primary GBM typically more

(02:07):
aggressive typically now lookingat her 82 KPS 60, she's clearly
not a candidate for that intensesix weeks Stutauba protocol.
Right that way. That'd be too much.
Way too much. So the question for you, the
clinician facing Misses Thompson, is what are her real
options? What can we actually offer her
that makes sense? That's a perfect example of the

(02:28):
dilemma. You really feel the way of that
decision? OK, what's the second case?
Second case, let's revisit someone maybe we talked about
before, hypothetically, Mr. Chen, 64 years old, he had a
great initial run. GTR, gross total restoration
follow the full step protocol. And did well.
Did really well. Yeah, 18 months, that's a good
outcome for GBM. But his latest surveillance MRI

(02:51):
It shows a new enhancing lesion,about 2cm, right at the edge of
his old resection cavity. Classic recurrence pattern.
Textbook recurrence. So for Mr. Chen, who responded
well initially, how do we approach this?
How do we manage recurrent GBM? Right, two very different, very
common challenges. And these two cases, misses
Thompson and Mr. Chen, they perfectly set the stage.

(03:12):
They show why we need evidence and thinking that goes beyond
just the original stub trial. It's about individualizing care,
isn't it? Using guidelines, sure, but
really tailoring it based on thepatient, their health, their
life, what they want. Absolutely.
Clinical judgement is huge. It's not just memorizing
protocols, it's understanding why we might deviate, why it's

(03:33):
sometimes necessary. So let's start with that first
scenario, managing GBM in older or frail patients.
What's the core philosophy here?You mentioned balancing efficacy
and quality of life. That's the heart of it, efficacy
versus quality of life. Why is the standard six week
chemo RT, the daily radiation with TMZ so tough for this
group? I mean, it sounds grueling even

(03:54):
for younger patients. It is grueling, 6 weeks daily
visits, concurrent chemo, then more chemo.
It's a significant physiologicalstress for someone older or
frail, like Misses Thompson. They might not even live long
enough to see the full benefit. That's the harsh reality.
They might gain a few months of survival, maybe, if they
tolerate it, but they will definitely experience the

(04:14):
toxicity, the fatigue, the nausea, the myelosuppression,
the potential cognitive effects.It could just wipe out any
quality of life they have left. Exactly.
It can make their remaining timemiserable, often without a
proportionate survival gain. This is why KPS is so critical
and why molecular markers like MGMT methylation become really

(04:35):
important guides. We're often training potential
quantity for guaranteed quality.That quality versus quantity
distinction is just vital here, adding good days, not just any
days. So how do we make this
practical? Is there a KPS based framework
we can use? Yes.
Absolutely. We can sort of stratify patients
based on KPS to guide the intensity of treatment.

(04:55):
Let's break it down. First, consider the fit elderly.
OK, Who fits into that category?These are generally patients 65
and older, but crucially they still have a good KPS 70 or
higher. They're mostly independent,
getting around OK. Right, still active to a degree.
Exactly. For this specific group, the key
trial, the one that really shaped our approach, is the
Perry trial. Yes, Perry, that was a big 1 /

(05:17):
500 patients, right? 65 plus.
That's the one a really important Canadian and European
study. They randomized these fit
elderly patients KPS 70 or more to get either short course
hypofractionated radiation alone. 40 grey and 15 fractions
over 3 weeks. Yep, 40 and 15.
Either that alone or the same. 40 and 15 with concurrent and

(05:40):
adjuvant TMZ. Just like stuff, but with the
shorter radiation. And what did Perry find?
What was the key take away? The results were pretty clear
cut. Adding the TMZ to the shorter
radiation course significantly improved median overall
survival. It went from about 7.6 months
with radiation alone up to 9.3 months with the chemo RT combo.
OK. Nearly a 2 month improvement in

(06:01):
median survival that's meaningful in GBM.
It is meaningful and it also improved progression free
survival. PFS went from about 3.9 months
to 5.3 months, so patients live longer and live longer without
the disease progressing. And critically, it was with a
three rent radiation course, not6.
Exactly, so you get a clear survival benefit but with a

(06:23):
significantly less burdensome treatment course compared to the
full stiff protocol. That balance is why 40 and 15
plus TMZ became the evidence based standard for these fit
elderly patients. That makes perfect sense.
A really valuable option. OK, so that's the fit elderly.
Look at the next group, the the frail patients, maybe KPS 50 to
60 like our Mrs. Thompson case, right?

(06:44):
For this group, the calculation changes significantly.
Combined modality therapy doing radiation and chemo together is
almost certainly too toxic. Just too much burden for them.
Way too much burden. The side effects would likely
outweigh any small survival gain.
So we pivot. We go to single modality
therapy. Just radiation or just chemo?
Exactly. And the critical decision point

(07:06):
here, the thing that really guides the choice between those
two is that biomarker we mentioned, MGMT promoter
methylation status. O6 methyl guanine DNA methyl
transferase, always methyl. Is.
But it's so important here. MGMT status is the key and the
evidence guiding us comes primarily from two big trials,
the NOA 08 trial from Germany and the Nordic trial.

(07:28):
OK, so how do those trials and the NGMT status give us an
algorithm for someone like Mrs. Thompson?
It's actually quite elegant based on those trials if the
tumor is MGMT methylated. Meaning it's potentially more
sensitive to TMZ. Correct.
If it's methylated, you offer TMZ monotherapy, just the
chemotherapy pills. The NOAO 8 trial for example,

(07:48):
show that for these methylated patients, TMZ alone nearly
doubled event free survival compared to radiation alone.
It's something like 8.4 months versus 4.6 months, a huge
difference. Wow OK so methylated means TMZ
alone is clearly better. Clearly better now if the tumor
is MGMT unmethylated. Meaning less likely to respond
to TMZ. Right, then you offer
hypofractionated radiation alone.

(08:09):
The same trials show that radiation was superior to TMZ in
that specific unmethylated setting.
So MGMT stats basically tells you methylated gets TMZ,
unmethylated gets radiation because combining them is too
toxic for this frail group. That's a really clear biomarker
driven pathway. Very helpful.
Now for those unmethylated patients getting radiation
alone, what about the fractionation you mentioned 40

(08:31):
and 15? Are there shorter options?
Yes, and this is really important for practicality and
quality of life. The Rome trial, which is
combined with an IAEA trial, looked at this specifically in
frail patients. What did Romania show?
It gave us fantastic flexibility.
It found no significant difference in survival between
the three-week course 40 Gray and 15 fractions, and a much,

(08:54):
much shorter one week course, 25grey and five fractions. 25 and
five just one week of treatment.Exactly.
Think about that from missus Thompson, 82, frail KPS, 60 core
prognosis likely with unmethylated GBM.
Reducing her hospital visits from 15 down to 5 was a huge
improvement in convenience. Less travel, less burden on her

(09:14):
and her family. Massive difference in logistics
and just hassle. Right.
And you're delivering A meaningful palliative benefit
without compromising survival compared to the longer course.
It's about making the treatment as humane and convenient as
possible. That 25 and five regimen is an
excellent option for these frail, unmethylated patients.

(09:35):
That's incredibly valuable information.
Maximizing convenience is so key.
OK, now what about the the patients at the lowest end of
the performance spectrum? PPS Less than 50.
Yeah, this is a really difficultsituation for patients with a
KPS below 50, the focus shifts dramatically.
It moves away from active anti cancer treatment almost

(09:56):
entirely. Towards palliative care.
Unequivocally towards palliativecare and best supportive care.
The key evidence here comes fromthe courts trial.
What did courts tell us? Courts essentially confirmed
what clinicians suspected. For GBM patient.
With such a low KPS, the burden,the toxicity, the stress of any
active treatment, radiation or chemo is likely to outweigh any
tiny potential benefit. The morbidity is just too high.

(10:19):
So active treatment might actually do more harm than good.
In these cases, yes, our focus has to be on managing symptoms,
headache, seizures, weakness, ensuring comfort, maintaining
dignity, supporting the patient and family.
Best supportive care is the mostappropriate and compassionate
approach. It's a hard conversation, but
necessary. A very important point about

(10:41):
knowing the limits of our interventions.
OK, let's pivot now to our second main challenge, managing
recurrent glioblastoma, Mr. Chens situation.
This is universally tough. It really is.
Recurrence is formidable and thefirst thing we and the patient
need to understand is that no treatment at this stage is
curative. The goals have to shift.

(11:01):
Completely. We're aiming to palliate
symptoms, try to prolong qualitytime, and preserve neurological
function for as long as we reasonably can.
And what's the first thing you should think about?
Always, always, always. Is there a clinical trial
available? Participation in a trial should
be the preferred option if possible.
That's where progress happens, and it gives patients access to
potentially novel therapies. Good point.

(11:23):
OK, if a trial isn't an option and you're considering
reradiation hitting the area again with radiation, who's a
good candidate for that? It sounds risky.
It does carry risks, absolutely.You're radiating tissue that's
already seen a significant dose,so patient selection is key.
The best candidates usually havea good KPS still, maybe 70 or
higher. Still relatively functional.

(11:44):
Right. And importantly, they've had a
reasonable time interval since their first course of radiation.
What counts as reasonable six months?
A year. Generally, we think at least six
months and ideally longer like ayear or more.
A longer interval suggests the tumor was initially controlled
well. Maybe it's slower growing and
the patient might tolerate and respond better to more local

(12:05):
therapy. If someone recurs really quickly
or their KPS is plummeting, re irradiation is probably not a
good idea. OK, that makes sense.
And the main evidence guiding reradiation recurrent GBM comes
from RTO twelve O 5 right? Yes, RTOG 12O5 is the landmark
trial here, really important study.
It took patients with recurrent GBM and randomized them.

(12:26):
One group got bevacizumab alone.That's Avastin.
Which was already used for recurrence.
Exactly. Bevacizumab alone versus
bevacizumab plus RE irradiation.The RE irradiation dose was 35
Gray in 10 fractions over 2 weeks.
OK. So Bev versus Bev plus RT, what
was the primary endpoint survival?
Yes, overall survival was the primary endpoint and

(12:50):
unfortunately the trial did not meet it.
No OS benefit. No significant difference in
overall survival. Median OS in both arms was
pretty similar around 10 months or so.
Adding rear radiation didn't make patients live longer
overall in the recurrence setting.
OK, so no overall survival benefit, but I feel like there
was something else significant found in 12 O 5.
Yes, and this is the clinically crucial part.

(13:13):
While OS wasn't improved, rear radiation significantly improved
progression free survival PFS. OK.
So it delayed the tumor from growing back again.
By a significant margin, the sixmonth PFS rate was nearly
doubled. It went from about 29% with Bev
alone to 54% with Bev plus RE radiation.
Wow, 29 to 54% at six months, That's a big difference.

(13:33):
It's a huge difference. Think about what that means for
the patient. Doesn't mean they live longer
overall necessarily. That means they live longer
without the tumor progressing. That translates to more time
with stable or improved neurological function, better
symptom control. It's a really meaningful
palliative benefit. Buying good quality time
essentially. Exactly.
It buys time, often good qualitytime, before the next

(13:56):
progression. That's incredibly valuable for
these patients. That's a great way to frame it.
And just to clarify the role of bevacizumab Bev itself, what you
mentioned it was in both arms of12/05, has it ever shown an OS
benefit in GBM? That's a key point to hammer
home no. Despite improving PFS and often
helping with symptoms like swelling, bevisizumab has not

(14:16):
been shown to improve overall survival in GBM.
Not in the upfront setting that was shown in the Ivalio and RTOG
08/2 on trials, and not in the recurrent setting either.
Based on the EOR TC-261-O ONE trial.
It helps symptomatically, delaysprogression, but doesn't extend
overall life. Important for managing
expectations. Very important distinction.

(14:37):
OK. Let's switch gears now to
something that has shown a survival benefit and generated a
lot of buzz, Tumor treating fields or TT fields.
IS TT fields definitely one of the biggest advances in GBM
treatment in recent years? What exactly is it?
It sounds kind of sci-fi. How does it work?
It does sound a bit futuristic, doesn't it?

(14:57):
It's a completely different approach.
Basically, patients wear these transducer arrays like
specialized patches on their shaved scalp for most of the
day. OK, and these patches do what?
They generate low intensity intermediate frequency
alternating electric fields, usually around 200 kHz.
These fields pass through the brain non invasively.
And the electric fields target the tumor.

(15:19):
They preferentially affect rapidly dividing cells like
cancer cells. The key is that these specific
electric fields disrupt mitosis,the process of cell division.
They interfere with the formation and function of the
mitotic spindle, that crucial structure that pulls chromosomes
apart when a cell divides. So it messes up cell division in
the cancer cells. Exactly.

(15:39):
It causes abnormal chromosome segregation, the cell gets stuck
in mitosis and eventually undergoes program cell death.
Apoptosis. And a big advantage is that it's
a physical modality, so its toxicities don't really overlap
with chemo. Fascinating mechanism and the
trial that really put this on the mat was.
EF14EF14 yes, that was the pivotal phase three trial, huge

(16:00):
impact. They took newly diagnosed GBM
patients after they had finishedtheir initial standard
chemeradiation, the stoop protocol part.
OK. So during the maintenance TMZ
phase. Precisely, they randomized them
to get either standard maintenance TMZ alone or
maintenance TMZ plus TT fields. The patients had to wear the
device for at least 18 hours a day.
And the results were. Striking, Really striking.

(16:22):
A clear, significant survival benefit.
The kind of benefit we hadn't seen since Stupid Self.
What were the numbers? How much did survival improve?
Median overall survival jumped from 16.0 months in the TMZ
Alone group to 20.9 months in the group that got TMZ plus DT
Fields. Almost 5 months improvement in
median OS. That's huge for GBM.
It's massive, but maybe even more impressive was the long

(16:45):
term survival, the five year survival rate.
It went from just 5% with TMZ alone to 13% with the addition
of TT Fields. Wow, more than doubled the five
year survival rate. More than doubled, going from 5
to 13% at five years for GBM. That's monumental.
And that magnitude of benefit isexactly why TT fields recede in

(17:06):
NCCN Category one recommendation.
It became part of the standard of care for newly diagnosed GBM
during maintenance. That really underscores the
impact. But practically speaking,
wearing a device for 18 hours a day, that sounds challenging.
Are there downsides or controversies?
Oh, absolutely. It's not a simple pill.
Compliance is a huge factor. Patients have to be really
motivated and dedicated to wear it that much.

(17:28):
There's managing the wires, changing the arrays, the
cosmetic aspect of a shaved headand the device.
It's a big lifestyle adjustment.I can imagine.
What about side effects? The main side effect is skin
toxicity under the arrays. Redness, irritation, sometimes
itching or even breakdown. It requires diligent skin care,
rotating the array positions OK.Any other considerations?

(17:48):
Well, there's the cost in logistics, although insurance
coverage is generally pretty good now.
And you know, ongoing research is looking at using it in
recurrent disease, combining it with other therapies, maybe
optimizing the fields. It's an evolving area, but the
EF14 data for newly diagnosed isundeniable.
A truly transformative therapy despite the practical
challenges. OK, this has been a fantastic

(18:10):
discussion covering these complex areas.
Let's try to crystallize the main takeaways.
Maybe some clinical pearls? Sounds good to lock these in
Pearl #1 for your fit elderly GBM patients older than 65 KPS
70 plus. The standard is hypofractionated
chemo RT-40 grey and 15 fractions with concurrent and

(18:30):
adjuvant PMZ. Remember the Perry trial showed
this improves median OS to 9.3 months versus 7.6 for RT alone.
OK Pearl #2 for the frail elderly with MGMT methylated
GBM, think single agent TMZ monotherapy is preferred.
NOA ZO8 showed an improved eventfree survival significantly
compared to RT 8.4 versus 4.6 months.

(18:51):
Pro #3 for those same frail elderly patients but with MGMT
on methylated GDMTMZ won't work as well, so hypofractionated RT
alone is superior. And remember row MEAEA, you
could use a convenient 25 Gray and five fractions course.
Got it. Pearl #4 Tumor treating fields.

(19:11):
Adding TT fields to maintenance TMZ for newly diagnosed GBM
gives that big survival boost. Median OS up from 16 to almost
21 months based on EF14 and CCN category one.
Pearl #5 recurrent GBM rear radiation, typically 35 grey and
10 fractions, doesn't improve overall survival which stays
around 10 months, but RTD twelveO 5 showed it does significantly

(19:33):
improve progression free survival, nearly doubling the
six month rate. Buys good quality time.
Excellent. And the final Pearl number six
devekizumab, just remember, despite improving PFS sometimes
it has not shown an overall survival benefit in upfront GBM
Evalio RTG 0825 or recurrent GB MERR TC29C61-O1 manage
expectations. Exactly.

(19:54):
Those cover the key points from today's discussion, I think.
Perfect. Now let's put this into action.
Time for our Board blitz segmentready for some cases.
Let's do it. Always good to test the
application all. Right case 1.
You have an 80 year old woman. KPS is 60.
She just got diagnosed with an MGMT unmethylated glioblastoma
from a biopsy. She's clearly not fit for
aggressive chemo RT. What's the most appropriate

(20:14):
management? A standard 60 Gray chemo RT post
up BTMZ monotherapy C hypofractionated radiation to 25
Gray in five fractions or D Bestsupportive care only.
OK, 80 years old, KPS 60 MGMT unmethylated.
Let's think through the options.A stoop protocol?
Definitely not KPS 60 is too frail.

(20:36):
Agreed too. Toxin monotherapy?
No, because her tumor is MGMT unmethylated.
We know from N OAOA and Nordic that RT is better than TMZ for
unmethylated tumors in this setting.
Right, TMZ likely wouldn't work.Well, the best supportive care
only probably not yet. KPS 60, while frail, often still
warrant some active palliative treatment.
We reserve BSc usually for KPS less than 50.

(20:58):
So that leaves. That leaves C hyperfractionated
radiation to 25 grey and five fractions.
This fits perfectly. She's frail.
MGMT on methylated so RT is indicated over TMZ and the
rowing EA trial showed 25 and 5 is non inferior to 40 and 15 for
survival and frail patients but way more convenient.
It's the ideal palliative RT regimen here.
Excellent reasoning, hits all the key points.

(21:21):
Frailty MGMT status, convenience.
OK case 269 year old man. But this time KPS is 90, very
fit. He's had a GTR of a GB M.
You're counseling him on adjuvant therapy.
Which regimen has the highest level of evidence for improving
OS in this specific population? A60G and 30 fractions with chemo
stop. B40G and 15 fractions with

(21:42):
chemo. C40G and 15 fractions alone or
DTT fields alone. OK, 69 years old, KPS 90 SO fits
the fit elderly category. We need the highest level of
evidence for this age Group, A SO60G plus chemo.
That's the standard for younger patients.
But is it the best evidence for age 69?
Maybe. Not the most specific evidence.
Exactly C40G on and 15 alone. Perry showed adding chemo was

(22:05):
better. DTT fields alone.
No, that's added to maintenance chemo not used alone upfront.
That leaves B 40 gene and 15 fractions with concurrent and
adjuvant TMZ. This is the regimen tested
specifically in patients 65 and older in the Perry trial.
So Perry's the highest level of evidence for his age group.
Precisely Perry directly compare40 and 15 plus TMZ in the over

(22:26):
65 and show the combined treatment improved survival.
So while stoop is the general standard for someone 65 or
older, the Perry regimen 40 and 15 plus chemo has the most
direct high level evidence supporting it.
Answer is B. Fantastic distinction.
Age matters for the specific evidence base.
OK, final board blitz case. Let's go back to Mr. Chen. 64
years old. Recurrence at 18 months after

(22:48):
finishing stoop KPS is still good at 90.
Which statement about rear radiation is most accurate?
A. It's expected to give
significant OS benefit. B.
It's contraindicated because he already had 60 GIC.
It's likely to improve PFS, but not OS or D It should only be
offered with concurrent Bev. OK.
Recurrent GBM, good KPS good interval 18 months.

(23:09):
Thinking about rear radiation, asignificant OS benefit.
No RTO G12O5 showed no OS benefit.
So A is out right? B contraindicated due to prior
60G? No, that's not an absolute
contraindication. RE radiation is definitely an
option for selected patients like Mr. Chen with good KPS and
interval. So B is out OK.

(23:30):
D only offered with concurrent Bev no, while twelve O 5 use
Bev. RE radiation can be considered
without it or potentially with other systemic agents and
trials. So D is too restrictive leaving
leaving C. It's likely to improve
progression free survival but not overall survival.
That perfectly summarizes the main finding of RTG 1205.
RE radiation offers a meaningfulpalliative benefit by delaying

(23:52):
progression even if it doesn't extend overall lifespan.
C is the most accurate statement.
Perfect. Those cases really helped
solidify the application of all that trial data.
Yeah, it forces you to integratethe different pieces of evidence
for specific patient scenarios. Very useful.
Well, today we've really, I think broadened our GBM toolkit.
We moved past that standard stepframework to figure out how to

(24:14):
tailor treatments for, you know,some of the most challenging
patients. We see that elderly, the frail,
those with recurrence and we touched on TT fields too.
Absolutely. And the recurring theme, the
real key take away is individualization.
It's not one-size-fits-all. You have to weigh the patient's
age, their KPS, those crucial molecular markers like MGMT, and

(24:35):
always their goals of care. What matters most to them?
Optimizing quality of life function, especially when cure
isn't on the table. Exactly right.
So looking ahead, our next session is going to be really
practical. We're doing our high grade
glioma treatment planning workshop.
We'll pull together everything on GBM and anaplastic glioma
volumes, contours and crucially,the dose constraints you

(24:55):
absolutely need to know for safetreatment delivery.
That's essential. Knowing the evidence is one
thing, but safely planning and delivering the radiation is
where it all comes together. That'll be a critical session.
Definitely, so you can get the show notes for today and access
complete practice oral boards over at radonsmartlearn.com.
That's RADONCSMARTL, earn.com, pronouncedradonsmartlearn.com.

(25:21):
And be sure to subscribe to Radon Smart Review so you don't
miss that planning workshop. Thanks for joining us.
Yeah, thanks everyone for tuningin.