This document provides information on the management of diffuse gliomas, including: 1. It defines diffuse gliomas and discusses their WHO classification, typically involving infiltration of normal brain tissue without clear borders. 2. Symptoms can include raised intracranial pressure, seizures, focal neurological deficits, and others depending on the tumor location. 3. Managing diffuse gliomas requires a multidisciplinary team including radiologists, neurosurgeons, oncologists and others. 4. Trial evidence is discussed regarding the use of radiotherapy and chemotherapy at different doses and timings for diffuse low-grade gliomas.

1. MANAGEMENT OF DIFFUSE GLIOMAS
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DR KANHU CHARAN PATRO
MD,DNB(RADIATION ONCOLOGY),MBA,FAROI(USA),PDCR,CEPC
HOD,RADIATION ONCOLOGY
Mahatma Gandhi Cancer Hospital And Research Institute, Visakhapatnam
drkcpatro@gmail.com M-9160470564

2. Definition
The term diffuse infiltrating means there is no
identifiable border between the tumour and
normal brain tissue, even though the borders
may appear well-marginated on imaging
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3. WHO-2016 classification
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4. 2016
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2007

5. 6/20/2021 5

6. Symptoms
• Compressive
– Raised ICT
• Headache
• Vomiting
• Irritative
– Seizure
• Global
• focal
• Destructive-rare
– Paresis
– Functional based on location
• Obstructive
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7. The team
• Neuroradiologists
• Neurosurgeons
• Neurologists
• Neuropathologist
• Radiotherapy oncologists
• Medical oncologists
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8. Some facts
• Diffuse astrocytomas, also referred to as low-grade infiltrative
astrocytomas, are designated as WHO II tumours of the brain.
• Commonly, astrocytomas are confined to white matter although they
can infiltrate and expand the adjacent cortex in later stages.
• However, oligodendroglioma is frequently a cortical-based tumor.
• Although contrast enhancement has been classically associated
with a higher degree of malignancy, contrast enhancement may be
seen in up to 20% of LGG
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9. Oligodendroglioma-cortical lcation
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10. CT IMAGE
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11. DIFFUSE
ASTRO -CT
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12. T1

13. T1-
Contrast

14. T2

15. T2 Flair

16. Perfusion

17. Perfusion

18. SWI

19. DWI-ADC
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20. MRS

21. 6/20/2021 21

22. T2-FLAIR
mismatch sign
• The T2-FLAIR mismatch sign describes the
MRI appearance considered a highly specific
radiogenomic signature for diffuse
astrocytoma (IDH-mutant, 1p/19q-non-
codeleted molecular status), as opposed to
other lower-grade gliomas.
• It is particularly helpful in distinguishing a
diffuse astrocytoma from
an oligodendroglioma that will not
demonstrate T2-FLAIR mismatch.
• On T2 weighted images, these tumours have
extensive areas of fairly homogeneous and
strikingly high signal.
• On T2-FLAIR, instead, the majority of these
areas become relatively hypointense in signal
due to incomplete suppression.
• At the margins of the tumour, a rim of
hyperintensity is usually seen.
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23. T2-FLAIR
mismatch sign

24. GRADE II OLIGO
[BLOOMING]

25. Algorithm

26. Surgery recommendation
• It is assumed that surgery should aim for the greater extent of resection as it
would Increase survival and potentially alter the natural history of the
disease: gross total removal or subtotal tumor removal (when feasible and
safe) is superior to biopsy in terms of decreasing the rate of tumor
progression and also have positive impact in overall survival estimation of
resection less than 50% would lead to consider biopsy.
• A retrospective multicentric study analyzing 1097 patients (in which the
assessed population was divided into three subgroups depending on the
extent of resection: 100%, 50–99% and less than 50%) showed that the
amount of residual lesion impacted on the course of the disease (OS was
10.5 and 14 years for patients with a less than 50 and 50–99% Extent of
resection, being unreached instead after 15 years for patients with no
residual tumor).
• Biopsy is indicated when diagnosis is needed in deep lesions (including
brainstem), diffuse and/or multicentric tumor or any other contraindication
for open resection.
• Biopsy can be stereotactic (framed or frameless) or open. Neuronavigated
non-framed biopsy is gaining acceptance.
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27. Layered diagnosis
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28. Molecular classification
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29. 6/20/2021 29

30. Mixed entity
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31. Oligodendroglioma
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Micrograph of an oligodendroglioma showing the characteristic branching,
small, chicken wire-like blood vessels and fried egg-like cells, with clear cytoplasm
and well-defined cell borders. H&E stain. Those with uniformly rounded nuclei and
perinuclear halo (‘‘fried egg’’) are considered oligodendrogliomas.

32. Diffuse astrocytoma
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1. Nuclear irregularities with fibrillary processes
are diagnosed as astrocytoma
2. Infiltrative, diffuse growth pattern with the
formation of secondary structures of Scherer
Moderately cellular
3. Irregular cell distribution
4. Nuclear atypia is typical, yet variable: enlarged
elongated hyperchromatic irregular nuclei
5. Variable amount of cytoplasm: may be scant
(naked nuclei) to moderate with processes
creating a fibrillary background
6. No mitotic activity (a single mitosis in a sizable
specimen is allowed)
7. No necrosis or microvascular proliferation
8. Variable microcystic change
9. Variable calcification

33. Gemistocytic astrocytoma
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1. Gemistocytes are cells swollen with
hyaline, pink cytoplasm that is reactive
for GFAP
2. Their hyperchromatic and angulated
nuclei are at the rim of the cells,
producing a bizarre caricature of a
reactive astrocyte.
3. A variant of diffuse astrocytic tumor is
gemistocytic astrocytoma,
characterized by [20% cells with
abundant eccentrically placed
cytoplasm, this variant tends to show a
rapid malignant progression

34. Gemistocytic
astrocytoma
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Gemistocytic astrocytomas are
characterised by a significant
gemistocytes population, which are large
cells with their cytoplasm filled with
eosinophilic material displacing the
nucleus eccentrically.
It is important to note that other
gliomas (e.g. fibrillary
astrocytoma and oligodendrogliomas)
can have occasional gemistocytes,
without being designated a
gemistocytic astrocytoma.
Some authors use a cut off of 20% of the
tumour cells being gemistocytes before
designating it as a gemistocytic
astrocytoma.
Although there are no specific features
which allow pre-biopsy diagnosis,
gemistocytic astrocytomas are almost
always supratentorial and usually
located in the frontal lobes

35. Molecular profile
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36. Radiotherapy trials
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TRIAL INCLUSION ARM RESULT
RTOG 9802 1. Age<40 years
2. GTS
No adjuvant 1. OS rates at 2 and 5 years were: 99
and 93%, respectively.
2. PFS rate at 5 year: 48%
3. In patients without unfavorable
prognostic factors the 2- and 5-year
PFS rates were 100 and
70%.respectively.
Shaw EG. J Neurosurg
(2008)

37. Radiotherapy trials
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TRIAL INCLUSION ARM RESULT
EORTC 22844 1. Low-grade
astrocytomas
Low dose RT
(45 Gy)
VS
High dose RT
(59.4 Gy)
1. No significant difference in the 5-
years OS between low-dose arm
(58%) and high dose arm (59%).
2. No significant difference in the 5-
years PFS (47% verss 50%)
Karim AB. Int J Radiat Oncol Biol Phys
1996

38. Radiotherapy trials
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TRIAL INCLUSION ARM RESULT
EORTC 22845
Interim
1. Low-grade
astrocytoma
Early RT
(54 Gy)
VS
No RT
1. Early RT showed an improvement in
TTP (4.8 versus 3.4 years; p = 0.02).
HR = 0.68 (95% CI 0.50–0.94).
2. No differences in OS: HR = 1.15 (95%
CI 0.67–1.74).
3. The 5-year OS rate were: 63 versus
66% (p = 0.49).
(Karim AB. Int J Radiat Oncol Biol
Phys(2002)

39. Radiotherapy trials
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TRIAL INCLUSION ARM RESULT
EORTC 22845 1. WHO grade II RT (54 Gy)
after biopsy
resection,
VS
No RT until
progression
1. Early RT was associated with an
improvement PFS (5.3 versus 3.4
years): HR = 0.59; 95% CI 0.45–0.77
(p = 0.0001).
2. No difference in OS (7.4 versus 7.2
years): HR = 0.97; 95% CI 0.71–1.34
8 (p = 0.872)
3. Seizure control also improved in
patients treated with early
radiotherapy.
Van den Bent MJ. Lancet
2005)

40. Radiotherapy trials
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TRIAL INCLUSION ARM RESULT
NCCTG/RTOG/
ECOG
1. WHO grade II
gliomas
Low dose RT
(50.4 Gy)
VS
High dose RT
(64.8 Gy)
1. No differences in 2- and 5-year OS
between low dose (94 and 75%) and
high dose arm (85 and 64%) (p =
0.48)
2. Patients treated with high doses
showed higher rates of severe
radionecrosis (5 versus 2.5%)
Shaw EG. J Clin Oncol.
(2002)

41. Radiotherapy trials
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TRIAL INCLUSION ARM RESULT
RTOG 9802 1. Age >40 years
and/or subtotal
resection
RT (54 Gy)
VS
RT (54 Gy)
And 6 cycles
of adjuvant
PCV
1. Post-RT + PCV conferring a survival
advantage over RT alone: median OS
13.3 versus 7.8 years (HR: 0.59; 95%
CI 0.42–0.83; p = 0.003).
2. Median PFS was prolonged in
patients who received PCV (10.4
versus 4.0 years): HR: 0.50; 95% CI
0.36–0.68 (p0.001)
Buckner JC. N Engl J
Med(2016)

42. Radiotherapy trials
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TRIAL INCLUSION ARM RESULT
RTOG 0424 LGG with >3 risk
factors for
recurrence (age >
40 years,
astrocytoma
histology,
bihemispheric
tumor, tumor
diameter[6 cm,
neurologic
function status
Concurrent
radiation
(54 Gy) with
TMZ f/b
monthly TMZ
1. The 3-year OS rate was 73% (95% CI
65.3–80.8%), significantly higher
than the historical control OS rate of
54% (p0.001).
2. The 5-year OS rate was 57.1% (95%
CI 47.7–66.5%), and the median OS
has not yet been reached.
3. The 3-year PFS was 59.2% (95% CI
50.7–67.8%) and median PFS was
4.5 years (95% CI 3.5–NA).
Fisher BJ. J Radiat Oncol Biol

43. Radiotherapy trials
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TRIAL INCLUSION ARM RESULT
EORTC 22033 LGG with at least
one high-risk
feature (aged>40
years,
progressive
disease, tumour
Size>5 cm, tumour
crossing the
midline, or
neurological
symptoms)
RT ( 50.4 Gy
VERSUS
Dose-dense
oral TMZ
(75 mg/m2
once daily for
21 days,
every
28 days, for a
maximum
of 12 cycles)
1. There was no significant difference
in PFS between TMZ group (39
months) and RT group (46 months):
HR: 1.16; 95% CI 0.9–1.5 (p = 0.22).
2. Median OS has not been reached.
3. Better PFS in IDH-mutant
noncodeleted patients treated with
radiotherapy: 55 versus 36 months.
HR 1.86; 95% CI 1.21–2.87 (p =
0.0043)
Baumert BG Lancet Oncol.

44. Radiotherapy trials
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TRIAL INCLUSION ARM RESULT
Wahl M,et al LGG and gross
residual disease
Monthly
cycles of TMZ
for up to 1
year or until
disease
progression
1. The median PFS and OS were 4.2
and 9.7 years, respectively.
2. Patients with 1p/19q codeletion
demonstrated a 0% risk of
progression during treatment
Neuro
Oncol.(2017)

45. 6/20/2021 45

46. IDH wild type LGG
• Low-grade gliomas that lack a mutation in IDH make up a relatively small
proportion of all low-grade gliomas and carry a significantly worse prognosis
compared with IDH mutant tumors
• There are no randomized trials to guide treatment in patients with IDH-wildtype
low-grade gliomas, and these tumors are underrepresented in historical studies
of low-grade glioma, including the RTOG 9802 trial reviewed above.
• Some of these tumors bear molecular similarity to glioblastoma (e.g., TERT
mutations, loss of heterozygosity of chromosome 10).
• In such cases, we propose to treat patients with immediate postoperative
therapy, regardless of extent of resection or other prognostic factors, with
radiation and chemotherapy.
• Whether to treat IDH-wildtype with RT ? PCV or with concurrent chemo-
radiotherapy with TMZ followed by adjuvant TMZ is an open question that
requires further studies.
• The rational to use the same regimen as in glioblastoma, the Stupp regimen is
the fact that IDH-wt astrocytoma has the same biology and natural history is
very similar to primary GBM
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47. Follow up
• Follow-up with FLAIR or T2-weighted MRI is the standard of
care.
• These MRI sequences are widely available and can be used
routinely in clinical protocols. Routine follow-up should also
include T1-weighted images before and after intravenous
contrast administration to detect malignant transformation
• Follow-up recommendation would be clinical evaluation with
particular attention to neurological function, seizures and
corticosteroid use
• MRI and Mini–Mental State Examination (MMSE) after the
completion of therapy, and then every 3–4 months for 1 year,
every 6 months for 2 years, and every year thereafter until
tumor progression is recommended outside clinical trials
(Level V), unless more frequent monitoring is clinically
indicated
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48. RANO response criteria for low-grade glioma
• CR
– Complete disappearance of the lesion on T2 or FLAIR imaging (if enhancement had been present, it must have resolved completely)
– No new lesions, no new T2 or FLAIR abnormalities apart from those consistent with radiation effects, and no new or increased enhancement;
– Patients must be off corticosteroids or only on physiological replacement doses
– Patients should be stable or improved clinically
• PR
– Greater than or equal to 50% decrease in the product of perpendicular diameters of the lesion on T2 or FLAIR imaging sustained for at least 4
weeks compared with baseline;
– No new lesions, no new T2 or FLAIR abnormalities apart from those consistent with radiation effects, and no new or increased enhancement;
– Patients should be on a corticosteroid dose that should not be greater than the dose at time of baseline scan, and should be stable or
improved clinically
• Minor response
– A decrease of the area of non-enhancing lesion on T2 or FLAIR MR imaging between 25% and 50% compared with baseline;
– No new lesions, no new T2 or FLAIR abnormalities apart from those consistent with radiation effect, and no new or increased enhancement;
– Patients should be on a corticosteroid dose that should not be greater than the dose at time of baseline scan, and should be stable or
improved clinically
• Stable disease
– Stable disease is present if the changes do not qualify for complete, partial, or minor response, or progression and requires:
– Stable area of non-enhancing abnormalities on T2 or FLAIR imaging;
– Patients should be on a corticosteroid dose that should not be greater than the dose at time of baseline scan, and should be stable or
improved clinically
• Progression
– Development of new lesions or increase of enhancement (radiological evidence of malignant transformation);
– A 25% increase of the T2 or FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids compared with baseline scan or best
response after initiation of therapy, not attributable to radiation effect or to comorbid events;
– Definite clinical deterioration not attributable to other causes apart from the tumour, or decrease in corticosteroid dose; or
– Failure to return for evaluation because of death or deteriorating condition, unless caused by documented non-related disorders
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49. Recommendations
1. The revised WHO classification of 2016 integrates molecular markers in the routine
histological diagnosis of CNS tumors.
2. The main molecular factors for subdividing LGG are IDH mutations, 1p19q
codeletions, ATXR and TERT mutations.
3. LGG may be subdivided into three groups:
A. Grade 2 diffuse astrocytoma IDH wt,
B. Grade 2 diffuse Astrocytoma IDH mut without 1p19q codeletion,
C. Grade 2 Oligodendroglioma that requires the following molecular features: IDH
mut and 1p19q codeletion.
4. MRI is the modality of choice for characterizing LGG but advanced MRI techniques,
such as Diffusion weighted imaging (DWI), MR Spectroscopy and Perfusion MRI,
complements the anatomic information obtained from conventional MRI.
5. Surgical resection is considered the first step to be done when dealing with LGG.
Currently is assumed that surgery should aim for the greater extent of resection.
6. As the management of LGG is complex, It is recommended that all cases of low-
grade glioma be discussed in a multidisciplinary committee before selecting a
therapeutic option
7. You can observe in LOW-risk groups
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50. Why not now?
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