LOW GARDE GLIOMA PANEL

1. LOW GRADE GLIOMA PANEL
5/5/2023 1
DR L N TRIPATHY
Senior Vice Chairman, Director
Senior Consultant, Neurosurgery
Medica Super specialty Hospital, Kolkata
ISNOCON 2023- KOLKATA
DR KANHU CHARAN PATRO
HOD, Radiation Oncology
Mahatma Gandhi Cancer Hospital & RI
Visakhapatnam

2. Dr
ADHITHYAN

3. Dr Amit
Kumar Ghosh

4. Dr Anila
Sharma

5. DR Nilesh
Mahale

6. Dr Vikas Jagtap

7. Dr Devleena
Gangopadhya

11. 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
5/5/2023 11

12. 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
5/5/2023 12

13. Case details
39-year male
• P/w –frontal headache
• Personality changes- 6 month
• Single episode of generalized seizure
• Disturbance with selective attention
MRI
• LT. temporal lesion
• 6cm in greatest dimension
• Solid cystic pattern
• No enhancement
• Midline shift
• Mass effect
• Ventricular effacement

14. Dr ADHITHYAN PLEASE
IMAGING PROTOCOL

15. RADIOLOGY
• PRESCRIPTION
• MRS,DIFFUSION,PERFUSION
• TRACTOGRAPHY
• RADIOMICS AND
RADIOGENOMICS

16. T1

17. T1-
Contrast

18. T2

19. T2 Flair

20. Perfusion

21. Perfusion

22. SWI

23. DWI-ADC
5/5/2023 23

24. MRS

25. 5/5/2023 25

26. 2HG MRS
5/5/2023 26
IDH MUTATION
IDH WILD
using 2 mM 2HG as threshold to discriminate IDH-mutated from wildtype tumors

27. T2-FLAIR
mismatch sign

28. GRADE II OLIGO
[BLOOMING]

29. DR AMIT PLEASE
SURGERY DETAILS

30. How will
you
proceed?
Observation?
Surgery
Which type of surgery
Surgical procedure

31. NEUROSURGERY
• What type surgery
• Eloquent location
• Stereotactic biopsy
• Imaging after surgery
• Awake craniotomy

32. 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.
5/5/2023 32

33. SURGERY
• PATIENT UNDERWENT SURGERY
• COMPLETE EXCISION
• BETTER AFTER SURGERY
5/5/2023 33

34. Dr ADHITHYAN PLEASE
POST OP IMAGING PROTOCOL

35. TIMING OF POST OP MRI
5/5/2023 35

36. 5/5/2023 36

37. 5/5/2023 37

38. NEUROPATHOLOGY
• Classification
• Histopathology
• IHC
• Molecular profile

39. DR ANILA PLEASE
H/P GUIDENCE

40. Brain tumor diagnosis
Next generation
sequence
[NGS]
Methylation profiling
Immunohistochemistry
[IHC]
Microscopic
Histology
40

41. Layered reporting in brain tumors
Thus, to display the full range of diagnostic information available, the use of
layered (or tiered) diagnostic reports is strongly encouraged, as endorsed by
the International Society of Neuropathology—Haarlem consensus
guidelines and the International Collaboration on Cancer Reporting.

42. Layered diagnosis
5/5/2023 42

43. H/ P REPORT
• DIFFUSE GLIOMA
• GRADE ll
5/5/2023 43
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

44. Oligodendroglioma
5/5/2023 44
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.

45. Atypia
Mitosis
Endothelial
Proliferation
Necrosis
AMEN SCORE
45

46. Defining and grading of IDH mutant and IDH wild
46

48. Adult diffuse gliomas – current status

49. Two deciding factors
5/5/2023 49

50. IDH MUTATION AND GLIOMA-GENESIS
5/5/2023 50

51. Mixed entity
5/5/2023 51

52. Diffuse glioma
Oligodendro glioma
IDH mutant
1p19q co-deleted
Glioblastoma
IDH wild
Diffuse glioma
IDH mutant
52

53. Diffuse glioma
Oligodendro glioma
IDH mutant
1p19q co-deleted
IDH wild
Glioblastoma
Diffuse glioma
IDH mutant
53
Grade-2
Grade-3
Grade-4
Grade-2
Grade-3

55. When will we call as glioblastoma?
• Diffuse astrocytoma IDH wild type with
• TERT promoter mutation
• Necrosis
• Microvascular proliferation
• EGFR gene amplification
• Combined entire gain of chromosome 7 and
entire loss of chromosome 10[+7/-10]
55

56. Revised schema of classification: post WHO CNS5

57. NIMHANS WEBSITE

58. FINAL REPORT
• DIFFUSE GLIOMA
• IDH MUTANT
• 1P/19q CO DELETION
• OLIGODENDDROGLIOMA
• GRADE ll

59. DR NILESH PLEASE
ADJUVANT TREATMENT

60. ADJUVANT
TREATMENT
Observation
Radiation
Conc. Chemo
Adjuvant chemo

63. 5/5/2023 63

64. Options
• RT alone
• RT- adj. PCV
• RT- adj. TMZ
• RT- conc. And adj. TMZ - 6
• RT- conc. And adj. TMZ - 12
5/5/2023 64

65. Planning for
observation
• Besides IDH wild-type status, other high-risk factors
include
– Age > 40 years,
– Subtotal resection/biopsy only,
– Astrocytic lineage (lack of 1p/19q codeletion),
– Neurologic deficits prior to surgery,
– Tumor diameter > 6 cm, tumor crossing the
midline of the brain,
– tumors located within or adjacent to eloquent
areas of the brain
• Patients without these risk factors can be considered at
low risk; therefore, after gross total resection, they
should be observed closely with surveillance MRI every
3 months initially, and if there is no demonstrated tumor
growth over a 1-year period, then the imaging interval
can be increased to every 4 months for another year,
and eventually every 6 months for the remainder of the
patient’s life
5/5/2023 65

67. Why not now?
5/5/2023 67

68. DR VIKAS PLEASE
DOSE AND TECHNIQUE

69. RADIOTHERAPY
PLANNIG IMAGE
DOSE
TARGET DELINEATION
TECHNIQUE

70. 5/5/2023 70

71. Technique and dose

72. GTV- CTV- PTV PARAMETERS

75. Case study

76. Post op images

77. Contouring details

78. DR DEVLEENA PLEASE
ABOUT CONC. AND ADJUVANT CHEMO

79. CHEMOTHERAPY
CONC. CHEMO
ADJUVANT CHEMO

80. Concurrent chemo
TEMOZOLOMIDE
VS
NO TEMOZOLOMIDE

81. Concurrent CTRT trial
5/5/2023 81
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 Phys.(2015)

82. For anaplastic astrocytoma IDHmt, the interim results of the CATNON trials strongly
suggest treatment with 59.4Gy radiotherapy in fractions of 1.8Gy followed by 12 cycles of
adjuvant temozolomide chemotherapy (200mg/m2 days 1–5 in a 4-week cycle

83. CODEL

85. Adjuvant chemo
• After radiation, patient received adjuvant PCV
(procarbazine, CCNU, and vincristine) due to 1p/19q
co-deletion (per RTOG 9802).

86. PCV trial
5/5/2023 86
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)

87. Follow up
MUTATED
WILD

89. EXTRA SLIDES

90. Radiotherapy trials
5/5/2023 90
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

91. Radiotherapy trials
5/5/2023 91
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)

92. Radiotherapy trials
5/5/2023 92
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)

93. Radiotherapy trials
5/5/2023 93
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)

94. Radiotherapy trials
5/5/2023 94
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

95. Radiotherapy trials
5/5/2023 95
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.

96. Radiotherapy trials
5/5/2023 96
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)

97. Recommendation -1
• People with oligodendroglioma, IDH-mutant, 1p19q codeleted, CNS WHO
grade 2 should be offered radiation in combination with PCV
• TMZ is a reasonable alternative to PCV when toxicity is a concern
5/5/2023 97

99. Recommendation -2
• People with oligodendroglioma, IDH-mutant, 1p19q codeleted, CNS WHO
grade 2, initial therapy may be deferred until radiographic or symptomatic
progression in some people with positive prognostic factors (eg, complete
resection and younger age) or concerns about toxicity

100. Recommendation -3
• People with oligodendroglioma, IDH-mutant, 1p19q codeleted, CNS WHO
grade 3 should be offered radiation in combination with PCV
• TMZ is a reasonable alternative to PCV when toxicity is a concern

101. GRADE 3 IDH MUTANT AND CODELETED TUMORS

102. Recommendation -4
• People with Astrocyoma, IDH-mutant, 1p19q NONcodeleted, CNS WHO
grade 2 should be offered radiation in combination with PCV
• TMZ is a reasonable alternative to PCV when toxicity is a concern
GRADE 2 IDH MUTANT AND NON-CODELETED TUMORS

104. Recommendation -5
• People with Astrocytoma, IDH-mutant, 1p19q NONcodeleted, CNS WHO
grade 2, initial therapy may be deferred until radiographic or symptomatic
progression in some people with positive prognostic factors (eg, complete
resection and younger age) or concerns about toxicity

106. Recommendation -6
• People with astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO
grade 3 should be offered RT with adjuvant TMZ

108. Recommendation -7
• People with astrocytoma, IDH mutant CNS WHO grade 4 may be treated like an
astrocytoma, IDH-mutant, non-codeleted, CNS WHO grade 3 (formerly anaplastic
astrocytoma; see Recommendation 6) or like a glioblastoma, IDH-wildtype, CNS WHO
grade 4

109. Recommendation - 8
• People with astrocytomas, IDH-wildtype, CNS WHO grade 2 or 3 may be
treated according to recommendations for glioblastoma

110. Recommendation -9
• Concurrent TMZ and RT should be offered to people with newly diagnosed
glioblastoma, IDH-wildtype, CNS WHO grade 4

111. Recommendation -10
• Six months of adjuvant TMZ should be offered to people with newly diagnosed
glioblastoma, IDH-wildtype, CNS WHO grade 4 who have received concurrent
RT plus TMZ

113. Recommendation -11
• Alternating electric field therapy may be added to adjuvant TMZ in people with
newly diagnosed supratentorial glioblastoma, IDH-wildtype, CNS WHO grade 4
who have completed chemoradiation therapy

115. Recommendation -12
• Bevacizumab is not recommended for people with newly diagnosed
glioblastoma, IDH-wildtype, CNS WHO grade 4

116. Bevacizumab is not recommended for people with newly
diagnosed glioblastoma, IDH-wildtype, CNS WHO grade 4
Benefits do not outweigh harms

117. Recommendation -13
• In people with glioblastoma, IDH-wildtype, CNS WHO grade 4 where the expected survival
benefits of a 6-week radiation course combined with TMZ may not outweigh the harms,
hypofractionated RT combined with TMZ is a reasonable alternative

119. Recommendation -14
• In people with glioblastoma, IDH-wildtype, CNSWHO grade 4 with older age, poor
performance status or with concerns about toxicity or prognosis, best supportive care
alone, hypofractionated RT alone (for MGMT promoter unmethylated tumors) or TMZ
alone (for MGMT promoter methylated tumors) are reasonable options.

121. Recommendation -15
• No recommendation for or against any therapeutic strategy can be made for
treatment of recurrent glioblastoma, IDH wildtype, CNS WHO grade 4
• People with recurrent glioblastoma should be referred for participation in a
clinical trial where possible

122. Recommendation -16
• No recommendation for or against any therapeutic strategy can be made for
treatment of diffuse midline glioma
• People with diffuse midline glioma should be referred for participation in a
clinical trial when possible

124. Thank you
5/5/2023 124