1) It provides an overview of the epidemiology, risk factors, WHO grading system and molecular markers of adult high grade gliomas. 2) The standard of care for treatment involves maximal surgical resection followed by radiotherapy and chemotherapy with temozolomide. 3) Prognostic factors like age, performance status, tumor location and extent of resection influence survival outcomes.

1. PATHOLOGY, MOLECULAR BIOLOGY &
MANAGEMENT OF HIGH GRADE GLIOMA
PRESENTER- Dr HARDIK SHARMA
MODERATOR- Dr RENU MADAN

2. EPIDEMIOLOGY & RISK FACTORS
• Yearly incidence of malignant glioma ∼6/100 000
• Gliomas - 80% of malignant brain tumors; Glioblastoma(GBM) – most common primary malignant brain
tumor
• Slight predominance in males (1.6times)
• In a report of the Hospital based Cancer registries, 2021, CNS tumors constituted 1.6 % of all malignancies
• Exposure to ionizing irradiation
• Rare hereditary syndromes carry an increased risk for glioma: Cowden-, Turcot-, Lynch-, Li-Fraumeni
syndrome and neurofibromatosis type 1.
• Viruses like RNA ,DNA virus- HPV, Adenoviruses
• Chemical agents a. Polycyclic hydrocarbons b. Alkylating agents
EANO GUIDELINES

3. WHO
GRADE
DEFINITION GLIOMAS
I low proliferative potential (hypercellular) Pilocytic astrocytoma, Pleomorphic
xanthoastrocytoma, Ganglioglioma,
Subependymal giant cell astrocytoma
II +/- nuclear atypia Diffuse astrocytomas and
oligodendrogliomas
III Nuclear atypia + brisk miotic activity Anaplastic astrocytomas and
oligodendrogliomas
IV Nuclear atypia + mitotic activity + necrosis and/or
microvascular proliferation
Glioblastoma

4. High Grade Glioma
▪ Grade 3 and 4 astrocytoma
▪ Grade 3 oligodendroglioma
▪ Glioblastoma (IDH wild type-4)

5. TUMOR TYPE CNS WHO
GRADE
CHARACTERSTIC MOLECULAR
ALTERATIONS
ADULT TYPE DIFFUSE GLIOMAS
• Astrocytoma IDH Mutant 2,3,4 IDH1,IDH2
• Oligodendroglioma IDH Mutant,1p/19q
Codeleted
2,3 IDH1,IDH2,1p/19q
• Glioblastoma IDH Wildtype 4 IDH-wildtype ,Ch-7 &10,TERT,EGFR
PEDIATRIC HIGH GRADE GLIOMAS
• Diffuse Midline Glioma, H3 K27 4 H3 K27,EGFR,EZHIP
• Diffuse Hemispheric Glioma, H3 G34 4 H3 G34
• Diffuse Pediatric HGG,H3-Wildtype & IDH
wildtype
4 IDH-wildtype, EGFR, PDGFRA, MYCN
• Infant Type Hemispheric Glioma NA RTK genes
WHO HIGH GRADE GLIOMA

6. Pediatric Type Vs Adult Type Gliomas
• Although, both share overlying histology
• But the genetic & biology are distinctively different
• Generally pediatric type - indolent despite “anaplastic” features & lack IDH mutation & 1p/19q
codeletion i.e genetic hallmark of adult type
• They harbor genetic profiling such as MAPK pathway alteration (Pediatric type)
• Do not depend upon the patient age , instead defined based on representative molecular
alterations, implicating that pediatric-type gliomas may occur in adults & vice versa

7. Molecular Biology-Adult High Grade Glioma

8. WHO 2016 2021

9. Molecular marker Biological function Diagnostic roles
IDH 1 OR IDH2 Gain of function mutation Distinguishes diffuse gliomas with IDH
mutation from IDH-wild-type glioblastomas
and other IDH-wild-type gliomas
1p/19q codeletion Inactivation of TSP on 1p and 19q Distinguishes oligodendroglioma, IDH-
mutant and 1p/19q-codeleted from
astrocytoma, IDH-mutant
Loss of nuclear ATRX Cellular proliferation & promotion of
cellular longevity
Loss of nuclear ATRX in an IDH-mutant
glioma is diagnostic for astrocytic lineage
tumors
Histone H3 K27 altered Histone H3.3 missense mutation affecting
epigenetics
Defining molecular feature of diffuse midline
glioma, H3.3 G34-mutant
Histone H3.3G34 altered Histone mutation affecting epigenetic
regulation
Defining molecular feature of diffuse
hemispheric glioma, H3.3 G34-mutant
MGMT promoter
methylation
DNA repair None, but is a predictive biomarker of benefit
from alkylating chemotherapy in patients
with IDH-wild-type glioblastoma

10. CDKN2A/2B homozygous
deletion
Encode CDKNA2A &2B ,regulators of
RB17 p-53 dependent signaling
A marker of poor outcome and WHO grade 4
disease in IDH-mutant astrocytomas
EGFR amplification Cell proliferation ; invasion & resistance to
induction of apoptosis
EGFR amplification occurs in ~40–50% of
glioblastoma, IDH wild type Molecular
marker of glioblastoma, IDH wild type,
WHO grade 4
TERT promotor mutation Cell proliferation; promotes cellular
longevity by increasing TERT expression
OCCUR IN -70% OF Glioblastoma,IDH
wild-type & >95% oligodendroglioma,IDH-
mutant
Molecular marker of glioblastoma wild-4
+7/-10 cytogenetic
signature
Gain of ch7 combined with loss of ch10 Molecular marker of glioblastoma, IDH wild
type, WHO grade 4 (
BRAFv600E mutation Oncogenic driver mutation leading to
MAPK pathway activation
Rare in adult diffuse gliomas but amenable to
pharmacological intervention

11. IDH1/2 mutation 1p/19q co-deletion MGMT promoter
methylation
Diagnostic Role DD glioma versus gliosis
Typical for transformed low-grade glioma
Pathognomonic for oligodendroglioma None
Prpgnostic Role Protracted natural history in IDH-mutated
tumours
Protracted natural history in 1p/19q
codeleted tumours
Prognostic for anaplastic glioma patients
(possibly with IDH mutations) treated with
RT or alkylating drugs
Predictive Role Absence of mutation suggests predictive role
for MGMT promoter methylation
Prolongation of survival with early
chemotherapy in 1p/19q-co-deleted
oligodendrogliomas
Predictive in GBM for benefit from
alkylating chemotherapy.Elderly GBM:
MGMT-methylated→TMZ; MGMT
unmethylated→ RT
Frequency:WHO-II
Diffuse Astrocytoma 70-80% 15% 40-50%
Oligodendroglioma 70-80% 30-60% 60-80%
Who G-III
Anaplastic
Astrocytoma
50-70% 15% WHO G-II
Anaplastic
Oligodendroglioma
50-80% 50-80% 70%
Who G-IV
Glioblastoma 5-10% <5% 35%
CLINICAL RELEVANT MOLECULAR MARKERS

12. Location & Spread Of Glioma
• Approximately 60% of gliomas are located in one of the cerebral hemispheres
 Frontal lobe(25.6%)>temporal lobe (19.6%)> parietal lobe (12.6%)
Glioblastoma multiforme is uncommon in the region of third ventricle(<1%) and rarely occurs
in posterior fossa
Although most of the Glioblastoma are centered in the deep white matter
Epicenter at the gray-white matter junction-10%
• Malignant gliomas tends to spread or recur in adjacent brain region along white matter tracts
• Spread outside the central nervous system is extremely rare
• Rarely , gliomas may spread systemically

13. History and Clinical Examination
• Clinical presentation: new onset epilepsy, focal deficits, including neurocognitive impairment,
and indicators of intracranial mass effect, such as headache, vomiting, and altered consciousness.
• History: duration of neurological symptoms and signs, familial risk or exogenous risk factors,
including exposure to radiation
• Physical examination: focuses on the detection of systemic cancer and contraindications for
neurosurgical procedures. Neurocognitive assessment, performance status should be documented.
▪ MMSE is widely used as a screening instrument to detect neurocognitive impairment

14. Imaging Of Brain
▪ MRI – gold standard
T2-weighted and fluid-attenuated inversion recovery sequences, and T1-weighted sequences before and after
gadolinium use, in at least one plane, is the standard method for the detection of a glioma
▪ MR Spectroscopy: differentiating tumor from radiation necrosis, grading tumors, assessing response; area
most abnormal → biopsy
▪ MR Perfusion: differentiating grade of tumor or tumor versus radiation necrosis; area of highest perfusion
→ biopsy
▪ CT: patients who cannot have MRI, shows calcification
▪ Amino acid PET helps define metabolic hotspots for biopsy
▪ Intra-arterial angiography can aid the surgical strategy

15. Diagnostic Characteristics
Tumor Imaging Characteristics
Glioblastoma
Multiforme
• Enhancing MRI or CT lesion, hypodense interior, often with associated
edema & necrosis
• Angiography: highly abnormal vasculature with arteriovenous shunting and
early venous drainage.
Anaplastic
Astrocytoma
• CT- inhomogeneous density
• T2-weighted FLAIR MRI - hyperintense, space-occupying lesions, patchy
enhancement after contrast administration and often have peritumoral
edema.
• Up to 30% can show no enhancement on CT or MRI.
• Abnormal vessels can be visualised by MRI angiography
Oligodendroglioma • Heterogeneous lesion that may or may not enhance on MRI or CT,
frequently
with calcification, cystic regions, or hemorrhage

16. 58-year-old with a glioblastoma who presented with gait disturbance
ADC
FLAIR T1C DWI

17. MRSPECTROSCOPY
Increase in choline & decrease NAA level in glioma Lactate level indicate necrosis but non specific

18. ANAPLASTIC
ASTROCTOMA
OLIGODENDROGLIOM
A

19. TREATMENT
• Surgery
• Radiotherapy
• Chemotherapy and Targeted Therapy
• Symptomatic management
Standard of care
Maximal surgical resection
+
Postoperative radiotherapy
and
Chemotherapy

20. Surgical Management
• Histological diagnosis for all patients - biopsy or decompression surgery unless there is a
specific contraindication
• Use of neuronavigation systems, Laser Interstitial Thermal Therapy, use of fluorescent
tumor localizing dyes such as 5-aminolevulinec acid
Type of resection Extent of resection
Biopsy <10%
Partial 10-50%
Subtotal 50-90%
Near-total >90%-94%
Gros -total >95%

21. ▪ Microsurgical resection of a right-sided recurrent IDHwt glioblastoma WHO grad IV using intraoperative
neuronavigation, neuromonitoring and 5-ALA fluorescence techniques.
▪ A: T1CE axial, sagittal and coronal planes including DTI fiber tracking (blue fibers). The green trajectories /
red points represent the pointer for intraoperative neuronavigation.
▪ B: Upper image: corresponding intraoperative 5-ALA fluorescence image taken from the area as depicted
by neuronavigation. Lower image: opening of the right ventricle due to critical involvement by tumor
formation.
▪ C: Postoperative MRI confirms gross total resection without residual contrast enhancement, no
perilesional ischemia (diffusion-weighted image upper right).

22. Influence of location and extent of surgical resection on survival of patients with
glioblastoma multiforme: results of three consecutive Radiation Therapy
Oncology Group (RTOG) clinical trials. Simpson et al , IJROBP 1993
o Significant correlation of age, Karnofsky Performance Status, extent of surgery, and primary site with survival.
There was no statistical difference in survival based on tumor size.
o The best survival rates occurred in patients who had at least three of the following features:
• < 40 years of age
• high Karnofsky Performance Status(80-100)
• frontal tumors, and
• total resection (17 months median)
Procedure Median survival
Total resection 11.3 months
Partial resection 10.4 months
biopsy 6.6 months

23. Goals of surgery: maximal safe resection
Diagnosis Alleviate symptoms
Decrease need for steroids Increase survival
• Early postoperative MRI (within 48 hours) -
confirms the degree of resection and can help with
radiotherapy planning ( to assess for the revision
surgery)
• Patients should be re-discussed at the specialist MDT
with histology and general performance status
details available.
• Patients should be staged using the WHO system.
• Adjuvant treatment should be commenced within 2
weeks of biopsy or 4 weeks of decompression
surgery.

24. MEDICAL MANAGEMENT
• ANTIEPILEPTIC DRUGS
Non Enzyme inducing anti seizure medications should be used eg: levetiracetam, topiramate,
valproic acid, lacosamide
Close monitoring for side effects
No role for primary perioperative prophylaxis (i.e. in patients who have never had a seizure)
Important to know about prior history of seizure

25. • STEROIDS
Corticosteroids, preferably dexamethasone (in conjunction with gastric protection if used at high doses) -
reduce symptomatic peritumoral vasogenic edema, neurological deficits and signs of increased
intracranial pressure
Lowest dose of steroids – shortest time possible
Downward titration of dose – whenever possible
Extensive mass effect – receive steroids for at least 24 hours before RT
Chronic corticosteroids (≥ 20 mg prednisone equivalents daily for ≥ 1 month) - consider prophylaxis for
osteoporosis and pneumocystis jerovecii pneumonia should be considered

26. RPA Score Based Prognosis
Class Patient Characterstics Median Survival
(Months)
I, II Astrocytoma
Age ≤50 yr, normal mental status or
age >50 yr
• KPS >70, symptoms >3 mo
40-60
III, IV Astrocytoma
• Age ≤50 yr, abnormal mental status
• Age >50 yr, symptoms <3 mo
Glioblastoma
• Age <50 yr
• Age >50 yr, KPS ≥70
11-18
V, VI Glioblastoma
• Age >50 yr, KPS <70 or abnormal
mental status
5-9

27. • Evaluated protein biomarkers + clinical variable (age, KPS,
extent of resection, neurologic function)
• Ki-67, c-Met and MGMT found to be significant biomarkers
Class Median OS (months)
I 21
II 16.6
III 9.4

28. High Grade Glioma
Adjuvant treatment Preferred Regime Other Recommended
Regime
Oligodendroglioma (3)
(KPS > 70)
• RT with adjuvant PCV
• RT with neoadjuvant PCV
• RT with adjuvant and
concurrent TMZ
• RT with adjuvant TMZ
Astrocytoma (3,4)
(KPS > 70)
• RT with adjuvant and
concurrent TMZ
• RT followed by adjuvant
TMZ
• RT with adjuvant PCV
• RT with neoadjuvant PCV
High Grade glioma (KPS < 70) Single modality:
• RT (hypofractionation
preferred) or
• TMZ (if tumor is MGMT
promoter methylated)
EANO GUIDELINES

29. Glioblastoma
Preferred Regime Other Recommended
Regime
Useful In Certain
Circumstances
Adjuvant
treatment
RT with concurrent and
adjuvant TMZ + TTF
• RT with concurrent and
adjuvant TMZ ( age < 70y and
KPS <60)
• TMZ (if tumor is MGMT
promoter methylated and KPS
<60 or age >70 and KPS > 60)
• RT with conc and adj lomustine
and TMZ (if tumor is MGMT
promoter methylated, KPS >
60, and age < 70y)

30. Survival Curves Of Patients Who Received: Median Survival
A) Best conventional care but no radiotherapy
or chemotherapy
14 weeks
B) BCNU 18.5 weeks
C) Radiotherapy 36 weeks
D) BCNU and radiotherapy 34.5 weeks
Walker et al 1978

31. • Radiotherapy significant influence on the
survival of patients
• The specific relationship between 50 & 60Gy
indicates a 1.3 times increase in median life
span associated with the higher dose (p =
.004)
RT Dose Median survival
No 18 weeks
45Gy 13.5 weeks
50Gy 28 weeks
55Gy 36 weeks
60Gy 42 weeks
1979

32. • 1.Age 18 - 70 y
• 2.Randomized 1:1
• Partial brain RT 60 Gy
• Partial brain RT 60 Gy / TMZ → TMZ
• 3.Improved Median survival
• 12.1 → 14.6 months
• P < 0.001
• 4.Improved 5 yr Survival
• 1.9% → 9.8%
• 5.More Grade 3-4 haematological toxicity
with TMZ i.e 7% only
2005

33. MGMT methylation status- EORTC PHASE III
• Regardless of treatment, MGMT methylation was a favorable
prognostic factor (p<0.0001)
• MGMT methylation strongest predictor outcome: 23 mo vs 13
mo
• MGMT methylated cases
• MS was 21.7 vs 15.3 mo for chemoRT vs RT alone
• MGMT un-methylated cases:
• Difference in overall survival favoring the temozolomide-plus-
radiotherapy group was only marginally significant (p=0.06 )
• MS was 12.7 vs 11.8 mo for chemoRT vs RT alone
2009

34. 2019
• GBM with methylated MGMT
• 60Gy + con & adj TMZ Vs 60Gy + TMZ+Lomustine
• Median OS 31mo Vs 48 mo (p=0.0492)
• Median PFS 16.7mo, not different

35. • Arm 1 XRT with TMZ & Bevacizumab Vs Arm 2 XRT with placebo & TMZ
• Addition of BEVACIZUMAB significantly prolonged PFS survival (p<0.001)
• Median PFS 10.6 months vs 6.2 months
• However, the median OS was not significantly different in both arms
• Rates of adverse events was higher with bevacizumab than placebo
2014

36. TUMOR TREATING FIELDS
• the placement of noninvasive transducer arrays on the scalp and the delivery of low intensity (1 to 3 V/cm),
intermediate frequency (100 to 300 kHz), alternating electric fields to the tumor.
• Lead to tumor cell kill during
• 1. metaphase - disrupting the formation of the mitotic spindle, and
• 2. cytokinesis - dielectrophoretic dislocation of intracellular constituents resulting in
apoptosis.
• Most effective - applied in the direction of the division axis of the dividing cell, and therefore, two sequential
field directions are applied to tumors by using two perpendicular pairs of transducer arrays in order to increase
the efficacy of TTFields.

37. TUMOR TREATING FIELDS
o 1. KPS > 70; median age 56
o 2. Randomized 2:1 after 60Gy, TMZ
Adj TMZ + TTF
Adjuvant TMZ
o 3. Improved median survival from time
of randomization
16→20.9 mth P<0.001
o 4. Toxicity – dermatitis in 52%
o 5. Improved OS: >18 hours/day

38. ELDERLY GLIOBLASTOMA
NCIC (Roa JCO
2004)
• Age>60, KPS >50
• 60Gy/30# vs 40
Gy/15#
• No diff in MS:
5.1 vs 5.6 mth
Nordic Trial (Malmstrom
Lancet 2012)
• Age > 60y, GBM
• 34Gy/10# was not
inferior to 60Gy/30#
• Methylated MGMT
associated with better
survival for TMZ for
age > 70y
NOA-08 (Wick, lancet, 2012)
• Age >65y, KPS > 60, AA,
GBM
• TMZ(100mg/m2days 1-7 of
1 week on, 1 week off
cycles) VS 60 Gy/30# RT
• 8.6 vs 9.6 month median
survival
• MGMT Unmethylated – EFS
longer with RT
• MGMT methylated – EFS
longer with TMZ

39. CCTG/EORTC/TROG (Perry
NEJM 2017)
• Age > 65 y, ECOG PS 0-2
• 40 Gy/15# RT/TMZ → TMZ
better than 40 Gy/15# RT alone
• 9.3 vs 7.6 months median survival
• MGMT Unmethylated – 10 mth vs
7.9 mth
• PFS – 5.3 mth vs3.9 mth
• 1 yr survival rate 37.8% vs 22.2%.
• Arm 1 (25Gy/5#/5days) Vs Arm 2
(40Gy/15#/3.3weeks)
• Median OS (7.9 mo) Vs (6.4 mo)
• PFS- 4.2 mo Vs 4.2 mo
2015

40. Treatment Scheme For Elderly HGG

41. • RT with conc Temozolamide vs RT alone
• OS was 146 days vs 121 days (p=0.146)
• PFS was 109.5 days vs 77 days (p=0.028)
• Dose- 25GY/5#/5days

42. Minimizing the uncertainties regarding the effects of delaying radiotherapy for
Glioblastoma: A systematic review and meta-analysis Loureiro et al Radiother Oncol 2016
No evidence of a true effect on OS by delaying RT in GBM patients ( range 20-86 days)
Postoperative neoadjuvant temozolomide before radiotherapy versus standard
radiotherapy in patients 60 years or younger with anaplastic astrocytoma or
glioblastoma: a randomized trial
Malmstorm et al ActaOncologia 2017
GBM or AA, age < 60 y,
PS 0-2
2-3 cycles TMZ → RT RT only
Median
OS
GBM + AA 17.7 months 20.3 months
AA 95.1 months 35.2 months

43. Astrocytoma Grade 3-4
• Anaplastic astrocytomas, IDH-mutant, are the most common WHO grade III astrocytomas.
• Standard treatment includes maximal safe removal followed by radiotherapy and chemo
• RT with concurrent TMZ ~ RT with concurrent nitrosureas
• Slightly better PFS with TMZ

44. Grade-III GLIOMA (noncodeleted): Interim CATNON
1:1:1: randomization
• RT(59.4Gy)
• RT with concTMZ
• RT TMZ
• RT/TMZ 12 TMZ
Adjuvant TMZ improved OS
• OS- (116mo) (21mo)
IDH mutant but not in IDH wild
• Benefit from adj TMZ OS(82.3 mo) Vs
(47mo)
• No OS benefit conc TMZ
• Hematological toxicity- 8-12% but reversible

45. Oligodendroglioma Grade 3
• Relatively rare
• 1p19q codeleted and IDH1-mut or IDH2-mut
• Better prognosis than other high grade gliomas
• PCV added to RT
• CODEL trial ongoing: RT (59.4 Gy) + adj PCV vs RT + conc TMZ + adj TMZ ( result
pending)

46. 59.4 Gy/33# of RT 59.4 Gy/33# of RT → six cycles of adjuvant PCV
Median OS 30.6 months 42.3 months
Median PFS 13.21 months 24.3 months
Improved OS in pts with MGMT methylation and IDH mutations.
Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402
Cairncross et al JCO 2013
59.4 Gy/33# of RT PCV(4cycles) → RT
Median Survival 4.7 years 4.6 years
OS - 1p/19q codeleted AO/AOA 7.3 years 14.7 yrs
PFS - 1p/19q codeleted AO/AOA 2.9 y 8.4 y
OS - 1p/19q non codeleted AO/AOA 3.3 y 5.5 y
PFS - 1p/19q non codeleted AO/AOA 1 y 1.2 y
Long-term follow-up results of EORTC 26951: A randomized phase III study on adjuvant PCV chemotherapy in
anaplastic oligodendroglial tumors (AOD).
Van Den Bent et al JCO 2012

47. Temozolomide
• oral DNA alkylating agent
• good blood–brain barrier penetration
• favourable safety profile - myelosuppression,
notably thrombocytopenia dose-limiting toxicity
Nitrosoureas
• second choice after temozolomide for
glioma treatment
• higher efficacy of procarbazine, lomustine,
and vincristine over temozolomide in
patients with anaplastic glioma with a good
prognosis.
• Side effects: prolonged leukopenia and
thrombocytopenia
• Pulmonary fibrosis with carmustine
• Higher rates of discontinuation due to
toxicity
• Temzolamide is an alkylating agent &
result in DNA damage with displacing
alkyl group in different DNA positions
• MGMT plays an important role in DNA
repair enzymes by synthesizing repair
proteins
• MGMT promoter methylation results in
reduced expression of this gene &
increase response to alkylating agents

48. • In patients with GBM, OS & prognosis remains
dismal
• Use concurrent & adjuvant TMZ to
maximize the benefit of post-op
radiotherapy
• Patient with poor KPS score , considered for
hypofractionated RT, have similar median
survival rates as conventional RT
2013

49. RTOG 0525: A randomized phase III trial comparing standard adjuvant temozolomide
(TMZ) with a dose-dense (dd) schedule in newly diagnosed glioblastoma (GBM). Gilbert et al,
JCO, 2006
• Arm 1: standard TMZ (150-200 mg/m2 body surface area days 1 to 5 of 28)
• Arm 2: intensified regimen (75-100 mg/m2 body surface area days 1 to 21 of 28) for 6-12 cycles.
• Conclusion:
o Validated MGMT-promoter methylation as a favorable prognostic factor regardless of treatment.
o MGMT methylation was associated with improved OS (21.2 v 14 months), PFS (8.7 v 5.7
months)
o Dose-dense temozolomide was more toxic than standard dosing and did not significantly alter
PFS or OS regardless of MGMT status.

50. Is more better? The impact of extended adjuvant temozolomide in
newly diagnosed glioblastoma: a secondary analysis of EORTC and
NRG Oncology/RTOG
Blumentha et al, NeuroOncol, 2017
Conclusion:
• Treatment with more than 6 cycles of TMZ was associated with a somewhat improved PFS
in particular for patients with methylated MGMT
• OS was not affected by the number of TMZ cycles including the MGMT methylated
subgroup(p=0.52)
• Treatment with 6 cycles of TMZ was associated with improved PFS (p=0.03)
• Better in MGMT methylated patients
• Overall survival was not impacted by the number of TEMOZOLAMIDE

51. • C-TMZ Vs E-
TMZ(15.4mo Vs
23.8mo) p=0.044
• PFS (12.8mo
Vs16.8mo)
• 5% Vs 15%
2017

52. Radiotherapy Techniques
Stereotactic
Radiosurgery
Conventional
2D
3DCRT
Brachytherapy
Proton Beam
Therapy

53. Conventional 2D Approach- Whole Brain RT
• Position- supine
• Ask to patient to stare up straight to the roof
• Draw a line along the pupillary line on the
forehead
• Draw a line joining the lobule of the ear & the
lateral canthus of the eye & extend it to the
former line
• Rest of the two borders are flashed 1cm in air

54. Fluoroscopic simulation
▪ Left and right parallel oppose lateral field
▪ Anterior temporal lobe ,cribriform plate, posterior aspects
of eyes included
▪ Inferior field edge passing through C1-C2 junction &
base of skull
▪ Safety margin of at least 1cm ( flashed in air)
▪ Placing a radiopaque marker on both lateral canthus

55. Limitation Of Conventional Planning
▪ Irradiation of large volumes of brain with normal tissue also
▪ Higher toxicity and side effects
▪ Lack of 3D visualization of tumor
▪ 2D planning of 3D tumor
Radiotherapy for newly diagnosed malignant glioma in adults: a systematic review
The Cancer Care Ontario Practice Guidelines Initiative Neuro-Oncology Disease Site Group1
Laparriere et al, 2001
No significant difference in survival rates for whole brain radiation versus more local fields that
encompass the enhancing primary plus a 2 cm margin

56. • 80-90% of recurrence is local ( within 2cm of enhancing tumor on CT)
• Radionecrosis- 50% of patients treated with WBRT had grade3-4 white matter changes as
compared with 14% of patients treated only to local field
• 3DCRT makes partial brain irradiation for glioma possible & reduces neurotoxicity
• It may be recommended for multifocal disease , but it is rare and failure occur typically within
original disease

57. SIMULATION – CONFORMAL RT
▪ CT simulation supine with the head in a neutral
position
▪ Head immobilised in an individual Perspex or
thermoplastic shell
▪ Slice thickness: 2.5-3mm
▪ Postop MR fusion for better tumor delineation
▪ RT should start within 4-6 weeks of surgery

58. • Mean GTV increased by 46%
between early CECT and MRI,
the difference was only 4%
between delayed CT & MRI
• Delayed CECT is superior to
early CECT with MRI for target
delineation
EARLY CT DELAYED CT
POST OP MRI

59. Contouring
guidelines
MDACC
RTOG
EORTC
NRG

60. ORGAN AT RISK
▪ LENS
▪ B/L OPTIC NERVE
▪ B/L EYE
▪ OPTIC CHIASM
▪ BRAINSTEM
▪ B/L TEMPORAL LOBE
▪ SPINAL CORD

61. EORTC treatment volumes
(EORTC 22981/22961,
RTOG treatment volumes (RTOG 0525, 0825, 0913, and AVAglio
trials)
Phase 1 (to 60 Gy in 30 fractions) Phase 1 (to 46 Gy in 23 fractions) Phase 2 (14 Gy boost in 7 fractions)
GTV surgical resection cavity
plus any residual
enhancing
tumour (postcontrast T1
weighted MRI scans)
GTV1 surgical resection cavity plus any residual
enhancing tumour (postcontrast T1
weighted MRI scans) plus surrounding
oedema (hyperintensity on T2 or FLAIR
MRI scans)
GTV
2
surgical resection cavity
plus any residual
enhancing tumour
(postcontrast T1 weighted
MRI
scans)
CTV GTV plus a margin of 2
cm*
CTV1 GTV1 plus a margin of 2 cm (if no
surrounding oedema is present, the CTV is
the contrast enhancing tumour plus 2.5
cm.
CTV
2
GTV2 plus a margin of 2
cm
PTV CTV plus a margin of 3–
5 mm
PTV1 CTV1 plus a margin of 3–5 mm PTV2 CTV2 plus a margin of 3–
5 mm
TARGET DELINEATION OF GLIOBLASTOMA
*Margins up to 3 cm were allowed in 22981/22961 trial, and 1.5 cm in 26981–22981 trial.

62. RTOG EORTC

63. MDACC GUIDELINES
• INITIAL PHASE (50 Gy):
GTV = Resection cavity and any residual
contrast-enhancing tumor(T1) but ignoring any
edema
CTV = GTV + 2 cm isotropic margin
Peritumoral edema was not intentionally
included in the CTV except for edema existing
within the 2-cm margin
PTV = CTV + 0.5 cm margin
• BOOST PHASE (10 Gy): PTV = GTV + 0.5cm
margin

64. NRG – Contouring Guidelines
• Careful delineation
of anatomic
pathways and
barriers to spread
can spare radiation
to uninvolved tissue
without
compromising target
coverage

65. GTV & GTV BOOST CTV & CTV BOOST PTV & PTV BOOST
GTV- RED & GTV BOOST- PINK CTV- RED & CTV BOOST- PINK PTV- RED & PTV BOOST- PINK
PGI PROTOCOL

66. Dose constraint of conventional 3D-CRT
OAR OBJECTIVE(S) End point
Brainstem Dmax<54 Gy; 1–10 cc < 59 Gy (periphery) Neuropathy (<5%) or necrosis
Optic Chiasm Dmax <55 Gy Optic neuropathy (<3%)
Cochlea Ideally one side mean <45 Gy ( Most protocols allow ipsilateral cochlea to
receive 60 Gy rather than compromise dose )
Sensorineural hearing loss
(<30%)
Eyes Macula <45 Gy Retinopathy
Lens Ideally <6 Gy Max 10 Gy
dose limits should never compromise PTV dose
Cataract
Optic nerves and
chiasma
Dmax <55 Gy or 1 % of PTV cannot exceed 60 Gy Optic neuropathy (<3%)
Brain Dmax <60Gy Symptomatic necrosis
(<3%)
Hippocampus Dmax ≤6 Gy & V3Gy ≤ 20% Cognitive impairment
Spinal cord Dmax <50Gy Grade >2 myelopathy (<1%)

67. • No significant difference in the mean PTV(initial) among the groups (p = .24), whereas a
significant reduction in mean PTV boost was observed with the MDACC protocol compared
with the RTOG protocol
• No statistically significant differences were observed in treatment-related acute toxicities and
steroid requirements between both arms
• Central recurrences: commonest in both groups
• Statistically significant differences in QoL favoring those treated with MDACC protocol

68. RTOG VS EORTC
• Perfusion- and diffusion weighted MRI potentially add information about the regional blood
volume and microstructural architecture of the high-grade glioma.
• No difference in progression-free or overall survival was observed
• Larger PTVs failed to produce a significant reduction in marginal or distant recurrences

69. 3DCRT VS IMRT/VMAT
• Sparing of normal brain
• Local boosting of tumor alone to higher doses
• IMRT especially useful in presence of critical structures close to- optic nerve, brainstem, dose
escalation , etc
• IMRT did not significantly improve target coverage compared with 3D-CRT
• However, it resulted in a decreased Dmax to the spinal cord, optic nerves, and eye by 16%, 7%,
and 15%
• It is unlikely that IMRT will improve local recurrence without dose escalation However, it might
result in decreased late toxicities associated with radiotherapy
• VMAT achieved equal or better PTV coverage and OAR sparing while using fewer monitor units

70. • A-68Ga-Pentixafor fused PET increased uptake in LT
F-T region with GBM
• B- IHC evidence of CXCR-4 expression on the tumor
• The affinity of this tracer help in developing
CXCR4 targeting radiotherapeutics
• A- 38 yr male pt with GBM radiological
evidence of residual disease
• B- Repeat scan post 3month (post-op) showed
disease progression

71. • GBM patients 60Gy/30# Vs 67Gy/30# ( boost 21Gy/7#)
• Slightly higher median OS as compared to historical data that dose escalation is feasible
First image- PENTIXAFOR PET show active disease Third image- Phase 1 dose color wash
Second image- Target volume delineation Fourth image- dose color wash including SIB

72. • Pt diagnosed with grade (1-4) glioma
• Proton vs Photon therapy
• PBT associated with improved OS (45.9mo vs
29.7 mo ) to XRT
• Retrospective analysis supports ongoing
prospective trials comparing the two modalities
2018

75. EXPECTED SURVIVAL OF GLIOMA
Nat Rev Neurol. Author manuscript; available in PMC 2020 June 10
HIGH GRADE GLIOMA MEDIAN SURVIVAL
Oligodendroglioma - IDH mutant ( 1p/19q codeletion) 17.5 years
Oligodendroglioma - IDH mutant ( no 1p/19q codeletion) 6.3 years
Oligodendroglioma – IDH wild 1.6 years
Astrocytoma - IDH mutant 9.3 years
Astrocytoma - IDH wild 1.9 years
Glioblastoma - IDH mutant 3.6 years
Glioblastoma - IDH wild 1.2 years
Glioblastoma MGMT methylated 21.2 mo
Glioblastoma MGMT unmethylated 14 mo

76. PSEUDOPROGRESSION
• Radiochemotherapy and immunotherapy - transient worsening of contrast enhancement on MRI for
several months in approximately 10-30% of patients, sometimes associated with symptoms of intracranial
mass-effect
• Diagnosis - challenging
 Dynamic susceptibility contrast–enhanced MRI: neoangiogenesis → accompanies neoplastic growth;
treatment-related changes increase vascular permeability without neoangiogenesis.
 Amino-acid PET imaging may be helpful: brain tumours - increased protein synthesis; amino acid
tracers →imaging modality.

77. A 31-year-old male patient with prior
resection of a right frontal
glioblastoma multiforme presented
later with a 1-cm enhancing nodule
concerning for recurrence compared
with pseudoprogression
A. Magnetic resonance image of the
new nodule.
B. Map of relative cerebral blood
volume demonstrates increased
flow in the nodule (arrow).
C. Spectroscopic imaging
demonstrates an elevated choline
peak compared with
D. Normal contralateral brain
parenchyma in the same patient

78. DSC perfusion in pseudoprogression & progressive disease
A. T1C & rCBV map show enhancing lesion in surgical bed after RT in a patient of GBM , white arrow
show rCBV 0.5 in comparison with c/l lobe indicating (Pseudoprogression)
B. T1C & rCBV map show enhancing lesion close to the margin of radiation field. White circle show rCBV
2.8 in comparison with c/l lobe indicating predominance malignant cells ( Progressive disease)

79. 56 year old male – GBM – Pseudoprogression
A. T1 contrast MRI 1 week after an operation show ring enhancement
B. After RT, marked enhancement in the margins following which he developed rt sided hemiparesis
C. At that time T1 MRI showed ^se in mass effect , midline shift which turned to soap bubble
appearance- radiation necrosis
D. Pt improved clinically & after 4months, fading of the enhancing lesion & decrease in mass effect

80. RANO Criteria
▪ 12 weeks post-RT : progression can only be determined if the majority of the new enhancement is
outside 80% Isodose line or with pathologic confirmation
RANO criteria CR PR SD PD
T1 enhancing disease None >50% decrease <50% if but < 25%
if
> 25%
T2/FLAIR Stable/decreased Stable/decreased Stable/decreased increase
NEW LESION None None None Present
CORTICOSTEROID
USE
None Stable or Stable or NA
CLINICAL STATUS Stable/improved Stable/improved Stable/improved Declined

81. Management of Recurrence
• Surgical excision
• Chemotherapy- Temozolamide/Carmustine/Lomustine
• Bevacizumab-FDA approved
• Alternating Electrical field therapy
• Re-irradiation
• Locally delivered Carmustine (Gliadel) Wafers
Implanted into surgical cavity – modest survival advantage with newly diagnosed ¾
Gliomas, or recuurent glioblastoma
Patients without systemic treatment options
Requires careful patient selection & a gross total resection
Studies in GBM have shown only marginal benefit

82. REIRRADIATION
▪ Young patient
▪ Good KPS score
▪ Long interval since previous RT > 6months
▪ Previous dose should be know
▪ Tumor size and location should be taken into
account when deciding whether re-irradiation
would be safe

83. • ReRT(35GY/10#) and conc bevacizumab Vs bevacizumab(10mg/kg) alone
• First prospective randomized multi-institutional study
• Median PFS 7.1 Vs 3.8 months (p=0.05)
• Median OS was similar
• Overall, ReRT was shown to be safe and well tolerated

84. • Re-irradiation of brain tumors – increasingly
considered because of developments in
radiation technology & imaging make high
accurate targeting of recurrent tumors
▪ Further, exploration of the role of re-irradiation
on its own or in combination with novel agents
is needed
Systematic review 2016

85. Stereotactic Radiosurgery
• SRS: delivered using a conventional or modified LINAC, a Gamma Knife (Elekta Corp., Stockholm,
Sweden) or a robotically controlled miniaturized linear accelerator (CyberKnife).
• Radiosurgery appears to be a reasonable option for small well-circumscribed high-grade gliomas that
recur after prior conventional large-field radiotherapy and chemotherapy
• For lesions larger than 4 cm and/or located in critical regions - Fractionated Stereotactic
Radiotherapy
• KEY REQUIREMENTS FOR OPTIMAL STEREOTACTIC IRRADIATION:
i. Small target/treatment volume
ii Sharply defined target
▪ Accurate radiation delivery
▪ High conformality
▪ Sensitive structures excluded from target
Properties

86. Brachytherapy & Radiocolloid Solutions
• Selection criteria for brachytherapy:
i. small size (<5 to 6 cm),
ii. tumor confined to one hemisphere,
iii. no transcallosal or subependymal spread,
iv. well circumscribed on CT or MRI, and
v. accessible location for the implant.
• A balloon based system, GliaSite, placed into the cavity at the time of surgery - recurrent malignant gliomas
whose largest spatial dimension is <4 cm and are roughly spherical.
• After treatment planning, the balloon is filled with a liquid that contains organically bound I125 and treatment is
completed within 3 to 7 days.
• 3D Ir192 HDR BT (Ir Knife) allows intratarget dose escalation with superior conformity.
• Stereotactic 125I brachytherapy with TMZ chemotherapy was shown to be effective for treatment of
thalamic glioblastoma

87. Targeted Therapies For Recurrent Glioblastoma
EORTC 26101 phase III trial exploring the combination of bevacizumab and
lomustine in patients with first progression of a glioblastoma
• Lomustine (90mg/m2) every six weeks vs lomustine & bevacizumab(10mg/m2) every two
weeks f/b best investigation
• Median OS 9.1 months vs 8.6 months (p =0.625)
• PFS was longer with addition of bevacizumab 4.2 vs 1.5 months
• Bevacizumab with progressive glioblastoma despite PFS does not confer a survival advantage
• Methlyated group showed a longer median OS 13.5 mo vs unmethylated group was 8 mo

88. Vaccine & immune checkpoint inhibtors for glioblastoma
• DCVax- a dendritic cell (DC)-based personalized cancer vaccinewith purified tumor-specific antigens
or tumor cell extracts derived from tumor at the time of resection.
• Epidermal Growth Factor Receptor Variant III as a Vaccine Target for Glioblastoma
• Heat Shock Protein-Based Vaccine
• Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO) targets the neurotropic
poliovirus receptor CD155, which is abundantly expressed on glioblastoma cells.
• Phase-III trial of NIVOLUMAB vs BEVACIZUMAB failed to show any survival difference between
the two arms

89. CONCLUSION
• Molecular markers are well established in adult and pediatric type gliomas
• IDH1 mutation is a strongest prognostic marker
• There is no definite treatment guidelines for the pediatric type high grade glioma til
• Despite of molecular markers, standard of treatment remains same
• PCV regimen is more sensitive for oligodendroglial tumor as compared to TMZ
• Role of bevacizumab is established in reccurent glioblastoma

90. THANK YOU