Evidence based management in High grade gliomas - Seminar Dr Yamini Baviskar

1. EVIDENCE
BASED
MANAGEMENT
OF HIGH
GRADE
GLIOMAS
YAMINI BAVISKAR
SHUBHI AGRAWAL

2. FLOW OF SEMINAR
INTRODUCTION & EPIDEMIOLOGY
WHO CLASSIFICATION
DIAGNOSTIC APPROACH
MANAGEMENT STRATEGIES
PROGNOSTIC FACTORS
SPECIAL CONSIDERATIONS

3. WHAT IS A HIGH GRADE
GLIOMA?
Malignant glioma corresponds to anaplastic glioma (WHO grade III)
and GBM (WHO grade IV)
ANAPLASTIC
ASTROCYTOMA
(WHO GR III)
IDH
MUTANT
IDH
WILDTYPE
ANAPLASTIC
OLIGODENDROGLIOMA
(WHO GR III)
GLIOBLASTOMA
(WHO GR IV)
IDH MUTANT
90%
Primary/ de novo
IDH WILDTYPE
10 %
Secondary
DIFFUSE MIDLINE
GLIOMA H3K27M
MUTANT
ANAPLASTIC
PLEOMORPHIC
XANTHOASTROCYT
OMA – WHO GR III
NOS

4. EPIDEMIOLOGY
– CNS tumors 2-5% of all neoplasms
– Gliomas - most commonly diagnosed primary malignant
intracranial neoplasms in adults (60% GBM)
– Malignant gliomas (grade III or IV) - 20% of all primary brain
tumors (16% GBM)
– Peak age in Western countries - High grade tumours  75-
84 years, Low grade tumours  35-44 years
– In India - median age of glial tumors a decade earlier
– Males affected more frequently
– Risk factors –
• Age
• Exposure to ionising radiation
• Familial genetic disorders
• ??Raw meat/ ??Pesticides
Ostrom Q et al, The Epidemiology of
Glioma in Adults: a “State of the
Science” Review. Neuro-oncology (2014)
Dasgupta et al; South Asian J Cancer. 2016
Brain Mets
(60-72%)
Primary CNS
tumours
(28-40%)
Benign
(63%)
Malignant (37%)
Gliomas (80%)
Glioblastoma
(54%)
Other glial
tumours
Others
(20%)

5. WHO CLASSIFICATION - 2016
– Historically - based on concepts of histogenesis, with different
putative cells of origin and their levels of differentiation.
– Incorporation of genetically defined entities and major restructuring
- 2016
– WHO grade determination made on the basis of histologic criteria.
– Diagnosis  histopathological name followed by genetic features
– Greater diagnostic accuracy, better patient management and more
accurate determination of prognosis and response

6. M
O
R
P
H
O
L
O
G
Y
For GBM , Any
3/4 histological
features suffice
to make the
diagnosis.
Histological
Criteria
Nuclear
atypia alone
N. Atypia +
Mitosis
Nuclear atypia,
Mitotic activity,
Vascular proliferation
Necrosis
AA AO
GBM
GRADING
Adopted from St. Anne-Mayo
grading system, 1988

7. HISTOPATHOLOGY –
1. PHENOTYPE IDENTIFICATION
– ASTRO, ODG, GBM
2. WHO GRADE – III / IV
3. MOLECULAR MARKERS -
– IHC – IHC for mutant IDH1
(R132H), IHC for ATRX, If
midline then IHC for
H3K27M
– FISH for 1p19q codeletion
– DNA sequencing

8. M
O
L
E
C
U
L
A
R
M
A
R
K
E
RS European Association for Neuro-Oncology (EANO)
guideline on the diagnosis and treatment of adult
astrocytic and oligodendroglial gliomas

9. General
(Raised ICP)
• Headache
• Seizures
• Nausea / vomiting
• Blurring of vision
Focal
(related to
tumor
location)
• Aphasia
• Motor weakness
• Sensory loss
• Loss of vision
Presenting
symptoms

10. DIAGNOSTIC APPROACH
1. Detailed history – Onset, duration, course, associated symptoms,
drug history
2. General physical examination + meticulous neurological examination
3. Imaging –
 CECT Brain
 CEMRI with T1, T2 , T2 FLAIR, T1C sequences – phenotype
identification, edema, critical structure compression, hydrocephalus,
surgical planning.
 Diffusion and spectroscopy, tractography should be performed
whenever possible.
 Functional imaging
4. Histopathological confirmation

11. Oligodendroglioma
• 5-10% of all gliomas
• Peak incidence: 30 to 40 years
• Location: cortex or subcortical white matter
• Most commonly found in frontal lobes
• Slow growing
• CT: Hypo to isodense
• MRI: T1: hypointense , T2: hyperintense
– Heterogeneous due to calcification (70-
90%), cystic degeneration and haemorrhage
CT T1+C
T2 FLAIR

12. Astrocytoma
• 30-40% of all gliomas
• Peak incidence: 40 - 50 years
• T1: hypointense compared to white matter
• T2: hyperintense/heterogeneous
• T2-FLAIR: relative hypointensity of most of
the tumor except a hyperintense rim (T2-
FLAIR mismatch sign)
• T1 C+ (Gd) : enhancement +
• MR perfusion: elevated cerebral blood
volume
• MR spectroscopy
– increased choline-to-creatine ratio
– NAA preserved or mildly depressed
– no significant lactate
T1+C
FLAIR

13. Glioblastoma
 50-60% of all glial tumours
 Peak incidence: 65 - 75 years
 CT: irregular hypodense centre representing necrosis, irregular
margins, ring enhancement, surrounding vasogenic oedema,
haemorrhage occasionally
 MRI:
 T1: central heterogeneous signal (necrosis or intratumoural
haemorrhage) ,
 T2: hyperintense
 T1+C: variable enhancement, typically peripheral and irregular
with nodular components
 MR perfusion: rCBV elevated
 MR spectroscopy
 choline: increased
 lactate: increased
 lipids: increased
 NAA: decreased
 myoinositol: decreased
T1+C
T2 FLAIR
T1+C

14. MR Spectroscopy &
Perfusion

15. TREATMENT STRATEGIES
•MAXIMAL SAFE RESECTION
•ADJ RADIOTHERAPY + CONC CT
•ADJUVANT SYSTEMIC THERAPY

16. SURGERY
– Most effective method of rapid reduction of tumour burden, hypoxic cells and
necrotic radio - & chemo - resistant center.
Primary aim of surgery in gliomas
1. perform a maximal safe resection of the tumor
2. to relieve raised intracranial pressure & mass effect
3. to obtain tissue for diagnosis and molecular studies
Issues with surgery –
– Location of disease - Eloquent cortex, basal ganglia, or brain stem are not
amenable to surgical intervention
– Diffuse infiltrative nature of tumor – complete surgical resection impossible

17.  No prospective randomized evidence
 Case series of GBM show surgery alone extends life for a few months
GTR PARTIAL RESECTION BIOPSY ONLY
MEDIAN SURVIVAL 11.3 months 10.4 months 6.6 months
Influence of location and extent of surgical resection on survival of patients with GBM:
Results of 3 consecutive RTOG clinical trials - Simpson, J.R et al, IJROBP, 1993
N = 645
Retrospective review - Lacroix et al
• N = 416 (1993 - 1999)
• Partial resection (<98%) MS – 8.8 months vs total resection(>98%) MS – 13 months
• Five independent predictors of survival - Age, KPS, extent of resection, degree of necrosis
and enhancement on preoperative MR
J Neurosurg. 2001 Aug;95(2):190-8

18. – MDACC , retrospective review of prospectively maintained database - 1993 to 2012
– OS - with 100% removal of contrast enhancing tumor, with or without additional resection of
surrounding FLAIR abnormality region, C/W those undergoing 78% to < 100% EOR of enhancing
mass lesion Resection of 100 % T1C
tumour, N = 876
EOR >/= 78 % but
<100% N = 353
Median survival 15.2 months 9.8 months
Resection of >/= 53.21% of surrounding FLAIR abnormality
beyond the 100% T1C resection VS less extensive resections
Median survival - 20.7 m vs 15.5 months, p < 0.001).
Additional removal of a significant portion of the FLAIR abnormality region, when
safely feasible, may result in the prolongation of survival without significant increases
in overall or neurological postoperative morbidity
JNS , 2016

19. Surgical Techniques

21. RADIOTHERAPY
Case series in GBM

22. – N = 222 Anaplastic glioma (90%
GBM)
– Sept 1969 to Oct 1972
– BCNU +RT and RT alone survived
the longest, combination therapy
had a higher percentage of
survivors at 18 months than RT
alone
ARMS MEDIAN SURVIVAL
BEST CONVENTIONAL CARE 14 WEEKS
BCNU ALONE 18.5 WEEKS
RT ALONE 35 WEEKS
BCNU + RT 34.5 WEEKS
BTCG 69-01 study demonstrated significant (doubled) survival
with adj. RT over supportive care, and resulted in adj. RT
becoming a standard treatment

23. Ph III RCT,
N = 474, Gr III and IV glioma (61% GBM)
No adj chemo
60Gy/30#/6 weeks
2 Gy/#
MS - 12 months
45Gy/20#/4 weeks
2.25 Gy/#
MS - 9 months
p =0.007
1991

24. Autopsies of patients of GBM treated
with 70 – 80 Gy of EBRT revealed
1. Areas of viable tumor in irradiated
field - indicating that tumor
eradication is not achieved with
70 – 80 Gy
2. Marked radiation necrosis in
normal tissue at tumour periphery
of tumor
3. High risk : benefit ratio in
exceeding RT dose beyond 60 Gy.
- Salazar et al

25. How High could be the dose?
DOSEESCALATION
BRACHYTHERAPY
BOOST
SRS BOOST
HYPERFRACTIONATION

26. Randomized study of brachytherapy in the initial management of patients with
malignant astrocytoma - Laperriere et al
Inclusion criteria : Biopsy-proven supratentorial malignant astrocytoma, <6 cm in size, not crossing midline
or involving corpus callosum
1986 - 1996
– MS for patients randomized to brachytherapy or not were 13.8 vs. 13.2 months, respectively, p = 0.49
– Toxicities : Neurologic decline requiring high-dose steroids, intracerebral bleeding, exacerbation of
seizures, infection
Stereotactic radiation implants have not demonstrated a statistically
significant improvement in survival in the initial management of patients
with malignant astrocytoma

27. RTOG 90-06
Phase III RCT
Malignant glioma
N = 712
Both arms received 80 mg/m2 BCNU on days 1–3 q8 weeks for 1 year
HYPERFRACTIONATED
ARM
72 Gy/ 60#/6 weeks
1.2 Gy/# - BID
CONVENTIONAL RT
ARM
60Gy/ 30#/ 6 weeks
2 Gy/# - OD
No significant difference!
Median survival - 11.3 mo vs. 13.1 mo (p=0.20)
Median PFS time of 5.7 mo vs. 6.9 mo (p=0.18)
Overall acute or late treatment-related toxicity same.

28. RTOG 93-05
N = 203
Supratentorial GBM (tumor ≤4 cm)
Dose of radiosurgery was tumor size–dependent and ranged from 15 Gy for largest to 24 Gy for smallest
tumors.
Postoperative SRS
followed by EBRT
(60 Gy) plus BCNU
Postoperative
EBRT with
BCNU alone
At a median follow-up time of 61 months, Median survival in
Radiosurgery group - 13.5 months Vs Standard treatment group – 13.6 months
No significant differences in 2- and 3-year survival rates & in patterns of failure between the two arms.
Quality of life deterioration & cognitive decline at the end of therapy, compared with baseline, were
comparable.
Stereotactic radiosurgery followed by EBRT and BCNU does not improve the
outcome in patients with GBM nor does it change the general quality of life or
cognitive functioning.

29. TARGET VOLUMES
 CT scans & correlative autopsy data: 90% of
relapse within a 2-cm margin
 Toxicity (necrosis & cognitive dysfunction) a/w
escalated doses of WBRT
PBRT – Standard of care
BTCG 80-01 –
 Shapiro et al
 Randomized
 WBRT – 60.2 Gy vs WBRT 43 Gy f/b PBRT 17.2 Gy
 No significant survival differences

30. TECHNIQUE
– Standard radiation technique – CONFORMAL RADIATION
In-field, marginal, or
distant if greater than
80%, 20-80%, or less than
20% of the recurrent
volume fell within the
95% isodose line,
respectively.
Gebhardt et al. Radiation Oncology 2014, 9:130
http://www.ro-journal.com/content/9/1/130

31. 2002
TO SUMMARIZE!

32. CHEMOTHERAPY
– ISSUES –
– Does not adequately penetrate normal or non-enhancing tumor-infiltrated brain,
– Actively effluxed out of the brain parenchyma by p – glycoprotein and other active
transporter substrates
– Resistant to most conventional chemotherapeutic agents.
– Origin : Results of early Phase II trials of the nitrosoureas, which documented
response rates of 10-40% in patients with recurrent glioma in the 1970s with
carmustine (BCNU) - 1,3-bis(2-chloroethyl)-l-nitrosourea
– Crosses blood-brain barrier

33. – 16 RCTs , 3000 patients, compared the survival rates of patients who received RT alone or CTRT
(nitrosoureas)
– 10.1% increase in survival at 1 year for RT plus chemotherapy. This effect is greater in the AA
patients.
– Median survival then was 4 – 6 m in post surgery no adjuvant
treatment.
– Median survival 9.4 m with adjuvant RT alone
– Median survival 12 m with adjuvant radio chemotherapy
1993

34. NCOG 6G61
– RCT
– Anaplastic glioma + GBM
– Adjuvant chemotherapy after 60 Gy of EBRT
– Carmustine (BCNU) vs PCV (combination of Procarbazine,
lomustine (CCNU),and vincristine
– PCV produced longer survival and time to tumor
progression than BCNU
– With PCV, time to progression and survival
doubled for anaplastic glioma patients in the
50th and 25th percentiles other than GBM.
1990

35. TEMOZOLOMIDE & MGMT
Oral alkylating agent
Acts nonspecifically on both cancerous and normal cells alike
Cancer cells divide more rapidly than normal tissue - more sensitive
Prodrug  passes easily through BBB due to small molecular size
 spontaneous intracellular hydrosis into potent MTIC (methyl
triazeno imidazole carboxamide)  MTIC methylates
nucleobases (mostly guanine base)  hampers replication of
DNA
Induces arrest in G2/M phase in GBM cells
Radiation-enhancing effect
– Increases radiation-induced DNA double-strand breaks
– Inhibits radiation-induced invasion via inhibition of integrins
1999

36. – MGMT gene encodes a DNA-repair protein that
removes alkyl groups from the O6 position of
guanine (an important site of DNA alkylation)
– Restoration of the DNA occurs by consuming the
MGMT protein.
– If left unrepaired, chemotherapy-induced
lesions, especially O6 -methylguanine, trigger
cytotoxicity and apoptosis.
– High levels of MGMT activity in cancer cells
create a resistant phenotype by blunting the
therapeutic effect of alkylating agents 
treatment failure.
– Epigenetic silencing of the MGMT gene by
promoter region methylation is associated with
loss of MGMT expression and diminished DNA-
repair activity

37. – RCT
– Primary end point -
OS
– RT + TMZ -
prophylaxis against
Pneumocystis
carinii (inhaled
pentamidine or oral
trimethoprim–
sulfamethoxazole )
RT + TMZ RT alone
Radiotherapy plus continuous daily TMZ
(75 mg /m2 of BSA OD, 7 days/ week
from the first to the last day of
radiotherapy), f/b 6 cycles of Adj.
TMZ(150 to 200 mg/m2 x 5 days during
each 28-day cycle)
Radiotherapy
alone (60 Gy/
30#/ 6 weeks,
Focal RT, 2 Gy/
#, 5 days/week)
Median Survival 14. 5 months 12 months
Two-year survival
rate
26. 5 % 10.4 %
2005

38. Grade 3 or 4 hematologic toxic effects:
• Concomitant RTx + TMZ: 7 %
• RTx alone: 0 %
• Adjuvant TMZ: 14 %
2009
 A benefit of combined therapy was recorded in all clinical
prognostic subgroups, including patients aged 60–70 years.
 Methylation of the MGMT promoter was the strongest predictor for
outcome and benefit from temozolomide chemotherapy
OS AT RT + TMZ (%) RT ALONE (%)
2 YRS 27.2 10.9
3 YRS 16 4.4
4 YRS 12.1 3
5 YRS 9.8 1.9

40. – N = 289 patients
– At progression, 80% of patients randomly assigned to RT had chemotherapy.
– 65% of patients experienced grade 3 or 4 toxicity, 1 patient grade V
JCO, 2006
PCV + RT RT ALONE
PCV plus RT RT ALONE
Median survival 4.9 years 4.7 years
Progression-free survival 2.6 years 1.7 years
Patients with 1p19q codeleted tumors lived
longer than those with noncodeleted tumors.
PCV plus RT: 14.7 vs 2.6 years, p.001
RT: 7.3 vs 2.7 years, p .001
PCV + RT RT ALONE
Median survival
1p19q codeleted
14.7 7.3
Median Survival
1p19q noncodeleted
2.6 2.7
Longer PFS,
no survival
benefit seen
2013

41. 2009
– Median time to treatment failure, PF survival and
overall survival were similar for arms A and B1/B2
– Good prognostic players -
– Hypermethylation of the MGMT promoter region
– Mutations of IDH1 gene
– Oligodendroglial histology

42. – Humanized monoclonal antibody against vascular endothelial growth factor A
– Randomized, double-blind, placebo-controlled trial
– 637 GBM patients treated with Radiotherapy (60 Gy/30#) and daily TMZ.
– Bevacizumab or placebo added from week 4 of radiotherapy and continued for up to 12 cycles of
maintenance chemotherapy
– No significant difference in OS between bevacizumab and placebo group (median, 15.7 vs 16.1 mon.)
First-line use of bevacizumab did not improve OS in patients with newly diagnosed GBM. PFS was
prolonged (10.7 months vs. 7.3 months) but did not reach the pre-specified improvement target.
– Modest increases in rates of hypertension, thromboembolic events, intestinal perforation, and
neutropenia in the bevacizumab group. Over time, an increased symptom burden, a worse quality of life,
and a decline in neurocognitive function were more frequent in the bevacizumab group.

43. RCT , June 2011 - April 2014, N = 141
Standard
temozolomide
chemoradiotherapy
Conc + 6 m Adj.
6 courses of lomustine (100
mg/m2 on day 1) + TMZ
(100-200 mg/m2 per day on
days 2-6 of the 6-week
course)
CCNU + TMZ TMZ ALONE
MEDIAN SURVIVAL 48.1 MONTHS 31.4 MONTHS
ADVERSE EVENTS >/= GR 3 51 % 59%
Lomustine-temozolomide chemotherapy might improve survival compared with temozolomide
standard therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter.
Interpret with caution, owing to the small size of the trial.

44. The sample size was based on the assumption that lomustine-
temozolomide could increase 2-year overall survival from
48·9%18 to 70·0% (overall survival in the UKT-03 trial was
75%)

45. – GBM cells characterised by high motility and invasiveness, requiring complex cell–
matrix interactions.
– Integrins (family of cell–cell and cell– extracellular matrix adhesion molecules),
implicated in various cellular processes (eg, cell survival, proliferation, migration,
invasion, and angiogenesis), and thus support tumour development
– αvβ3 and αvβ5 integrins - key mediators of crosstalk between tumour cells & brain
microenvironment in GBM, overexpressed on tumour cells and vasculature
CELENGITIDE

46. Cilengitide - standard dose of
2000 mg intravenously twice
weekly on days 1 and 4,
beginning 1 week before
starting TMZ – RT
1 h IV infusion starting 4 h
before RT, TMZ given orally
within 2 h after completion of
cilengitide infusion and at
least 1 h before RT.
Continued for up to 18
months or until disease
progression or unacceptable
toxic effects
Median overall survival was 26.3 months in both the groups
No PFS benefit either
Adverse effects – Headache, fatigue
Thromboembolic events
N = 545

47. SOME OTHER ATTEMPTS
NAME OF THE STUDY YEAR DRUG TESTED RESULTS
RTOG 0825
Ph III
Newly diagnosed GBM
2007 Adjuvant TMZ + Bev Vs
Adj. TMZ + Placebo
Better PFS, No OS benefit
AVAglio
Ph III RCT
Newly diagnosed GBM
2014 Bevacizumab + TMZ
Vs Placebo + TMZ
Improved PFS, No OS benefit
Increased adverse events associated
with Bev.
GLARIUS
PH II
Newly diagnosed MGMT unmethylated
2016 Bevacizumab + Irinotecan
Vs Temozolomide
BEV+IRI had superior PFS after 6 m
rate and median PFS compared with
TMZ. However, No OS benefit
EORTC 26082
Phase II
Newly diagnosed MGMT unmethylated
2016 Temsirolimus Vs TMZ Temsirolimus was not superior to
temozolomide
Wick et al
Ph III
Progressive GBM
2017 CCNU + Bevacizumab vs
CCNU alone
Somewhat prolonged progression-
free survival, No survival advantage
over treatment with lomustine alone

48. PROGNOSTICATION
Validation of a novel molecular RPA classification in glioblastoma (GBM-molRPA) treated with chemoradiation: A
multi-institutional collaborative study ,2018

49. SPECIAL CONSIDERATIONS
POOR PROGNOSIS GBM
TUMOUR TREATMENT FIELDS
GLIASITE

50. POOR PROGNOSIS HGG
– Older patients or those with a poor performance status
– Median survival in the range of 6–9 months
We recommend maximum safe resection followed by a short course of focal
radiotherapy as the standard of care in the majority of poor prognosis gliomas. In a
small minority of patients (with life expectancy of less than 3 months) a more
humane approach may be to offer best supportive care only.
Poor-prognosis high-grade gliomas: evolving an
evidence-based standard of care
Tejpal Gupta and Rajiv Sarin

51. – N = 100, GBM patients, age >=60, KPS >=50
– Conv RT (60Gy/30#/6 weeks) vs short course RT
(40Gy/15#/3 weeks)
– MS 5.1 months conventional arm vs 5.6 months in
short course RT arm (p=0.57)
– Significantly fewer patients (23% vs 49%, p=0.02)
required increase in post RT steroid dosage in short
course RT arm
Abbreviated course of RT seems to be a reasonable
option for older patients with GBM

52. N = 562
Median age was 73 years (range, 65 to 90).
MONTHS SCRT + TMZ SCRT ALONE
Median
overall
survival
Overall 9.3 7.6
MGMT methylated 13.5 7.7
MGMT unmethylated 10 7.9
Median PFS 5.3 3.9

53. Patients with confirmed anaplastic astrocytoma or
glioblastoma, age older than 65 years, and a
Karnofsky performance score of 60 or higher
N = 584
Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients
with malignant astrocytoma.
MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and
could aid decision-making.

54. TUMOUR TREATMENT FIELDS
– Alternating electric fields

55. NovoTTF-100a versus physician’s choice chemotherapy In
Recurrent Glioblastoma:
A Randomised Phase III Trial - Stupp et al
2012

56. – TTF-related adverse events were mild (14%) to moderate (2%) skin rash beneath transducer arrays
– Severe adverse events –
– 6% - TTF and 16% chemotherapy (p = 0.022)
– Quality of life analyses favored TTF therapy
– Total monthly therapy cost ~ $21,000, or about $86,000 when used an average of 4.1 months (median
treatment duration) for the typical patient

57. Surgery + local therapy – Gliadel wafers
– Implantation of BCNU (carmustine)-wafers in surgical
cavity intraoperatively
– BCNU released over 2-3 weeks
Improved survival in recurrent cases (Brem et al, Lancet
1995)
– Ph III trial from Germany (Westphal et al, Neuro Oncol
2003)
N= 240, Newly diagnosed GBM showed improvement in
median survival (MS) from 12m to 14m after implantation
Local delivery obviates blood brain barrier (BBB)
– FDA approved in new cases
– Local toxicity - CSF leak 5%, Intracranial hypertension 9%

58. GLIASITE

59. THANK
YOU
MENTORS
Dr Tejpal Gupta
Dr Abhishek Chatterjee