CNS tumors Management

1. PRESENTER- DR. JASMEET SINGH TUTEJA
MODERATOR- PROF. SEEMA GUPTA

2.  Gliomas arise from supportive cells (glial cells) that surround nerve cells.
 Most common type of primary brain tumours.
 4 types of glial cells-
 Astrocytes- balance of chemical in brain, wound healing & repair.
 Oligodendrocytes- myelin synthesis
 Ependymal cells- CSF (ventricular lining)
 Microglial cells- defend brain from disease- causing factor.
Different type of gliomas vary in treatment management & prognosis.

3. EPIDEMIOLOGY
Incidence - 17th position
Death – 12th position
 Incidence – 10th position
 Death – 10th position

4. Environmental
 Ionizing radiation (meningioma, gliomas, sarcomas) - 2.3% incidence in
prophylactic cranial irradiation in children
 Petrochemicals (formaldehyde, vinyl chloride, acrylonitrite)
Hereditary
 Cowden, Turcot , Lynch and Li-Fraumeni (gliomas)
 Gorlin (PNET),
 Neurofibromatosis I & II (meningiomas, optic nerve gliomas, schwannoma)
 Von Hippel Lindau syndrome (hemangioblastoma)
first-degree family member shown to have increase risk approximately two-fold

6. WHO classification Lyon 2007 –
 Histological criteria
 Morphological criteria
 In 2014, a meeting held in Haarlem, the Netherlands, under the auspices of the
International Society of Neuropathology, 2016 WHO Classification was formed
attended by 117 contributors from 20 countries to formulate guidelines
Why new classification ?
 Inter/ Intra observer variation
 Traditional histologic grading does not provide good prognostic power.
 Within the same tumour subtype and grade – a lot of variation in prognosis

7. Primary focus was on:
• Molecular markers
• Hence, Integrating Genotypic & Phenotypic parameters to make final
diagnosis

8. NEW CHANGES:
 Molecular parameters were introduced
 More objective and more precisely defined entities
 Improved tailoring of patient therapy
 Better classification for research purpose
 Wastebasket categories: NOS
 Need of more focused study of these less defined group => clarification of their status
Can we rely on molecular parameters alone? & skip
histology?

9. 9

10. 10

15. Brainstem
• Difficulty swallowing, speaking
• Drowsiness
• Headaches
• Hearing loss
• Muscle weakness
• Hemiparesis
• Uncoordinated gait
• Vision loss, ptosis, strabismus
• Vomiting
Frontal lobe
 Behavioural and emotional changes
 Impaired judgement , Impaired sense of smell
 Memory loss
 Hemiplegia
 Cognitive dysfunction
 Vision loss
 Papilledema Temporal lobe
• Impaired speech
• Seizures
• Homonymous superior
quandrantanopsia
• Auditory hallucinations
• Abnormal behaviour
Occipital Lobe
• Visual field deficits
• Visual hallucinations
Parietal lobe
 Impaired speech
 Inability to write
 Lack of recognition
 Seizures
 Spatial disorder

17.  Imaging – MRI, CT , PET
 Biopsy (craniotomy/ stereotactic)
 CSF
 IHC
 Cytogenetics

18. 18

19.  Investigation of choice
MRI sequences :
 T1 weighted
 T2 weighted
 T2 weighted FLAIR
 T1 post contrast
 Diffusion weighted imaging
 Magnetic resonance spectroscopy
 Magnetic resonance perfusion study

20. Anatomical details
 CSF – dark
 Gray matter – gray
 White matter - white
 Most Pathologies – dark

21. Anatomical details of T2W
 Pathological details
 Gray matter – bright
 White matter – dark
 CSF- bright

22. FLAIR
 Similar to T2 except
free water
suppression
(inversion recovery)
 Pathology – bright
 Good for lesions near
ventricles or sulci

23.  Diagnosis - made on axial images.
 T2Wt- and FLAIR - display the margins of a tumor and its surrounding edema or a
direct tumor infiltration.
 The sagittal & coronal images - confirm exact location

25.  Non-invasive physiologic imaging that
measure relative levels of tissue
metabolites
 Complements MRIs

26.  Guidance for stereotactic biopsy.
 Differentiates between Psuedoprogression &
Recurrent gliomas.
 11C Methionine (MET-PET)- uptake is
correlated with tumour proliferation  superior
contrast & tumour delineation.
 FET-PET (18F- fluoro-ethyl-L-tyrosine)-
longer half life

27.  Stereotactic frame or scalp fiducials
 CT or MRI is performed and the data are loaded into an image guidance
system.
 A target and entry points are selected, and the trajectory is visualized on a
workstation.
 The entry point - patient’s scalp, and a small burr hole or twist drill hole is
made.
 The biopsy needle is passed to the appropriate depth, and tissue samples are
obtained.

28.  Essential for staging tumors with a propensity for CSF spread (medulloblastoma,
germ cell tumors, and CNS lymphoma).
 best done before surgery or more than 3 weeks after surgery, as long as intracranial
pressure is not elevated.
 Tumor markers in the CSF may help in making the diagnosis.

30. Important exception is pilocytic
Astrocytoma which enhances with
contrast because the blood vessels
go degenerative changes and in
contrast the HGGs enhance
because because of microvascular
proliferation.
How to recognise blood in
the MRI?
– look for severe hyper
intensity with a surrounding
black border in the FLAIR
sequence
Cerebral metastases can often be confusing with HGG.
There are some useful characteristics when trying to differentiate
these radiologically.
1. cerebral mets usually occur in the gray/white junction,and
less common in deeper brain,
2. do not involve the periventricular white matter and
3. rarely ever goes to the corpus callosum.
4. cerebral mets are well circumscribed usually and they do not
have multiple areas of heterogenous contrast enhancement –
i.e. looks like a single round bright rim with a single dark
centre in T1w image with Contrast.
In contrast GBM – centers on the sub-cortical white matter, with
subependymal and corpus callosum extension seen frequently. There
can be multifocal GBM that looks like many small GBMs but they are
all embedded in a single unit / area of FLAIR enhancement.

31. 31
WHO
Grade
Definition Gliomas
I Circumscribed tumors of low proliferative
potential associated with the possibility of cure
following resection (Low proliferation)
Pilocytic astrocytoma, Pleomorphic
xanthoastrocytoma, Ganglioglioma,
Subependymal giant cell astrocytoma
II Infiltrative tumors with low proliferative
potential with increased risk of recurrence
(Nuclear atypia)
Diffuse astrocytomas (IDHmut/IDHwt) and
oligodendrogliomas (IDH mut, 1p19q codel)
III Tumors with histologic evidence of malignancy,
including nuclear atypia and mitotic activity,
associated with an aggressive clinical course
(PLUS Mitoses)
Anaplastic astrocytomas (IDHmut/IDHwt) and
anaplastic oligodendrogliomas (IDH mut,
1p19q codel)
IV Tumors that are cytologically malignant,
mitotically active, and associated with rapid
clinical progression and potential for
dissemination (PLUS Necrosis Vascular
proliferation)
Glioblastoma (IDH mut/wt)

32. CLINICALLY RELEVANT MOLECULAR MARKERS
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
Prognostic 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 grade II
Diffuse astrocytoma 70%–80% 15% 40%–50%
Oligodendroglioma/
oligoastrocytoma
70%–80% 30%–60% 60%–80%
WHO grade III
Anaplastic astrocytoma 50%–70% 15% 50%
Anaplastic
Oligodendroglioma/
oligoastrocytoma
50%–80% 50%–80% 70%
WHO grade IV
Glioblastoma 5%–10% <5% 35%

33.  Neuroradiologists
 Neurosurgeons
 Neurologists
 Neuropathologist
 Radiation oncologists
 Medical oncologists
 Neuro-rehabilitation
3/7/2022 33

34. LOW GRADE
GLIOMA

35.  Grow relatively slowly
 Diffuse infiltrative pattern
 Most transform in high grade gliomas- with aggressive clinical course &
shortened OS
 Treatment modalities include: surgery, radiotherapy, & chemotherapy
 Management of LGG is complex & controversial- MDT is essential.
 Estimated risks & benefits of adjuvant therapies (PFS, OS & neurocognitive
preservation) should be discussed with the patient whenever possible.

36. 36

37. 37

38. T2-FLAIR
MISMATC
H SIGN
 The T2-FLAIR mismatch sign- highly specific
radiogenomic signature for DIFFUSE
ASTROCYTOMA (IDH-mutant, 1p/19q-non-
codeleted molecular status)
 Helps in distinguishing a diffuse astrocytoma from
an oligodendroglioma.
 On T2 weighted- tumours have extensive areas of
fairly homogeneous and strikingly high signal.
 On T2-FLAIR - 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.
38

39. 39

41. 41

44.  CONSIDER MAXIMAL SAFE RESECTION
 AIM TO:
1. Obtain a histological & molecular diagnosis
2. Remove as much as tumor as safely as possible
3. To preserve or improve QOL especially by controlling seizures.
 Why?
-Greater extent of resection can improve OS
 How?
-Consider intraoperatively MRI & U/S, awake craniotomy with
language & other appropriate functional monitoring.

45.  Extent of resection & post surgical residual volume are independent prognostic
factor significantly associated with longer OS.
 Surgical excision is also independent prognostic factor correlating with increased
malignant PFS*
Advantage of extensive resection:
 Across all molecular subtypes.
 Even min. residual volume negatively affects OS- most relevant for IDH-mut
astrocytomas (in oligodendroglioma – trend towards better OS)
 Consider 2nd look op to remove minor residuum if safely possible.

46.  Post-operative radiotherapy
 Decisions largely based on risk factors and extent of resection

47. • No overall survival benefit from immediate RT vs delayed RT (7.4vs 7.2 yrs)
• Improved progression free survival with immediate RT by ~24 months but at expense of
toxicity (e.g. neuro-cognitive) median 5.4 vs 3.7 years
• Better seizure control (25% vs 41% at 1 yr)

48. Absence of OS benefit for early RT suggest that RT slows
progression of LGG’s but does not prevent malignant
transformation & that RT given at time of radiological PD is
equally effective.

49. • Grade 2 glioma (any subtype).. High risk
• <40 AND subtotal resection
• >40 years (any biopsy/surgery)
• 54Gy in 30 fractions +/- 6 x PCV q8 weekly

50. • Improved overall survival with addition of PCV
• Median: 13.3 vs 7.8 years
• 10 year OS: 60% vs 40%
• Largest benefit in oligodendroglioma
• Use for oligodendrogliomas as above
• Not significant for astrocytoma….. In practice, tend not to use adjuvant chemotherapy here.....
Wait & watch.
• Improved progression free survival with PCV
• 10 year PFS: 21% vs 51%

51. Prognostic factors for survival in adult patients with cerebral low-grade glioma.

54. IMAGING SUGGESTIVE OF LOW GRADE
GLIOMA
>80-90% resection
possible?
Resection (often awake craniotomy)
Biops
y
Observation to
determine
behaviour
Ye
s
N
o
Integrated diagnosis (inc cytogenetics IDH, 1p 19q, MGMT, TERT) confirms
G2
Assess risk factors for progression: Age >40, sub-total resection / biopsy, size >6cm,
crosses midline, poor cytogenetics, symptomatic (but not seizures), adverse radiology (eg
enhancement)
High Low
Decide with patient whether to use immediate non-surgical treatment or
observe
(influenced by level of risk and patient’s wishes)
Observation
(Consider more surgery
or non-surgical
treatment if progresses
Q: Is it high grade
now?)
Non-surgical
treatment
Olig
o
RT +
Astrocytom
a
R
?treat as GBM
if G2
astrocytoma
?chemo
alone if
gliomatosis

55. HIGH GRADE GLIOMA

56. 56
Anaplastic
Astrocytoma
Anaplastic
Oligodendroglioma

57. T1 T2 T1W + Gad
GLIOBLASTOMA

58.  Stereotactic image guided biopsy is accurate & safe way to get to even relatively
inaccessible areas of the brain such as basal ganglia & thalamus.
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.
Simpson et al , IJROBP 1993

60.  Patients with grade III (=anaplastic) oligodendroglial tumours
 RT vs RT (59.4Gy) + adjuvant PCV
 Median OS: 42.3 vs 30.6 months
 PFS also improved (Median PFS: 24.3 VS 13.2 Months)
 Improved outcomes also in patients with IDH mutations and methylated tumours
 Therefore: consider adjuvant PCV for grade III oligos (by modern classification these are all co-
deleted)

61. More benefit in patients with 1p19q co-deletion: trend towards improved OS here, not
in non-co-deleted.
Overall survival in both treatment arms for (A) the patients with 1p/19q-codeleted tumours
(B) the patients with non–1p/19q- codeleted tumours
Progression Free survival in both treatment arms for (A) the patients with 1p/19q-
codeleted tumours (B) the patients with non–1p/19q- codeleted tumours
CO-DELETED TUMOUR- OS was not
reached in RT+PCV vs 112 months in RT group
NON-CODELETED TUMOUR- OS 25 vs 21
months
CO-DELETED TUMOUR- PFS- 157
VS 50 MONTHS (RT + PCV VS RT)
NON CO-DELETED TUMOUR- 15
VS 9 MONTHS (RT + PCV VS RT)

62. 59.4 Gy/33# of
RT
PCV → 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 2.7 y 2.6 y
PFS - 1p/19q non codeleted AO/AOA 1 y 1.2 y

63. Adults (>18) with newly diagnosed 1p/19q World
Health Organization (WHO) grade III
oligodendroglioma were randomized in 3 arms:
• Radiotherapy (RT-59.40Gy) alone;
• RT with concomitant and adjuvant temozolomide; or
• TMZ alone

64. INTERIM RESULT OF CODEL TRIAL:
 TMZ-alone patients had significantly shorter PFS than patients treated on
Radiotherapy arms.
 The ongoing CODEL trial trial has been redesigned to compare RT + PCV versus
RT + TMZ.

66. Design- Patients with histologically confirmed Anaplastic Astrocytoma were randomized to 2 arms-
• RT+TMZ
• RT+NU
Results. Median survival time was 3.9 (RT/TMZ arm) vs 3.8 years (RT/NU ARM).
Conclusions. No significant improvement in OS , PFS & TTP in both arms
RT+TMZ was better tolerated.
IDH1-R132H mutation was associated with longer survival.

67. oSlightly better PFS with TMZ
oHigher toxicity and discontinuation rates with nitrosureas
IDH positive with a better OS in IDH-positive patients
(median survival time 7.9 vs 2.8 y)

68. • Grade III gliomas which were NOT 1p19q co-
deleted
• Improved overall survival in arms with adjuvant
temozolomide
• Larger advantage in MGMT methylated (70%)
• Therefore, consider adjuvant temozolomide for
non-co-deleted Grade III gliomas (now =
anaplastic astrocytoma).

70. The 2nd interim analysis declared futility of concurrent TMZ
(median OS was 66.9 months with concurrent TMZ vs 60.6 months
without concurrent TMZ)
By contrast, adjuvant TMZ improved improved OS compared with
no adjuvant TMZ (median OS 82.3 months vs 46.9 months)
Adjuvant TMZ therapy, but not concurrent TMZ chemotherapy, was
associated with a survival benefit in patients with 1p/19q non co-
deleted anaplastic glioma
https://doi.org/10.1016/S1470-2045(21)00090-5

71. Design- Patients with anaplastic gliomas randomized 2:1:1 In 3 arms:
• standard radiotherapy (RT) (arm A),
• Procarbazine, lomustine and vincristine (PCV) (arm B1), or
• Temozolomide (TMZ) (arm B2).

72. There is no differential activity of primary chemotherapy versus RT in any subgroup of
anaplastic glioma. Molecular diagnosis is superior to histology.

73. http://www.jnccn.org/content/12/5/665.full

75. Patient were randomized in 2 arms:
• RT alone (60Gy) vs
• RT+TMZ  TMZ (6cycles)

76. Median PFS 6.9 vs 5 months
Median Survival- 14.6 vs 12.1 months
2- year survival rate- 26.6 vs 10.4 months

77. • GBM: 60Gy in 30 fractions RT +/- concurrent temozolomide 75mg/m2 then 4 week
break then adjuvant temozolomide 150-200mg/m2 x 6 months
• Given with prophylactic oral Septrin (co-trimoxazole) 960mg during RT
• Addition of temozolomide improved overall survival:
• Median 12.1 months vs 14.6 months
• 2 year OS: 10.4% vs 26.5% (unheard of in GBM before)
• Well tolerated
• 90% completed at least 90% of planned temozolomide
• 7% grade 3 or 4 toxicity
• Patients with complete resection did better
• 2 year OS: 37%
• Patients with methylated MGMT did better
• 2 year OS: 46%

79. MGMT promoter methylation has been
demonstrated as the strongest prognostic
& predictive marker for outcome, and the
added benefit of Temozolomide.

80. MGMT
gene(10q26)
Encodes DNA
repair protein
Removes alkyl
groups from
the DNA
(DNA repair)
TMA alkylates
O6 position of
guanine
Resistance to
alkylating
agents
(removal of
alkyl group by
MGMT)
Methylation of
the MGMT
promoter
silences
expression of
the protein
Cytotoxicity
and apoptosis
by alkylating
agent (TMZ)

81.  Retrospective study (morning vs evening intake)
 Survival benefit in median OS when patients take TMZ in
morning versus in evening. (mOS of 2.13 years in AM vs
1.63yrs in PM)
Morning TMZ administration improves survival with patients with GBM.
https://doi.org/10.1093/noajnl/vdab041

82. 82
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 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.

83. 83
Role of Bevacizumab in newly diagnosed GBM
Citation Arms Median OS
(months)
RTOG 0825
Gilbert NEJM 2014
60 Gy + TMZ → TMZ 16.1
60 Gy + TMZ → TMZ + BEV 15.7
AVAglio
Chinot NEJM 2014
60 Gy + TMZ → TMZ 16.7
60 Gy + TMZ → TMZ + BEV 16.8
No significant benefit in median OS on addition of Bevacizumab.

84. ELDERLY GBM

85. • Nordic and German trial have randomized patients into 3 arms- conventional RT,
hypofractionated RT (34GY in 10#) and temozolomide alone
• Interpretation- Standard Radiotherapy was associated with poor outcome in patients
more than 70 years.
• Both TMZ & hypofractionated RT were associated with longer survival & can be
considered as standard treatment options in elderly GBM.
https://doi.org/10.1016/s1470-2045(12)70265-6

86.  Age >70 is a dreadful prognostic factor in
GBM
 Perry et al NEJM 2017 patient were
randomized in 2 arms:
 RT 40Gy in 15 fractions +/-
temozolomide concurrent
75mg/m2 and adjuvant 150-
200mg/m2 for up to 12 cycles
 Patients ≥65 years, PS 0-2
 Addition of TMZ improved overall
survival
 9.3 months vs 7.6 months
 Addition of TMZ improved PFS
 5.3 months vs 3.9 months
 Consider TMZ-RT 40Gy in 15 fractions
and adjuvant TMZ if >70 and PS 0-2

87. • Patients with Butterfly Glioma have almost poor performance status.
• Poor PS patients have dreadful outcome
• PS 3 and <70 years: consider 30Gy in 6 fractions over 2 weeks (or 25Gy in 5
fractions over one week (Roa et al JCO 2015))

88. • <70 years, GBM
• PS 0/1: chemoRT 60Gy in 30 fractions + adjuvant temozolomide x 6
• PS 2 (not butterfly): 60Gy in 30 fractions
• PS 3 (or PS 2 butterfly glioma): 30Gy in 6 fractions over 2 weeks
• PS 4: steroids and best supportive care
• >70 years, GBM (?top age)
• PS0-1: chemo RT 40Gy in 15 fractions + adjuvant temo up to 12 cycles
• PS 2: possibly temozolomide alone or hypofractionated RT (need MGMT) status.
Consider BSC.
• PS3/4: steroids and best supportive care
• <70 years, grade III
• PS 0-1: RT 60Gy in 30 fractions
• 1p19q co-deleted oligo: adjuvant PCV
• Non-1p19q: adjuvant temo

89. https://www.nice.org.uk/guidance/ng99/resources/visual-summary-for-glioblastoma-management-pdf-

90. 90
Tumor-treating fields involve
• Transducer arrays are placed on scalp. These are connected to electric field generator. Light weight
battery pack is carried by patient and worn for atleast 18 hours a day. Transducer arrays delivers low
intensity, intermediate frequency, alternating electric field which acts by disrupting mitosis and
inducing 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.
TUMOR TREATING FIELDS

91. 91
oKPS > 70; median age 56
oRandomized 2:1 after 60Gy, TMZ
Adj TMZ + TTF
Adjuvant TMZ
oImproved median survival from time
of randomization
16→20.9 months
oToxicity – dermatitis in 52%
oImproved OS:
>18 hours/day

93.  Corticosteroids, preferably dexamethasone reduce symptomatic peritumoral vasogenic
edema, neurological deficits and signs of increased intracranial pressure
 Lowest dose of steroids – shortest time possible
 No need for prolonged steroid therapy after tumour resection or for prophylaxis during
radiotherapy in asymptomatic patients
 Downward titration of dose – whenever possible
 Extensive mass effect – receive steroids for at least 24 hours before RT
 Monitor for side effects
 Chronic corticosteroids (≥ 20 mg prednisone equivalents daily for ≥ 1 month) - consider
prophylaxis for osteoporosis and pneumocystis jerovecii pneumonia should be considered

94. 94
Antiepileptic Drugs
▪ Increased risk of thromboembolic events due to a tumour-induced hyper-coagulable state, as a
consequence of neurological deficits, immobilisation and steroid use.
▪ Prophylactic anticoagulation is not recommended
▪ No contraindication for the use of standard anticoagulants in patients with proven thrombosis.
Anticoagulants
▪ Non Enzyme inducing anti seizure medications should be used eg: levetiracetam, topiramate,
valproic acid
▪ Current guidelines recommend tapering AEDs 1-2 weeks after surgery and avoiding long-term
prophylaxis.
▪ No role for primary perioperative prophylaxis (i.e. in patients who have never had a seizure).

96.  SUPINE, HEAD IN NEUTRAL POSITION
 HEAD IMMOBILISED- Perspex or thermoplastic shell.
More rigorous immobilization with a stereotactic frame.
 I.V. contrast 1mg/kg most of time 50mg i.v.
 Thin-slice CT imaging is recommended (at 1–2 mm
slices) from the vertex to the C3-C7 and, for ease of
fusion, ideally should match the MR image slice
thickness.
 Multimodal MR fusion, using at least the contrast
enhanced T1 and FLAIR sequences
 PET/CT fusion can be helpful distinguish between
postradiation changes and disease recurrence on MR
imaging.

97.  3D-CRT remains standard for the majority of
GBM
 IMRT/ VMAT is - volumetrically or spatially
challenging tumours.
 Proton beam radiation therapy due to its
“Bragg peak effect, safer than traditional photon
radiation therapy
 Boron neutron capture therapy (BNCT),
increases the efficacy in destruction of tumor

98. • Superior: skin fall off
• Anterior: skin fall off
• Posterior: skin fall off
• Inferior: cranial base
2 opposed lateral fields.
 A rectangular treatment field over the
cranial vault with the collimator angled so
as to place the inferior border 1–2 cm
below a line drawn from the medial
canthus to the mastoid tips.
 A small block is carefully placed to shield
the globes while still allowing adequate
coverage of the anterior–inferior extent of
the cranial contents
Whole-brain RT

99. Anaplastic astrocytoma Phase 1 Phase 2
60 Gy in 30# 46 Gy in 23# 14 Gy in 7#
59.4 Gy in 33# 45 to 50.4 Gy in 1.8 Gy/# 9 to 14.4 Gy in 1.8 Gy/#
Anaplastic
oligodendroglioma
Phase 1 Phase 2
60 Gy in 30# 50.4 Gy in 28# 9 Gy in 5#
Studies interrogating dose escalation beyond 60 Gy using standard
fractionation have not demonstrated any survival benefit.
LGG- 54Gy in 30 fractions or 50.4Gy in 28 fractions (EORTC 22844)

100.  GTV- non-enhancing tumour extent (T2/FLAIR)
 CTV- GTV+1-1.5cm
 PTV- CTV + 0.5cm

101. EORTC treatment volumes 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)
GT
V
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)
GT
V2
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 PTV
2
CTV2 plus a margin of
3–5 mm
*Margins up to 3 cm were allowed in 22981/22961 trial, and 1.5 cm in 26981–22981 trial.
TARGET DELINEATION OF GLIOBLASTOMA
Stupp et al.(2005) Chinot et al (2014) Gilbert (2014)

102. RTOG- 2 phases of target volume delineation.
(A) The initial GTV includes postoperative peritumoral edema based on the
axial T2 fluid-attenuated inversion recovery sequence (red line); the initial
CTV (green line) includes postoperative peritumoral edema plus a 2 cm
expansion in all directions.
(B) The boost GTV includes the surgical cavity and residual enhancement
based on the axial T1 sequence with gadolinium (red line) and the boost
CTV is a 2 cm expansion in all directions (green line)
EORTC-1 phase of target volume
delineation.
GTV: surgical cavity and residual
enhancement based on the axial T1
sequence with gadolinium (red line) and
CTV is a 2 cm expansion in all directions
(green line).
Zhao et al Onco Targets Ther 2016

103.  Principles of intensity-modulated
radiotherapy (IMRT)-based planning for
dose-escalated HFRT.
 The two regions are prescribed differential
doses using IMRT, with the high-dose area
receiving higher tumour biological
effective dose from increased dose and
higher fraction size.
 This technique is inappropriate for
tumours in close proximity to critical
structures.
Hingorani et al 2012 BJR

104. 104
From left to right: transition from 2D RT to 3D RT to intensity modulated
radiotherapy to intensity modulated proton therapy harnesses the potential
for sparing normal, uninvolved brain substructures from unnecessary RT
dose; whether this produces meaningful patient clinical benefit is a subject of
current clinical trial testing.
2D 3D IMRT
IM Proton
Therapy

105. 105
OAR OBJECTIVE(S)
Brainstem D <54 Gy; 1–10 cc < 59 Gy (periphery)
Chiasm Dmax <55 Gy
Cochlea Ideally one side mean <45 Gy ( Most protocols allow
ipsilateral cochlea to receive 60 Gy rather than compromise
dose )
Eyes Macula <45 Gy
Lacrimal glands Dmax <40 Gy
Lens Ideally <6 Gy Max 10 Gy
dose limits should never compromise PTV dose
Optic nerves and chiasma Dmax <55 Gy or 1 % of PTV cannot exceed 60 Gy
Pituitary Dmax <50 Gy
Hippocampus Max ≤16 Gy and no more than 9 Gy to 100 % volume
OAR definitions and dose limits in GBM patients
(individual adaptation necessary according to the clinical situation)
M. Niyazi et al. / Radiotherapy and Oncology 118 (2016)
Based on the University of Maryland treatment planning guidelines

106. ACUTE
 Fatigue
 Erythema
 Alopecia
 Headache
 Nausea
 Vomiting
LATE
 Somnolence
 Neurocognitive impairment –
hippocampal sparing)
 Brain Necrosis

107. FOLLOW UP
 Brain MRI every 3-6 month followed by serial imaging up to 3-5 years & then
atleast annually is recommended according to NCCN followed with clinical
correlation

108. • Occurs in about 30% of patients
• Most within 3 months of chemo-RT
• Represents endothelial damage and subsequent hypoxia
• Scan looks worse, patient often well, but not always
• Increased enhancing lesion
• Increased FLAIR
• Tricky to differentiate from recurrence
• Advanced imaging/ Radiologist may help
• Reduced relative CBV (cerebral blood volume) supports diagnosis of pseudo-progression
(increased in recurrence)
• MR-spectroscopy: Low choline:NAA ratio (≤1.4) or low choline (=low levels of metabolites)
or high lactate supports diagnosis of pseudo- progression
• Diffusion weighted imaging: Elevated ADC (apparent diffusion coefficient) supports diagnosis
of pseudo-progression= less impedance of water motion (in recurrences have lots of cells
impede water motion)

109. First progression Definition
Progressive disease < 12
weeks after completion of
chemoradiotherapy
Progression can only be defined using diagnostic imaging if there is new enhancement outside of
the radiation field (beyond the high-dose region or 80% isodose line) or if there is unequivocal
evidence of viable tumor on histopathologic sampling
Note: Given the difficulty of differentiating true progression from pseudoprogression, clinical
decline alone, in the absence of radiographic or histologic confirmation of progression, will not be
sufficient for definition of progressive disease in the first 12 weeks after completion of concurrent
chemoradiotherapy.
Progressivedisease≥ 12
weeks after
chemoradiotherapy
completion
1.New contrast-enhancing lesion outside of radiation field on decreasing, stable, or increasing
doses of corticosteroids.
2.Increase by ≥ 25%in the sum of the products of perpendicular diameters between the first
postradiotherapy scan, or a subsequent scan with smaller tumor size, and the scan at 12 weeks or
later on stable or increasing doses of corticosteroids.
3.Clinical deterioration not attributable to concurrent medication or comorbid conditions is sufficient
to declare progression on current treatment but not for entry onto a clinical trial for recurrence.

110.  Surgical resection
 Chemotherapy: TMZ/ Carmustine/ Lomustine
 Locally delivered CARMUSTINE OR GLIADEL wafers:
o Implanted into the surgical cavity →modest survival advantage
o It offers statistically significant but marginal improvement (31 vs 23
weeks) in OS after re-operation of HGG.
o Significant peritumoral edema is a recognized side-effect.
o Requires careful patient selection and a gross total resection.
o Specialist centres only
 Trial: Westphal et al
 HGG: maximum surgical resection +/- gliadel wafers, followed by RT
 2.3 month increase in median survival with gliadel
 11.3 months to 13.9 months
 Greater gain (4.2 months) if ≥90% resection 110
 Bevacizumab-FDA approved
 Alternating Electrical Field Therapy
 Re-Irradiation
 Best Supportive Care

111. 111
▪ Cognitive deficits, personality changes, and mood disturbances are major comorbidities.
▪ “Chemobrain” - severe cognitive dysfunction that can persist after the cessation of
treatment↔ chemotherapeutic agent-induced inflammation in the hippocampus, which is
involved in learning and memory
▪ Endocrinopathies are common – surgery, steroid, RT – monitor and manage
▪ Psychiatric comorbidity treated with psychotherapy and pharmacotherapy
▪ Early discussion of goals of care and involvement of palliative care should be considered
▪ Diverse support - nurse specialists in neuro-oncology, social workers, counsellors,
clinical psychologists, palliative-medicine professionals, and patient focus groups.
▪ Rehabilitative measures should be explored during and after tumour-specific therapy

112.  Externally generated ionizing radiation is used to eradicate a
define target without the need to make an incision.
 Target is defined by high resolution sterotactic imaging.
 Usually delivered in single session (maximum of 5) using
stereotactic guiding device. ( strict immobilization)
 Multiple non opposed radiation beams converge on target in
the brain avoiding normal tissues.
 Highly conformal
 Can be delivered using a conventional or modified LINAC, a
Gamma Knife or a robotically controlled miniaturized linear
accelerator (CyberKnife), particle beam accelerator or
multisource Co60 unit
Leksell Stereotactic system
trUpoint ARCH SRS/SRT Syste

113. 113
 Used 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:
 Small target/treatment volume
 Sharply defined target
 Accurate radiation delivery
 High conformality
 Sensitive structures excluded from target
Radiobiology: achieving increased cell kill from a higher dose per fraction → expose more tumor
antigens to stimulate immune responses both against the irradiated tumor and also possibly against
more distant nonirradiated tumor (referred to as the abscopal response) and reducing the effect
from accelerated tumour cell repopulation by shortening the overall treatment time

114. 114
 4 phases:
1. placement of the head frame,
2. imaging of the tumor location,
3. computerized dose planning, and
4. radiation delivery
SRS dosing: RTOG 9005
results
< 2 cm 24 Gy
2.1 -3 cm 18 Gy
3.1 – 4 cm 15 Gy

115. 115
BEVACIZUMAB
o Monoclonal antibody that binds to VEGF and inhibits the growth of tumor blood
vessels
o Prolongs OS either alone or in combination with a cytotoxic agent by about 4
months in recurrent glioblastoma but not in primary Glioblastoma
CILENGITIDE- no established role (CORE trial)
ANTIANGIOGENIC THERAPY
Vaccines for Glioblastoma
o DCVax- a dendritic cell (DC)-based personalized cancer vaccine with purified tumor-
specific antigens or tumor cell extracts derived from tumor at the time of resection.
o Epidermal Growth Factor Receptor Variant III as a Vaccine Target for Glioblastoma
o Heat Shock Protein-Based Vaccine
o Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO) targets the
neurotropic poliovirus receptor CD155, which is abundantly expressed on glioblastoma
cells.

116. 116
Biomarkers
• EGFRvIII amplification is targeted by EGFR vaccine rindopepimut.
• KIT amplification or mutation is target is targeted by KIT inhibitor imatinib
• PDGFRA amplification is targeted by PDGFR inhibitor dasatinib
• PTEN deletion or mutation is targeted by AKT inhibitor or mTOR inhibitor voxtalisib
• MDM2 amplification is targeted by a MDM2 inhibitor such as AMG232
• TP53 wild-type is targeted by a MDM2 inhibitor such as AMG232
• RB1wild-type is targeted by CDK4/6 inhibitor ribociclib
MicroRNAs→ Dysregulation → pathogenesis of glioblastoma
Targeting miRNA(s) could alter multiple genes simultaneously and may prove more effective
than targeted focused at targeting single gene or pathway
CAR-T cell therapy
• Multiple infusions into the ventricular system of CAR-T cells targeting the tumor-associated
antigen IL-13 receptor alpha 2 (IL13Ra2) in a patient with recurrent multifocal
• Intravenous delivery of a single dose of autologous CAR-T cells targeting EGFRvIII
mutation in patients with recurrent GBM → feasible and safe

117. 117
Convection-Enhanced Delivery: use of intracerebrally implanted catheters to deliver a drug
into the brain parenchyma or tumor, at a slow but continuous rate of flow.
• Topoisomerase-I inhibitor, topotecan
• Thermosensitive liposomes can encapsulate drugs to release them at the target site
• Angiopep-2 (An2) for BBB transcytosis and anti-CD133 MAb for specific delivery to glioma
stem cells have been incorporated in a dual-targeting immunoliposome encapsulating
• Targeting molecule transferrin helps the transport of drug to glioblastoma which contains
abundant transferrin receptors on the surface
• Genetically engineered bacteria that selectively destroys tumor cells while sparing the
normal brain tissue
Direct Delivery of Therapeutic Agents
Gene Therapy
• Viral vector mediated insertion of drug sensitivity genes
• Insertion of tumor suppressor genes: Transfer of wild type p53 or p27, Retinoblastoma
gene transfer