discussed evolution of treatment in brain tumors

1. EVOLUTION OF TREATMENT STRATEGIES
FOR BRAIN GLIOMAS
By Dr Anil Gupta
Moderator Dr Amit Bahl

2. Introduction
 Glial cells are supportive cells in
CNS
 Makes 90% of brain
 Gliomas refers to neoplastic
transformation of normal glial
cells
 Astrocytoma refers to tumours
that have histologic features
similar to astrocytes.

3. WHO grade I Astrocytoma
Well
defined
character
Early age of
onset
Lack of
invasiveness
Good
prognosis
Types
- Pilocytic astrocytoma
- Subependymal giant cell astrocytoma
- Pleomorpic xanthoastrocytoma
Pediatric age group

4. Diffuse Gliomas
 Have similar growth patterns and behaviours
 Share same genetic driver mutations IDH1
and IDH2 genes.
 Share similar prognostic markers.
 Has similar management (conventional or
targeted)
 “Diffuse astrocytoma is more similar to
oligodendroglioma than it is to pilocytic
astrocytoma”
Not curable by surgical resection
Includes grade II and grade III astrocytic and
oligodendroglial tumors, grade IV glioblastomas, as
diffuse gliomas of childhood

5. Epidemiology
Distribution of Primary Brain and CNS Tumors by Histology Distribution of Primary Brain and CNS Gliomas by Histology Subtypes
CBTRUS Statistical Report: NPCR and SEER, 2009-
2013
Brain tumors account for only 2 percent of all cancers
60-62% are metastatic brain tumors
Overall incidence rate for primary brain and CNS tumors is 21.03 per
100,000

6. Trends of incidence on the basis of age
Age-Adjusted Incidence Rates in Children and
Adolescents of Brain and CNS Tumors
Age-Adjusted Incidence Rates of Brain and CNS
Tumors
CBTRUS Statistical Report: NPCR and SEER, 2008-
2012

7. Survival rates
Histology 1 yr OS2 yr OS 3 yr OS 4 yr OS 5 yr OS
10 yr
OS
Pilocytic astrocytoma 98 96.6 95.5 94.6 94.2 92
Diffuse astrocytoma 74.4 63.6 57.3 53 49.7 39.3
Anaplastic astrocytoma 64.4 45.9 37.4 32.8 29.7 20.9
Glioblastoma 39.3 16.9 9.9 7 5.5 2.9
SEER 18 Registries, 2000-2013

9. Incidence in Future?
0
5,000
10,000
15,000
2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022
US
France
Germany
Japan
• Number of newly diagnosed cases of glioblastoma is expected to increase in
the US, France, Germany, and Japan
Decision Resources: Glioblastoma Multiforme. September 2013

10. Evolution of Grading in Glioma

11.  Is a mean of predicting biological behaviour of a neoplasm
 Determines prognosis
 Directs treatment strategies
 The Kernohan system
- Based on the degree of presence of multiple
- features (i.e., anaplasia, cellular and nuclear pleomorphism,
hyperchromasia, vascularity, cellularity, necrosis,
endothelial proliferation, and mitotic rate)

12. St Anne-Mayo grading system
 Nuclear Atypia
 Mitoses
 Epithelial proliferation
 Necrosis
Is binary and
 1 criterion = grade 2
 2 criteria = grade 3
 or 3 or 4 criteria = grade 4
WHO grading system
A
M
E
N
Grade I
St Anne Mayo grading
diffuse astrocytoma without atypia (rare)
WHO grading system
More circumbscribed pilocytic astrocytomas

13. • Uses causal probabilistic models, also
known as Bayesian networks to grade
gliomas
• Is a computerized statistical model
Pros
• Prevents interobserver variability
• Easily reproducible
Still in developmental phase

14. Evolution in brain tumor classification

15. Pre WHO classifications
 Classification of tumors of Glioma Group (1926)
 Tumors of central nervous system (1952)
 International union against cancer (1965)
 Atlas of the histology of brain tumor (1972)
- the forerunner of the official WHO editions
- adjectives ‘‘benign,’’ ‘‘semibenign,’’ ‘‘semimalignant,’’ and ‘‘malignant’’
were attributed to heterogeneous groups
 Atlas of Gross Neurosurgical Pathology (1975)

16. WHO brain tumor classification
“the blue books”
The First
edition
(1979)
• Histological typing of
tumours of the
nervous system
The second edition (1993)
• Reflected the advances brought about by the introduction
of immunohistochemistry into diagnostic pathology
The third edition (2000)
• Incorporated genetic profiles as additional aids
• Concise commentary on clinico-pathological characteristics
of each tumour type
The fourth edition (2007)
genetic profile updated
Diagnosis, classification and grading based solely on morphology

17. Changes in astrocytic tumors
 Explosion of molecular data
-Better insight into biology of human disease
(diagnostic, prognostic and/or predictive value)
– How should clinically relevant molecular information be
incorporated into nervous system tumor classification?
• Clinical applications lagging behind
– Few translated into tangible medical advances
– Most remain unused
Since 2007

18. 1. Diagnostic entities should be defined as narrowly as possible
2. Diagnoses should be “layered
3. Determinations should be made for each tumor entity as to whether
molecular information is required
4. Some pediatric entities should be separated from their adult
counterparts
5. Input for guiding decisions regarding tumor classification should be
solicited from experts in complementary disciplines of neuro-oncology
6. Entity-specific molecular testing and reporting formats should be
followed in diagnostic reports
ISN-Haarlem consensus 2014

19. Multi layered reporting format
Layer 1: Integrated diagnosis (incorporating all tissue-based information)
Layer 2: Histological classification
Layer 3: WHO grade (reflecting natural history)
Layer 4: Molecular information
Layer 1 : diffuse astrocytoma, IDH
mutant type, grade II
Layer 2: gemistocytic astrocytoma
Layer 3 : II
Layer 4 :IDH mutant, ATRX loss

20. WHO 4th edition
revised 2016
WHO 4th edition
(2007)
Strongly
discouraged,
only in rare
cases where
both 1p19q
codeletion
and ATRX
positive
NOS- when
IHC
inconclusiv
e or not
available

21. Molecular testing
IDH1 and IDH2 (isocitrate dehydrogensase) mutations
 Good prognostic marker
 Can be done by IHC, PCR or pyrosequencing
1p19q co-deletion
 Mainly seen in ODG
 Good prognostic factor
 Can be done by PCR, FISH
ATRX gene mutation (alpha thalassemia-mental retardation, X linked)
 Seen in 45% of anaplastic astrocytoma
 Considered as hallmark of astrocytoma
 ATRX loss is a good prognostic factor
 Can be done by IHC,FISH, PCR
NOA-04 trial

22. MGMT (O-6 methylguanine methyltransferase)
promotor status
 Is crucial for genome stability
 It repairs methylation of DNA
 It also reverses the cytotoxic effects of
alkylating agent
 Inactivation of MGMT makes it sensitive
to alkylating agent
 Is a prognostic and predictive marker
 Done by PCR, pyrosequencing
In PGI, panel of IDH1, ATRX, Ki67, p53,
GFAP is done routinely
1p19q codeletion is done by FISH
MGMT promotor status is not done
M Hegi et al NEJM
2005
HGGs

24. The RTOG RPA model for prognosis of
glioblastoma
Age <50 or >50
KPS score (< vs. ≥ 90
for patients < 50
y or < vs. ≥ 70
for patients ≥ 50
y
Extent of
resection
Resection vs
biopsy
Neurologic
function
Able to work or
not
Original (1998 ) Modified
(2010)Age <50 or >50
KPS score (< vs. ≥ 90 for
patients < 50 y or <
vs. ≥ 70 for patients
≥ 50 y
Extent of resection Resection vs biopsy
Neurologic function Able to work or not
Mental status Normal or abnormal
RT dose <54.4 Gy or >54.4
Gy
Excluded
AA
RTOG trials
74-01, 79-
18, and 83-
02, 90-06
and 94-11

25. Evolution in Imaging

26. Early era Precision neuroradiology
First 50 years

27. Early era
Plain radiograph Pneumatoencephalograms Cereberal angiography
After discovery of X
rays 1918 1928

28. Precision neuroradiology
Radiotracer uptake CT Scan MRI
1971 1977

29. Newer imaging modalities
Functional MRI
Magnetic resonance spectroscopy (MRS)
Diffusion-perfusion
MRI
Radio Genomics
Eloquent
areas

30. • Treatment-induced changes in brain permeability introduce challenges in detecting response
to therapy and disease recurrence by MRI[1]
Challenges in Response Assessment:
Pseudoprogression and Pseudoresponse
Pseudoprogression
Apparent increase of tumor lesion
on imaging that is not due to
actual tumor growth
Pseudoresponse
Apparent decrease of tumor lesion
on imaging that does not reflect
true tumor reduction
Often occurs with antiangiogenic
agents such as bevacizumab
Observed in 5%–31% patients* after
RT/chemotherapy
• -Also been observed after treatment
with immunotherapies, but is often
followed by tumor regression
• -Apparent increases in tumor lesions
in these cases may be a result of
immune-cell infiltration of the tumor

31. Evolution in treatment

32. Surgery
± Adjuvant
treatment
Treatment of Glioma

33. Surgical resection of brain tumor
Goals of surgical resection:
(1) Establishing histological diagnosis
(2) Tumor cytoreduction for:
- improving neurological status
- Possible change in tumor kinetics
Advent of brain surgery
 1873: Gupta Longati first discovered Brain Cancer
 In 1879, first successful brain tumor surgery was done to remove blood clots
 Early 1990s brain tumor surgery was frequently done
 With betterment in anaesthesia and imaging, perioperative mortality reduced

34. Gross total tumor resection is
associated with longer survival
8-yr PFS after STR without adjuvant therapy
is 56% if residual tumour is 1.5 cm3 and 45% if the volume
is >1.5 cm3
Neurosurgery 68:1548–1555, 2011
Complete resection (>90% cure
rate)
Incomplete resection (70% to
80% 10 yr- OS)

35. Treatment of WHO grade I astrocytoma
 Complete surgical resection whenever
feasible is curative and mainstay therapy
 Near total excision results in delayed
recurrence and malignant transformation
 Resection difficult in optic pathway,
hypothalamus ,deep midline structures
 In these instances if asymptomatic , can be
kept on observation
Potentially curable by surgical
resection

36. Diffuse gliomas
 Generally not considered surgically curable, due
to diffuse brain infiltration
Not curable by surgical resection
J Neurooncol 2015
35 retrospective studies attempted to correlate EOR with OS in
LGGs
• 6 of these studies showed no correlation
• 3 studies showed a correlation but was not significant
• 23 showed it increases OS
lack of class I evidence and limited examples of class II
evidence,

37. Advances in surgery
Neuronavigation
 5- ALA fluorescent porphyrins
 Use of intraoperative MR
 Helps in complete resection of tumor
Intra-operative cortical stimulation mapping
 Identifies functionally critical areas (eloquent brain)
by placing electrodes on functional areas
 In PGI, awake craniotomy is performed, in tumor
such as insular gliomas
glioma cells

38. More patients in the iMRI group had complete tumour resection (23 [96%] of 24 patients)
than in the control group (17 [68%] of 25, p=0·023
Postoperative rates of new neurological deficits did not differ between patients in the
intraoperative MRI group (three [13%] of 24) and controls (two [8%] of 25, p=1·0
Contrast-enhancing tumour was resected completely in 90
(65%) of 139 patients assigned ALA compared with 47
(36%) of 131 assigned white light p<0·0001

39. Recurrence
 Diffuse gliomas tend to reccur
 Patients with glioblastoma invariably recur despite optimal upfront treatment with
the majority of recurrences occurring within the first year
Publication Location in relation to original site
Wallner et al (1989) <1 cm
Gasper et al (1992) <4 cm
Choucar et al (1986) 90% occur at site of tumor

40. • Decrease local failure
• Delay recurrence
• Prolong survival
Adjuvant treatment
Radiotherapy Chemotherapy Targeted therapy Tumor treating fields Gene therapy Immunotherapy

41. Radiotherapy
Conventional
2D approach
3 dimensional
conformal
radiotherapy
(3DCRT)
Brachytherapy
Stereotactic
Radiosurgery
Proton Beam
Therapy

42. Early era of radiotherapy in glioma
1940s, kilovoltage X-rays
whole brain RT
1960s , megavoltage X-
rays or 60Cobalt
teletherapy whole brain
RT
1970s there was a move
away from whole brain
radiotherapy for the entire
course of treatment.

43. Manual marking for Whole Brain RT
 Upper, lateral border- 1cm flash in air
 Lower border- inferior orbital ridge to tragus
dose:20 – 40 Gy in 5 to 20 fractions

44. Flouroscopy simulation
 Left and right opposed lateral fields
with 6-10mv photons
 Anterior temporal lobe, cribiform
plate, posterior aspect of eyes
included
 Inferior field edge in lower border of
C2 vertebrae and base of skull
German Helmet
technique
Limitations
-Most recurrences were in
close proximity to the
original tumour
-Survival differences
between WBRT and coned
down RT were not
significant (Shapiro et
al;BTCGTrial 8001. J Neurosurg
1989)
-Neurotoxictiy

45. Coned down 2D planning

46. Place a field

47. Conventional planning
Limitations
 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

48. Immobilization
MRI fusion
Delineation of
Target &
critical
organs
Steps of 3DCRT
Planning CT

50. Intensity Modulated Radiotherapy (IMRT)
 First launched in 1996
 It uses multiple small photon beams of varying intensities to precisely
irradiate a tumor
 The radiation intensity of each beam is controlled, and the beam shape
changes throughout each treatment

52.  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

53. Volumetric modulated arc therapy
(VMAT)
 Is a novel extension of IMRT wherein the dose is
delivered in a single gantry rotation while the
multileaf collimator leaves are in motion
 Launched in 2007

54. VMAT

55.  VMAT achieved equal or better PTV coverage and OAR sparing while using
fewer monitor units
 less time to treat high-grade gliomas

56. Proton beam therapy
RBE – 1.1 if compared
with Co60

57.  Low grade gliomas- younger age, better survival
 High grade glioma-more recurrences, dose escalation can be tried
Int. J. Radiation Oncology Biol. Phys., Vol. 45, No. 5, pp. 1117–1126, 1999
hr. J. Radiation Oncology Bid Phys. Vol. 22, pp. 287-294
Less integral dose, dose escalation
can be tried
With 90 CGE by
PBT
safe and efficacious, OS similar to photon

58. Contouring guidelines
 RTOG
Phase I-CTV- postoperative peritumoral edema plus a 2 cm margin( low grade 1 cm)
Phase II- CTV- residual tumor plus 2 cm margin
peritumoral
oedema as these
areas are believed
to contain high
concentrations of
tumour cells
EORTC- 2–3 cm
dosimetric margins
around the tumor
(as evaluated by
MRI)

60. Radiation doses
 Low grade gliomas
J Clin Oncol 20:2267-2276
(EORTC) STUDY 22844: 1996
2 Randomized trials
2-year actuarial incidence
grade 3 to 5 radiation necrosis
low-dose RT - 2.5%
high-dose RT- 5%
 High grade gliomas
Short course RT for elderly
 6.8 months --25 Gy/5#
 6.2 months --40 Gy/15#
De Castro et al 2017
RTOG 7401,BTSG 8001
no additional prolongation in
survival with doses >60Gy

61. Brachytherapy
 First used in 1953
 Placing radioactive material directly into or near the brain tumor
 Potential radiobiological advantages over EBRT :-
 Reduced damage to normal tissue
 More concentrated delivery of radiation to the tumor bed >80% of recurrences
are within 2 cm of the site of origin
 Low dose rate irradiation ( 1cGy/min)- better therapeutic ratio
Application of Brachytherapy :-
 Treatment option for recurrent tumors
 Primary RT
 Boost RT
 Can be used as radical or palliative treatment

62. Median survival 58.8 weeks vs 68.1 weeks for interstitial brachytherapy arm (p- 0.1)
Conclusion: no long-term survival advantage of increased radiation dose with 125I seeds in
newly diagnosed glioma patients
Another single institute prospective trial showed no survival advantage
Acute
Hemorrhagic complications (1-5%)
Infections
Poor wound healing
Raised ICT
Delayed
Radiation necrosis in 50% of patients Gutin et al
Atrophy
Gliosis
Progressive neurologic decline— occlusion of small and
great arteries

63. Stereotactic radiosurgery (SRS)
 “a single high-dose fraction of radiation, stereotactically directed to an intracranial
region of interest”
 A high ablative dose is applied to the lesion of interest
 Three widely used systems are
1. the Leksell Gamma Knife (Elekta, Stockholm, Sweden)
2. the Cyberknife (Accuray, Sunnyvale, CA, USA)
3. the Novalis (BrainLAB, Feldkirchen, Germany)
 Stereotactic radiotherapy (SRT) uses more than 1 fraction

64. Gamma Knife
 Launched by Lars Leksell in 1972
 Mechanical focusing of 192 radiation sources of
cobalt allows shaping of an extremely defined
irradiated volume in the brain
 The stereotactic head frame guarantees the precision
needed to protect healthy brain tissue and directs
the radiation focus into the target.
15Gy (3.1 – 4cm), 18Gy (2.1 to 3cm) or 24Gy (2cm or less)

65. Cyberknife
 Is a robot-controlled 6-MV linear accelerator (LINAC) with non-isocentric
cone beams
 Launched in 2007
 Non invasive

66.  Now generally accepted, that radiosurgery has no additive effect when given as
boost or in connection to initial standard treatment with surgical resection and
fractionated radiotherapy
 Reserved for recurrences
 Fractionated RT cannot be repeated and the surgery not always possible in
recurrence. Survival in recurrences after -
 SRS  6.5 to 30 months
 Resurgery 3.5-9 months
 Temozolamide  4.5 months
 bevacizumab  4.5 months
SRS has proven to be an
effective alternative treatment
option

67. Radiotherapy in Grade I astrocytoma
Defintive
 In children, with cerebellar and optic pathway
pilocytic astrocytoma
 In adults used for hypothalamic pilocytic
astrocytoma
Post Operative Radiotherapy
 Residual – progression
 Recurrent
Timing of adjuvant radiotherapy
Immediate
post-
operative
Delayed
In young children with
unresectable, non-progressive
low grade gliomas
In adults and older
children with
impractibility of repeated
surgical excision, extent
of residual disease,
location of tumor
proton beam therapy is often considered for these
patients

68.  Who undergo a gross total resection have a 52% risk of tumor progression 5-years
after surgery, warranting close follow-up and consideration for adjuvant treatment.
Diffuse low grade astrocytoma
Shaw et al;J Neurosurg 109:000–000, 2008
EORTC 22845 randomised trial
Lancet 2005; 366: 985–90

69. Radiotherapy in high grade gliomas
 The irradiated cases had a 6-month survival
rate of 64 per cent and a one-year survival
rate of 19 per cent;
 The non-irradiated cases a 6-month survival
rate of 28 per cent and a one-year survival
rate of 0 per cent
A. P. Andersen (1978) Postoperative Irradiation of
Glioblastomas: Results in a Randomized Series, Acta
Radiologica

70. Chemotherapy
 Drug therapies are effective for only few types of CNS tumors
(eg primary CNS lymphoma)
 But are useful for adjunctive therapy for many CNS tumors
 Poor efficacy due to :-
 difficulty in crossing blood brain barrier
 active transport mechanism of drug efflux
 high plasma binding of agents
 intrinsic and acquired resistance
 High intratumoral interstitial pressure
Only low molecular weight lipophilic drugs
freely cross the BBB

71. Chemotherapy in WHO grade I
astrocytoma
 Chemotherapy is often utilised as the initial therapeutic option in young
children to avoid long term sequelae of RT
 Multi centric trial suggestive of 50% of reduction in volume of tumor vs
none in placebo group

72. Chemotherapy in low grade diffuse gliomas
18 to 39 years of age with STR or biopsy
EBRT 54 Gy/ 30#/6 wks
PCV- 6 cycles
N Engl J Med. 2016;374(14):1344.
No trials comparing
temozolamide with PCV for
grade II
High risk diffuse LGGS

73. Chemotherapy in high grade glioma
Nitrosoureas
 Historically were standard choice of chemotherapy
 Lipid-soluble agents and can cross the BBB
 BCNU has mainly been evaluated as single-agent
therapy
 Dose 150 to 200 mg/m2 i.v6 to 8 weekly
 Toxicities myelosuppression, drug-induced
pulmonary fibrosis increases with cumulative
dosages

74. P
F
S
o
s
Grade III Grade IV
1988

75. Toxicity PCV Temozolamide
hematolgical 9% 4%
Neuro-Oncology 8, 253–260, 2006

76. PCV regimen

77. Dose modifications
Side effects

78. Temozolamide Regimen

79. FDA approval
1999- PCV refractory anaplastic
astrocytoma
2005-Newly diagnosed
glioblastoma

80. Carmustine wafers (GLIADEL® Wafer)
 Are biodegradable copolymers
impregnated with the alkylating
agent carmustine BCNU (3.5%)
 Developed in order to overcome the
limitations of blood-brain barrier
impermeability to antineoplastic
agent
 Is implanted in the brain along the
walls and floor of the cavity created
after a malignant glioma has been
surgically removed
• Median survival was 13.1 months in the
Gliadel arm and 11.4 months in the placebo
arm for glioblastoma
Westphal et al (2003)
• Median survival was 53.3 weeks in the
treatment arm and 39.9 weeks in the placebo
arm (p < 0.05) for high grade glioma
Valtonen et al (1997)

81. Targeted therapy
 Challenges limiting the efficacy :-
 difficulty in crossing blood brain barrier
 heterogeneity of tumors
 lack of accurate and reproducible biomarker
 difficulty in assessing target modulation

82.  Bevacizumab received approval by the US Food and Drug Adminstration (FDA) in
2009 for use in recurrent GBM:
Trial Study Arms Ph Study Setting N ORR, % mPFS, mo mOS, mo
BRAIN
BEV
II
Recurrent
glioblastoma
167
28 4.2 9.2
BEV + irinotecan 38 5.6 8.7
NCI BEV II
Recurrent
glioblastoma
48 35 16 wks 31 wks
JO22506 BEV II
Recurrent
glioblastoma
(Japan)
31 28 3.3 10.5
AVAglio[ BEV + RT + TMZ vs
Placebo + RT + TMZ
III
Newly diagnosed
glioblastoma
921 NA 10.6 vs 6.2* 16.8 vs 16.7†
 Only transitory clinical and radiographic benefit for a few month
 Main benefit is secondary to reduction in cerebral edema
Sanchez et alOncol Lett. 2012 Nov; 4(5): 1114–1118.
Control group – TMZ
BVZ group- BVZ/CPT-11
BVZ/CPT-11
High dose bevacizumab 15 mg/kg 3 weekly
irinotecan 125mg/m2on D1, 8, 22, and 29

84. TT fields (tumor treating fields) Optune ™
 Creates alternating, “wave-like” electric fields that travel across the upper part of
the brain in different directions
 Side effects -scalp irritation from device use and headache.
FDA approval
2011- recurrent GBM
2015- newly
diagnosed GBM
Cost- $21,000 per month

85. Gene therapy
 Trials in humans have entailed the stereotaxic injection of viral vectors directly into brain tumors
to transfect the cells to synthesize genes leading to tumor cell destruction (Ram and Oldfeld,
1977).
Patients receiving VB-111 survived 15 months on average,
compared with 8 months on average for patients receiving
bevacizumab in recurrent glioblastoma
was safe and well-tolerated
Phase III trial going on
Phase II

86. Immunotherapy
 Based on concept of harnessing the
patient's own immune system to
stimulate an antitumor response
 Immunosuppression is inherently
associated with glioblastoma and is
mediated by a variety of
mechanisms
Rindopepimut
Study mPFS mOS
Sampson et al
(2010)
14.2 m 23.6 m
Sampson et al
(2011)
15.2 m 26 m

87. Evolution in response assessment

88. Levin criteria
WHO oncology
response criteria
Macdonald
criteria
AVAglio
the Response
Assessment in
Neuro-Oncology
(RANO)
Prior to 1990s Since 1990 In 2009 In 2010
edema and
mass effect
measured tumor
area by
multiplying the
maximal cross-
sectional
enhancing
tumor diameters
Complete
response,
partial
response,
stable
disease,
progressive
disease
the effectiveness of
RT and TMZ with or
w/o bevacizumab in
newly diagnosed
glioblastoma