Management of high grade brain tumors

1. Management of High Grade Glioma
Dr. Shreya Singh
JR-III
Department of Radiation Oncology
IMS, BHU
1

2. WHO Grading of Gliomas
Grade Histopathological
Characteristics
Tumor Types
High
Grade
Grade
III
Increased cellularity
Nuclear Atypia
Marked mitotic activity
• Anaplastic Astrocytoma
• Anaplastic
Oligodendroglioma
Grade
IV
Nuclear Atypia
Marked Mitotic activity
Endothelial proliferation
and /
Necrosis
• Glioblastoma Multiforme
• Gliosarcoma
Pathological Features and Grading :
2

3. Etiology and Epidemiology :
• 60% of all primary brain tumours are glial tumours and two-thirds of
these are clinically aggressive, high-grade tumours
• Men are more commonly affected than women
• The peak incidence occurs in the age range of 65 to 75 years
• Median survival time is inversely proportional to age
• Possible Risk Factors – (However, the absolute risk is low)
• exposure to electromagnetic fields
• chemical exposure - nitrosamines
• previous exposure to therapeutic ionizing radiation
3

4. Pathways of Spread
• WHO grade III to IV gliomas - tendency to directly infiltrate
adjacent brain tissue
• Lesions with direct access to the corpus callosum may extend
across the midline - classic “butterfly pattern”
• Diffusely infiltrative nature of these tumors makes complete
removal of all tumor cells impossible
• Leptomeningeal spread - occasionally
• Hematogenous and lymphatic spread - exceedingly uncommon
4

5. Clinical Features :
• Alteration in mental status
• Headache
• Visual changes
• Speech deficit
• Cranial nerve palsies
• Ataxia
• Motor deficits
• Sensory deficits
• Gait disturbance
• Seizures
5

6. Workup :
• History and Examination –
Complete history and physical examination with a
thorough neurological examination including a baseline
mini-mental status examination
Particular attention to ophthalmological and endocrine
findings, depending on the tumor location
Malignant gliomas cause high incidence of deep
venous thrombosis and subsequent risk of pulmonary
embolism - thus, attention to associated symptoms or
physical findings is required
6

7. Neuro-imaging :
• Magnetic Resonance Imaging – Investigation of choice
– Brain
– Spine
– Timings – Preoperative, within 72 hours after surgery
• CT scan (only where MRI is not feasible - implanted pacemaker/defi
brillator or other non-MRI compatible implanted devices, surgical
clips, or metal)
• Magnetic Resonance Spectroscopy
• Magnetic Resonance Perfusion
• PET-CT scan
• Molecular diagnosis
]
Can be considered to rule
out RT-induced necrosis or
“pseudoprogression” &
confirmation of response
or pseudoresponse
7

8. MRI :
• MRI, with and without gadolinium, is the imaging modality of
choice for evaluation of malignant brain tumors
• T1-weighted images are useful for defining anatomy and
should be obtained pre- and post-contrast
• T2-weighted images and fluid attenuation inversion recovery
(FLAIR) aid in detecting edema or infiltration of brain
parenchyma, including infiltration across the corpus callosum,
a not-infrequent finding in malignant gliomas
• The pattern of enhancement is useful in the differential
diagnosis of the lesion
8

9. Characteristics on MRI
WHO
Grade
Characteristics on MRI
I Well circumsrcibed enhancing lesions with cystic
component
II Usually ill-defined, diffuse, nonenhancing low-
density regions
III May show enhancement & necrosis,
Upto 1/3rd may not enhance
IV Vasogenic edema and ring enhancement around
central necrotic regions
9

10. Glioblastoma Multiforme
Peripheral enhancement and a
central necrotic region with
surrounding FLAIR/T2 signal change
indicative of vasogenic edema or
tumor infiltration 10

11. Anaplastic Glioma
Infiltrative, mass effect - may or may not enhance
11

12. MR Spectroscopy :
For analyzing the chemical
composition in area of
concern -
• N-acetylasparate is
decreased in gliomas
• Choline is increased in
tumors
• Lactate is present in
necrotic tumor, infection
or stroke
12

13. Pseudoresponse :
Pseudoresponse – A decrease in
the enhancement area on MRI
shortly after treatment
completion.
Pre-treatment Post-treatment 3.5 months
13

14. Pseudoprogression :
Pseudoprogression – An increase in the nontumoral
enhancing area on MRI shortly after treatment
completion which mimics tumor progression.
So enhancement is not a measure of tumor activity but rather reflects a disturbed BBB14

15. Molecular Diagnosis
15

16. Genetic Alterations Associated with High
Grade Glioma :
ATRX loss
16

17. WHO
Grade
Tumor Type IDH1/2
mutation
1p/19q co-
deletion %
MGMT promoter
methylation %
EGFR
%
Grade I Pilocytic astrocytoma <20
Grade II Diffuse Astrocytoma 70-80 15% 40-50
Oligodendroglioma 70-80 30-60 60-80
Grade III Anaplastic
Astrocytoma
50-70 15% 50
Anaplastic
Oligodendroglioma
50-80 50-70 50-75
Garde IV GBM 5-10 <5 35-40 ~40
Average prevalence of Genetic abnormalities in Gliomas
17

18. Prognosis
18

19. Clinical prognostic factors
(High Grade Glioma)
• Age at diagnosis - age >50 years is associated with
poorer prognosis
• KPS
• Extent of resection
• Duration of symptoms
• Neurologic status
19

20. Radiation Therapy Oncology Group Recursive
Partitioning Analysis of Malignant Gliomas
Class Patient Characterstics Median Survival
(Months)
I, II Anaplastic astrocytoma
• Age ≤50 yr, normal mental status or age >50 yr
• KPS >70, symptoms >3 mo
40-60
III, IV Anaplastic 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
20

21. General line of Management of Gliomas :
• Surgery
• Radiotherapy
• Chemotherapy and Targeted Therapy
• Symptomatic management
21

22. Glioblastoma Multiforme
22

23. Standard Treatment
Maximal safe surgical resection
+
Radiotherapy with concurrent temozolomide
chemotherapy
+
Subsequent adjuvant temozolomide
chemotherapy
23

24. Indications for Surgery :
• Resection with definitive intent
• Biopsy for diagnosis
• Palliative debulking for management of mass
• Shunting to relieve symptoms caused by increased
intracranial pressure or hydrocephalus
• Resection of recurrent disease in selected patients
24

25. Radiotherapy :
• Definitive treatment (with concurrent and adjuvant
chemotherapy) after resection or biopsy
• RT usually started within 5 weeks of definitive resection
• RT over supportive care –
BTCG 69-01 :
– Significant (doubled) survival with RT over supportive care
and resulted in RT becoming a standard component of
treatment.
25

26. Whole brain vs. Limited Volume RT :
Limited field radiotherapy (Preferred)
Most of the recurrence is local (within 2cm of
enhancing tumor on CT )
(Hochberg et al reported that 78% of recurrences of GBM were
within 2 cm of the margin of the initial tumor bed and 56%
were within ≤1 cm of the volume outlined by the CT scan)
Comparable outcomes to WBRT
Avoidance of neurotoxicity associated with WBRT
WBRT may be recommended for multifocal disease
26

27. Radiotherapy Volumes :
27

28. Radiotherapy Volumes :
28

29. Radiotherapy Dose :
• Standard Approach :
 59.4 Gy to 60 Gy in 30 to 33 fractions @ 1.8
to 2 Gy/fraction
 ‘Shrinking field’ technique
• Patients with poor prognostic factors :
 Short course , Hypofractionated RT
 34 Gy/ 10 fractions or 40 Gy/15 fractions)
• Older >65 yrs
• Low KPS
• Rapidly progressive neurological deficit
29

30. • No role of dose escalation or altered
fractionation
• Treatment with interstitial boost does not
prolong survival
• No survival advantage seen with use of radio-
sensitizer
30

31. Chemotherapy:
TEMOZOLOMIDE –
• The only chemotherapeutic agent that has demonstrated efficacy in
RCTs
• Oral, 2nd generation alkylating agent (derivative of dacarbazine)
• 100% bioavailability when taken empty stomach
• Continuous daily temozolomide works through silenced action of
methyl-guanine-methyl-transferase (MGMT) - an enzyme important
for repair of alkylating agent induced DNA damage in tumor cells
• No role of dose intense TMZ for newly diagnosed glioblastoma
patients 31

32. Roger Stupp et al
N=573, 85 centers MS (month) 2 yr SR % GR ¾ HT 5 yr SR %
RT 60Gy/30Fr 12.1 10.4 None 1.9
CCRT (TMZ 75mg/m2) f/b
6 x adj Tmz 150-200/m2
day 1-5 q28
14.6 26.5 7% 9.8
Original Article
N Engl J Med 2005; 352:987-996March 10, 2005
32

33. Tumor Treating Fields :
PRINCIPLE :
• Involves placement of non-invasive transducer arrays on
scalp
• Uses electric fields within the human body that disrupt the
rapid cell division exhibited by cancer cells
• Disrupt mitotic spindle microtubule assembly (metaphase and
cytokinesis)
• TTF therapy has not been shown to affect cells that are not
undergoing division
33

34. Tumor Treating Fields :
• Utilises-
o Low intensity ( 1 to 3 V/cm)
o Intermediate frequency (100
to 300 kHz)
o Alternating electric field
o Two sequential field
directions using two
perpendicular transducer
34

35. Tumor Treating Fields :
• RCTs show survival benefit
with prolongation of median
overall survival from 16 months
to 20.9 months
• Higher quality of life
• Approved for treatment of
recurrent and newly diagnosed
glioblastoma
35

36. • Carmustine impregnated biodegradable polymer (GLIADEL wafer) may be
considered for intraoperative placement if frozen section reveals high grade
glioma
• The wafer slowly undergoes biodegradation, releasing the active drug
• Advantage –
– Minimal systemic toxicity
– no limitation posed by the BBB
– delivery of very high local concentrations of chemotherapy.
• Studies in GBM have shown only marginal benefit
Gliadel Wafers :
36

37. Gliadel Wafers :
• Designed to be placed (upto 8 in number) in the
surgical cavity after glioblastoma resection to deliver
local chemotherapy, gets dissolved in 2-3 weeks
• Intended for tumors for which gross total resection is
possible
Median Survival (n=240)
Wafers: 13.9 months
Placebo: 11.6 months
• Ongoing studies are evaluating the possible value of
combining Gliadel and Temozolomide
Presse Med. 2007 Sep;36(9 Pt 2):1249-54. Epub 2007 Mar 12.
37

38. Treatment at Recurrence
• Management goals should be palliative
• Hospice referral for palliative care is reasonable
for many patients
• Palliative debulking may help selected patients by
relieving mass effect - probably extends survival
by about 4 to 6 months
• Bevacizumab – VEGF receptor inhibitor has been
approved as single agent for recurrent GBM –
causes vascular stabilization and protection
38

39. Other options under investigation :
o Repeat EBRT
o Carmustine wafers
o Radiosurgery
o Brachytherapy - GliaSite balloon Brachytherapy
o Chemotherapy - Temozolomide ; Procarbazine
o Tumor treating field
Treatment at Recurrence
39

40. Gliosarcoma
• Gliosarcoma is a rare primary malignant brain tumour
with a reported incidence of 1.8–5% of all
glioblastomas
• Biphasic tumor of the central nervous system and is
considered as a variant of glioblastoma multiforme
• The current accepted definition of primary gliosarcoma
is a well-circumscribed lesion with clearly identifiable
biphasic glial and metaplastic mesenchymal
components
40

41. • Unique features of gliosarcoma include-
o propensity to undergo extra-cranial metastasis
o distinct radiological features
o worse prognosis than GBM
41

42. • In clinical practice GSM are generally managed in
accordance with the prevailing guidelines for
GBM
• In patients with good functional status, optimal
treatment for GSM now includes maximal surgical
resection followed by radiotherapy and
chemotherapy
• This multi-modality management approach has
been extrapolated from GBM to become the
standard of care for GSM
42

43. Age <70 years Age >70 years
Poor PS (KPS <60)
• Hypofractionat
ed EBRT or
Temozolamide
Poor PS (KPS <60)
• Hypofractionat
ed EBRT or
Temozolamide
Good PS (KPS
>60)
• Standard focal
EBRT +
Concurrent &
adjuvant
Temozolamide
Good PS (KPS
>60)
• Hypofractionat
ed EBRT alone
• Maximal safe
resection
feasible
• Maximal safe
resection not
feasible
Maximal safe
resection +/-
Carmustine
wafer
STR or open
biopsy or
sterotactic
biopsy
Grade IV Glioma
43

44. Grade III Glioma
Anaplastic Oligodendroglioma
44

45. • 3.5% of all malignant gliomas and 30% of
oligodendroglial tumors
• Occur predominantly in adults, with median
age at diagnosis of 45 to 50 years
• Shows better prognosis and outcomes than
anaplastic astrocytoma
45

46. Molecular Genetics
• Deletions in 1p and 19q –
o Associated with longer progression-free survival,
overall survival, and chemo- and radiosensitivity
• Somatic mutations in the IDH1 gene –
o Strong positive prognostic factor
o Derive an overall survival benefit from the
addition of PCV chemotherapy to radiotherapy
(EORTC 26951 and RTOG 9402)
• MGMT promoter methylation
46

47. RTOG 94-02 : EORTC 26951 :
o Assessed 1p and 19q status in
patients with anaplastic
oligodendroglioma randomized
to receive PCV followed by RT
(NACT x 4) or RT alone
o Combined loss of 1p and 19q
resulted in a longer median
survival time
o Patients with anaplastic
oligodendroglioma were
randomized to receive RT
followed by PCV (Adj x 6) or
RT alone
o Presence of 1p or 19q loss
was found to be the most
important predictor of
outcome
47

48. 1p and 19q Co-deletions :
48

49. • 1p19q codeleted (which almost always harbor IDH
mutations), as well as the 1p19q noncodeleted, but with
IDH mutations, should be treated with combination
chemoradiotherapy
• 1p19q noncodeleted without IDH mutations, has the
worst prognosis (similar to GBM) and appears unlikely
to derive benefit from the addition of chemotherapy
49

50. Treatment :
Standard of care
Maximal surgical resection
+
Postoperative radiotherapy
and
Chemotherapy
50

51. Radiotherapy Volumes :
• The radiotherapy target volume includes-
 The postoperative cavity
 Any residual enhancing disease
 The FLAIR or T2 abnormality
• Partial brain fields are used
– Initial GTV - T2 or FLAIR abnormality
– Boost GTV – contrast enhancing volume or surgical bed
– CTV – 2-3 cm surrounding GTV, not expanding across natural barriers
• Postoperative FLAIR abnormality from anaplastic oligodendroglioma most
likely represents predominantly residual tumor with minimal contribution
from tumor-associated edema and therefore has to be included in the
target volume
51

52. Radiotherapy Dose :
• The commonly used radiotherapy dose on
prospective trials of anaplastic oligodendroglioma is
59.4 to 60 Gy
– Dose to initial volume – 46 Gy/23 fractions
– Dose to boost voume – 14 Gy/7 fractions
• These trials never took into account molecular
variability, and some have proposed that
consideration could be made to lower the RT dose to
54 Gy for tumors with favorable prognostic features
as to minimize long-term toxicity (e.g., 1p19q
codeleted)
52

53. Chemotherapy :
• Anaplastic oligodendrogliomas are generally chemosensitive
tumors primarily based on high response rates to PCV
• Both the 1p19q codeleted and any IDH-mutated (with or
without 1p19q codeletion) patients should receive
chemoradiotherapy (PCV), but the role of combinatorial
therapy for the 1p19q noncodeleted and IDH wild-type tumors
is questionable
53

54. • Procarbazine - 75mg/m2 per oral daily D8-D21
• Lomustine - 110mg/m2 per oral D1
• Vincristine - 1.4mg/m2 i.v. D8 & d29
*Shaw EG, Wang M, Coons SW, et al., Randomized trial of radiation therapy plus procarbazine, lomustine, and
vincristine chemotherapy for supratentorial adult glioma: J Clin Oncol 2012;30:3065-3070
6 To 8 week cycles,
Total 6 cycles (Adj)
PCV Regimen :
54

55. • Because of the significant toxicity associated with PCV
regimen, many clinicians prefer Temozolomide
• Longer PFS was observed with PCV compared to
Temozolamide in co-deleted patients
• Therefore, although temozolomide is widely used in lieu of
PCV, the data supporting this practice are weak
55

56. Grade III Glioma
Anaplastic Astrocytoma
56

57. Molecular Genetics :
• Anaplastic astrocytomas can be separated into molecular
subgroups based on 1p19q codeletion status and IDH
mutation status
1. With 1p19q codeletion and IDH mutation
• carries the most favorable prognosis
2. Without 1p19q codeletion but with IDH mutation
• carries an intermediate prognosis
3. IDH wild-type anaplastic astrocytoma
• carries the worst prognosis, comparable to GBM
57

58. Treatment :
Standard of care
Maximal surgical resection
+
Postoperative radiotherapy
and
Chemotherapy
58

59. Radiotherapy :
• Postoperative RT has been shown to provide a survival
advantage in several clinical trials
• The radiotherapy target volumes are similar to those for
anaplastic oligodendroglioma
• The radiotherapy dose is typically 59.4 to 60 Gy in 6 to 6.5
weeks
• Tumors with prognostically favorable molecular features could
be treated to a slightly lower dose of 54 Gy in 6 weeks given
the potential for extended survival with the addition of
chemotherapy (Temozolomide)
59

60. Temozolomide : CATNON Trial
60

61. • Adjuvant temozolomide chemotherapy was associated with a
significant survival benefit in patients with newly diagnosed non-
co-deleted anaplastic glioma
• MGMT methylation was observed in 42% of patients and was
prognostic for overall survival
• MGMT methylation did not predict for prolonged survival with the
addition of adjuvant temozolomide.
CATNON Trial
First Interim Analysis
Adjuvant TMZ Median
Survival
5 year
survival
PFS
No (n= 372) 41 months 44.1 % 19 months
Yes (n= 373) Not reached 55.9% 43 months
61

62. Chemotherapy
• In patients with anaplastic astrocytoma, (most
without combined allelic loss of 1p and 19q), the
addition of adjuvant temozolomide after
radiotherapy provides a survival advantage, and
IDH retains prognostic significance
• The exact role of concurrent temozolomide and
the impact of IDH mutational status have not
been fully defined for anaplastic astrocytoma
62

63. • Yung et al study
– 162 patients
– Treated with Temozolamide (150-200mg/m2 D1-D5 every 28
days) at 1st relapse
– Results
• 6 month PFS – 46%
• OS - 13.6 months
• ORR = 35% (CR = 8%, PR = 27%)
• Mild to moderate hematologic toxicity <10% of patients
• Conclusion
– Temozolamide is effective for the treatment of recurrent
anaplastic astrocytoma.
Temozolomide in Recurrent Anaplastic
Astrocytoma
63

64. Grade III
Anaplastic Ependymoma
64

65. Treatment
• Maximal surgical resection
(including 2nd surgery if possible)
o Good survival after total surgical resection
o Supratentorial disaese – poor prognosis (high grade,
large remaining disease after surgery)
• Post-op irradiation
o 10 year survival after RT – 50%
Practically, Complete resection rate – 40-60%
65

66. Post-op Radiation
• Total dose for primary intracranial ependymomas -
– 54 - 59.4 Gy/1.8-2.0 Gy per fraction
– Margins -
• GTV = tumor bed + any residual disaese
• CTV = GTV + 1-1.5 cm margin
• Large margins - in case of infilteration
• For spinal ependymomas
– 45 – 50.4 Gy/1.8 Gy per fraction
– 2 cranial & 2 caudal vertebral bodies to disease
• For sacral ependymomas or below conus medullaris
– Upto 60 Gy
66

67. Craniospinal Irradiation
• Indications
– Positive CSF cytology
• CSF dissemination rate = 15% after primary intracranial
ependymoma.
– Positive MRI for neuraxis spread
• CSI dose –
36 Gy/20 fractions to whole brain & spine, followed
by local field irradiation to spinal lesion to 45 Gy.
67

68. Anaplastic Glioma :
68

69. Symptomatic Treatment
69

70. Cerebral Edema :
• Glucocorticoids (usually dexamethasone) are
used preoperatively, postoperatively, and
during the early phases of irradiation to
decrease cerebral edema
• They should be tapered to the lowest dose
necessary to control symptoms (i.e., 25%
reduction in every 3 days)
70

71. • Patients with seizures rrequire anti-convulsants
• Anticonvulsants such as carbamazepine,
phenobarbital, and phenytoin induce hepatic
cytochrome P450 isozymes, which increase the
metabolism and clearance of several cancer
chemotherapy agents
• Non–enzyme-inducing anticonvulsants, such as
levetiracetam, lacosamide, lamotrigine, and
pregabalin are preferred
Seizures :
71

72. Sequelae of Treatment :
• Surgery :
– Bleeding and infections
– Focal neurological deficits
• Radiotherapy :
SUBACUTE
•Headache
•Somnolence
•Deterioration of pre
existing deficit
LATE
•Radiation necrosis
•High tone hearing loss
•Insufficiency of
hypothalamic-pituitary
axis
ACUTE
•Nausea and
vomiting
•Otitis externa
72

73. 73