RADIATION ONCOCOLGY

1. MANAGEMENT OF HIGH GRADE
GLIOMA
Dr. Sumit Agrawal
JR-II

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

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

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

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

6. WORKUP
• History and Examination –
Ø Complete history and physical examination with a thorough
neurological examination including a baseline mini-mental status
examination
Ø Particular attention to ophthalmological and endocrine findings,
depending on the tumor location
Ø 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

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

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

9. CHARACTERISTICS ON MRI
WHO Characteristics on MRI Grade
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

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

11. ANAPLASTIC GLIOMA
Infiltrative, mass effect - may or may not enhance

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

13. PSEUDO-RESPONSE
Pseudoresponse – A decrease in the enhancement area on MRI shortly after
treatment completion.

14. PSEUDO-PROGRESSION
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 BBB

15. MOLECULAR DIAGNOSIS

16. GENETIC ALTERATIONS ASSOCIATED WITH
HIGH GRADE GLIOMA
ATRX loss

17. AVERAGE PREVALENCE OF GENETIC
ABNORMALITIES IN GLIOMAS
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

18. PROGNOSIS

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

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

22. GENERAL LINE OF MANAGEMENT OF
GLIOMAS
• Surgery
• Radiotherapy
• Chemotherapy and Targeted Therapy
• Symptomatic management

23. GLIOBLASTOMA
MULTIFORME

24. STANDARD TREATMENT
Maximal safe surgical resection
+
Radiotherapy with concurrent temozolomide chemotherapy
+
Subsequent adjuvant temozolomide chemotherapy

25. 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

26. 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.

27. WHOLE BRAIN VS LIMITEDVOLUME 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

28. RADIOTHERAPY VOLUMES
28

29. RADIOTHERAPYVOLUMES

30. 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

31. • 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

32. 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

33. 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

34. TUMORTREATING 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

35. TUMORTREATING FIELDS
• Utilises-
o Low intensity ( 1 to 3 V/cm)
o Intermediate frequency
(100 to 300 kHz)
o Alternating electric field
o Two
directions
sequential
using
field
two
perpendicular transducer

36. TUMORTREATING FIELDS
• RCT
s show survival
with
benefit
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

37. • 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

38. 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.

39. TREATMENTAT 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

40. TREATMENTAT RECURRENCE
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

41. 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

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

43. • 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

44. 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

45. GRADE III GLIOMA
ANAPLASTIC OLIGODENDROGLIOMA

46. • 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

47. 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

48. 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 Patients with anaplastic
oligodendroglioma were
randomized to receive RT followed
by PCV (Adj x 6) or RT alone
o Combined loss of 1p and 19q
resulted in a longer median survival
time
o Presence of 1p or 19q loss was
found to be the most important
predictor of outcome

49. 1P AND 19Q CO-DELETIONS

50. • 1p19q codeleted (which almost always
IDH mutations), as well as the
harbor
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

51. TREATMENT
Standard of care
Maximal surgical resection
+
Postoperative radiotherapy and
Chemotherapy

52. RADIOTHERAPYVOLUMES
• 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

53. 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)

54. 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

55. • Procarbazine - 75mg/m2 per oral daily
• Lomustine - 110mg/m2 per oral
• Vincristine - 1.4mg/m2 i.v.
PCV REGIMEN
D8-D21
D1
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 To8 week cycles,
Total 6 cycles (Adj)

56. • 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

57. GRADE III GLIOMA
ANAPLASTIC ASTROCYTOMA

58. MOLECULAR GENETICS
• Anaplastic astrocytomas can be separated into
subgroups based on 1p19q codeletion status
molecular
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

59. TREATMENT
Standard of care
Maximal surgical resection
+
Postoperative radiotherapy
and
Chemotherapy

60. 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)

64. TEMOZOLOMIDE : CATNONTRIAL

65. • 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.
CATNONTRIAL 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

66. 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

67. • 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

68. GRADE III
ANAPLASTIC EPENDYMOMA

69. TREATMENT
• Maximal surgical resection (including 2nd surgery if
possible)
o Good survival after total surgical resection
o Supratentorial disease – 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%

70. 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

71. 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.

72. ANAPLASTIC GLIOMA

74. SYMPTOMATIC
TREATMENT

75. 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)

76. SEIZURES
• Patients with seizures require 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

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

78. THANK YOU