Management of low grade gliomas

1. Low Grade Glioma – Classification
and Management

2. Introduction
• MC primary brain neoplasm in adults
• Incidence : 6.5 per lakh
• LGG : WHO Grade I and II
• Includes
▫ Astrocytomas
▫ Oligodendrogliomas
▫ Mixed oligoastrocytomas

4. • All LGG have the potential to de-differentiate into
HGG
• MC
▫ Frontal lobes – 44%
▫ Temporal – 28%
▫ Parietal – 14%
• Mean age at Dx – 40yrs
• Male:female – 1:1

5. • MC histologic subtype
▫ Astrocytoma – 69%
▫ Oligodendroglioma – 21%
• MC presentation - seizures, headache
• Slow growth rate – 4mm/yr

6. Imaging
• Iso/hypointense on T1
• Hyperintense on T2
• Do not enhance
• Calcification – 20%
• No edema/necrosis
• MR spectroscopy
▫ Elevated Cho
▫ Decreased NAA
▫ Decreased creatinine

9. Genetic expression
• P53 – progress to secondary
GBM
• Methylation of MGMT
gene –better response to
alkylating agents
• 1p/19q co-deletion – better
response to chemo
• IDH1 and 2 mutation –
better survival
• IDH + ATRX mutation –
even better survival in Grade
II gliomas

11. Oligoastrocytoma
• WHO Grade II
• 3rd most common glial neoplasm
• Astrocytic component – IDH mutant, ATRX mutant,
Intact 1p19q
• Oligodendrogliocytic component - IDH mutant, ATRX
wild-type, 1p19q co-deletion

13. Pilocytic astrocytoma
• Juvenile pilocytic astrocytoma
• WHO grade I
• Large cystic lesion with brightly enhancing mural nodule
• 20% - calcification
• MC - cerebellum

14. • Optic nerves and chiasm
• Strong association with NF-1
• Pilocytic – elongated hair-like projections

17. SEGA

19. Pleomorphic xanthoastrocytoma
• WHO grade II
• A/w temporal lobe epilepsy –
75% seizures
• NF-1
• Children
• Cortical tumors with cystic
component
• Contrast enhancing
• Slow growing
• Reactive dural involvement –
Dural tailing
• Variable type of cells -
pleomorphic
• Lipid laden cells – xanthomatous
astrocytes

23. Chordoid glioma of the 3rd ventricle
• Slow growing
• Well circumscribed
• <100 cases
• Adults(Female:Male : 2:1)
• WHO Grade II
• Cords of cells
• Russel bodies(ER)
• Contrast enhancing

26. Angiocentric glioma
• WHO grade I
• Slow growing
• Children
• Intractable partial
seizures – 95%
• Few reported cases
• Spindle cells arranged in a
perivascular fashion
• Perivascular and sub-pial
growth
• A/w cortical dysplasia
• Non-enhancing

29. Astroblastoma
• Can be benign to aggressive
• Not yet graded
• Well-defined areas with
necrosis and degeneration
• Bubbly appearance

31. Diffuse Astrocytoma
• Low grade infiltrative astrocytomas
• Diffuse low grade gliomas
• Synonymous with fibrillary astrocytoma
• 2 molecular groups
▫ IDH mutant
▫ IDH wild
▫ Diffuse astrocytoma NOS
• 1p19q co-deletion should be absent

32. • Bimodal age distribution
▫ 6-12 yrs
▫ 20-45 yrs
• Seizure
• Fibrillary neoplastic astrocytes
with nuclear atypia
• Microcystic spaces with
mucinous fluid
• No contrast enhancement
• Suppresses on FLAIR (T2-
FLAIR mismatch sign)

35. Gemistocytic astrocytoma
• IDH mutant variety of low
grade astrocytoma
• Highly aggressive
• WHO grade II
• >20% Gemistocytes
• MC in frontal lobes
• Median survival – 2.5 yrs
• 5yr survival rate – 30%

38. Treatment options

39. Observation
• Deep seated lesions
• Eloquent areas
• Main concern – Treatment
associated risk and cost
• Problems
▫ Tumor progression
▫ Can become unresectable
▫ Radioresistant
▫ New deficits
▫ Intractable seizures
▫ Psychological stress

40. “ The new philosophy is to abandon the conservative wait-and-see
attitude to evolve toward an early, radical, safe and individualized
preventive functional surgical neurooncology”
H. Duffau
Institute of Neurosciences of Montpellier, France

41. Stereotactic biopsy
• Uncommon
• Diffuse lesions
• Sampling error
• Undergrading of tumor(30%)
• Specific regional targeting
• Frameless systems – morbidity
and mortality < 1%
• Death
▫ ICH
▫ SAH
▫ Cerebral edema

42. Surgery

43. Why to operate ??
• Tissue diagnosis
• Surgery improves OS
• Delays malignant transformation
• Preserves or improves QoL – control of epilepsy
• Changes glioma from a premalignant lesion to a chronic
disease under control for many years

44. Microsurgical resection
• Accessible lesion
• Local mass effect
• Raised ICP
• Intractable seizures
• Alleviation of mass effect
• Cytoreduction
• Reduce cerebral edema
• Improves Chemo/radio
sensitivity

45. Pre-symptomatic stage – unknown duration
Symptomatic period – 7yrs after initial presentation
Transformational stage – 2 to 3 yrs of rapid tumor progression
Rate of growth: 4mm/yr

46. Aids
• Intraoperative USG
• Intraoperative MRI
• Greater extent of resection

47. • Greater extent of resection
• Increases OS by ~150% (GTR v/s STR)
• Increases time to malignant transformation
• Claus et al – pts who underwent incomplete
resection had 5 times the r/o death v/s those who
underwent total resection(DLGGs)

48. • GTR – no visible lesion during surgery or on
post-op imaging
• NTR – Tumor <1.5cm3 on post-op imaging or
tumor bed enhancement <0.5cm
• STR – Tumor visible during surgery or postop
imaging >1.5cm3

49. • In 222 DLGGs on followup for 4 yrs, Duffau et
al found that 45 pts with >10cc residue died,
while only 17 pts with <10cc died. No pts with
complete resection died
• Schomas et al demonstrated that GTR and
radical STR improved OS in a series with 852
DLGGs

50. Surgery v/s Biopsy
• 5 year OS
• 82% v/s 54%
• Roelz et al – 126 pts with DLGG

51. Intraoperative fluorescence guided
Surgery
• 5-ALA
• Generates fluorescence in neoplastic cells
• Typically in malignant transformation
• BALANCE trial

52. BALANCE Trial
• Barrow 5-ALA Intra-operative Confocal Trial
• Combined use of 5-ALA and intraoperative confocal
microscopy in resection of LGGs
• Prospective Randomised Phase III trial
• Macroscopic fluorescence – not evident
• Micrscopic fluorescence at cell level +

53. Supratotal resection
• Conventional MRI underestimates the spatial extent
of Gliomas
• Resection beyong radiological margins
• Significantly reduces rates of malignant
transformation for a long period
• Reduces and delays need for adjuvant therapy

54. Recurrence
• Re-operation
• Multistage surgical approach
• Initial maximal function guided resection
• Second surgery several yrs later – optimization of
EOR while preserving QoL

55. Conceptual shift
• Image guided surgery towards a Functional-
mapping guided resection
• Tailor the resection upto individual functional
boundaries, with no margin
• Maximize tumor removal while preserving eloquent
structures

56. • Intraop electrostimulation mapping – gold
std in glioma surgery
• Sole method able to detect in real time the
cortico-subcortical neural networks
• Can detect inter-individual anatomo-
functional variability

57. Subpial dissection
• Preserve the entire vasculature – arteries and veins
• Minimize use of coagulation
• In-passing vessels should be spared
• Corticectomy on either side of each vessel

58. Stage 2
• Removal of brain invaded by the glioma using a
subpial dissection
• Sulcus identified, not opened
• Subpial dissection with aspiration of glioma, without
coagulation
• Preservation of pia-mater also avoids spasm

59. Chemotherapy

60. Regimens
• TMZ
• PCV (Procarbazine + Cecenu/Lomustine +
Vincristine)

61. TMZ
• Daily dose of 150 mg/m2 x 5days
• Dose increased to 200 mg/m2/d x 5 days
• Usually a cycle – 1 month

62. PCV
• Cecenu – D1(110 mg/m2)
• Procarbazine – D8 to D21(60 mg/m2)
• Vincristine – D8 and D29 (1.4 mg/m2 – max 2g)
• Cycle is repeated at 6-8 wks

63. • TMZ
• MTD decreased in 92% pts
• Tumor regrowth
▫ 16% of 1p-19q co-deleted tumors
▫ 60% in non-codeleted tumors
▫ 70% in tumors over-expressing p53

64. Seizure reduction
• >= 50% seizure reduction at 6m of TMZ initiation –
a/w objective MRI response at 12m and 18m
• Seizure improvement is an independent
prognostic factor for PFS and OS at 6/12/18 m
of TMZ onset
• AEDs – Levetiracetam, Lacosamide or Lamotrigine

65. QoL and chemotherapy
• TMZ alone or combined with surgery is able to
maintain or even improve the quality of life in
majority of pts

66. Chemotherapy and survival
• RT + chemo – doubles OS for DLGGs
• TMZ alone – improves 3 yr OS significantly
• If tumor volume <‘s >20% - lower postop
residual volume and better prognosis

67. Gonadotoxicity
• PCV
▫ prolonged azoospermia in 90-100% men
▫ Premature ovarian failure – 5 to 25% under 30 yrs
▫ Due to Procarbazine and Vincristine
• TMZ – not totally gonadotoxic

68. Other toxicities
• PCV
▫ Acute hematological toxicity
▫ Increased r/o leukemia(t-AML)
▫ T-MDS
▫ Severe peripheral neuropathy -V
▫ Lung fibrosis – C
▫ Intense asthenia and loss of wt
• TMZ
▫ Severe hepatitis

69. In short
Good prognosis Poor prognosis
• Small tumors(OS/PFS)
• Higher MMSE score(OS/PFS)
• 1p-19q co-deletion
• MGMT promoter methylation
• IDH mutation
• Baseline FND’s
• Shorter time since 1st
symptoms( <30wks)
• Astrocytic tumor type
• Tumors > 5cm

70. Radiation therapy

71. Radiotherapy
• Post-op radiation does not improve OS
• Better PFS ( 5.3 yrs v/s 3.4 yrs )
• Higher doses – more adverse effects, less survival
• 45 – 54 Gy – effective and safe

72. High risk LGG
• Age >= 40 + any extent of resection
• Age < 40 + STR or biopsy

73. • Hish risk LGG – Immediate radiotherapy
• Poorer PFS
▫ Tumor diam >= 4cm
▫ Astrocytoma/Oligoastrocytoma
▫ Post-op residual >= 1cm
• Residual d/s
▫ 1-2 cm – R/c 68%
▫ >2cm – 89%
▫ Hence post-op radiation

74. Role of SRT and SRS
• SRT in 5 sitting; SRS in single
• Unresectable small lesions
• Progressive Pilocytic astrocytoma
• DLGGs

75. Proton therapy
• Risk of secondary malignancy is double with
IMRT v/s proton therapy
• Young children – temporal lobe
• Pleomorphic xanthoastrocytoma

76. Response to radiotherapy
• RANO(Response Assessment in Neuro-
Oncology) guidelines in LGG
• Progression
▫ Increase in enhancement or devpt of new lesions
▫ 25% or more increase in T2 or FLAIR abnormality in
the presence of a stable/increasing dose of steroids
▫ Clinical deterioration in the absence of decreasing
steroid dose

77. Pseudoprogression
• 20% LGGs
• 1p19q co-deletion – 10 fold decrease

78. Recurrent tumors
• Biopsy
▫ 9% - radiation necrosis or radiation induced
sarcoma
▫ 2/3rd - transformation to high grade tumors
• SRS or SRT

79. Brainstem gliomas
• Fractionated radiotherapy
• 54 Gy in 1.8-2 Gy fractions
• Recurrence – Fractionated SRT

80. Emerging therapies for LGGs

81. Thermal therapy(4 types)
• Laser Interstitial Thermotherapy(LITT)
• High Frequency Focused Ultrasound(HIFU)
• RFA
• Cryotherapy

82. • Coagulative necrosis
• Breaks down BBB – better delivery of anti-
tumor agents

83. LITT
• Stereotactic Laser ablation(SLA)
• MR Guided Laser Interstitial
Thermotherapy(MRgLITT)
• Minimally invasive modality
• Mainly for HGGs

84. HIFU
• MRI guided high intensity focused
ultrasound(MRIgFUS)
• Currently FDA approved for essential
tremor(Thalamotomy – Vim)
• LGG , HGG, mets trials

85. Surgical approaches to improve
drug delivery

86. Convection Enhanced Delivery(CED)
• Stereotactically placed catheters driven by
positive pressure gradients
• Enhances diffusion
• Currently under trial in HGGs

87. Immunotherapy for LGGs

88. • Case report of a Peptide tumor vaccine in a dog
with Gemistocytic astrocytoma
• Induced cellular immune response
• Neurological improvement
• Complete resolution of the tumor in 450 days

89. • Pollack et al – Neuro-oncology 2014 and 2016
• Immune responses and outcome after
vaccination with Glioma-associated antigen
peptides for pediatric malignant brainstem and
non-brainstem gliomas
• 26 children – 13 showed immunological
response

90. Nutritional therapy

91. • Level III evidence
• Keto diet might improve survival in pts with
malignant gliomas and perhaps LGGs
• Persistent hyperglycemia was independently a/w
▫ decreased survival
▫ Increased recurrence
▫ Increased malignant transformation
• Moderate intake of folate – greater survival

92. Glioma in pregnancy

94. Bibliography
• Youmans
• Diffuse Low Grade Gliomas in Adults – Hugues
Duffau
• Radiopedia