3. • A glioma is a primary brain tumor that originates
from the supportive cells of the brain - Glial cells
•There are three types of glial cells from which
gliomas arise:
Astrocytes: Astrocytoma
Oligodendrocytes: Oligodendroglioma
Ependymal cells: Ependymoma
Introduction
NeuroglialCells
5. Location Specific Symptoms
• Most of the low grade gliomas present with seizure
• Seizures are associated with a better survival
• Presence of functional deficits predicts a poorer outcome
Frontal Tumors
• Personality change
• Abulia
• Loss of initiative
• B/L gliomas
can cause memory
loss, labile mood
& urinary incontine
nce
Temporal Tumors
• Auditory hallucinati
ons
• Superior Homonym
ous quadrantopia
• Impaired perception
of verbal commands
Parietal Tumors
• Homonymous
inf. Quadrantopia
• Hemianaesthesia
• Alexia
• Dysgraphia
• Apraxia
Occipital Tumors
• Visual aberration
• Perceptual disrupti
on of color size and
location
• B/L tumors cause
cortical blindness
6. WHO Grading of Brain Tumors
Based on four morphologic criteria: cytological atypia, mitotic activity, microvascular proliferation
(endothelial cell proliferation), and necrosis
• Grade I: Do not meet any of the criteria. Slow growing, nonmalignant, long-term survival
• Grade II: Meet only one criterion, i.e., only cytological atypia. Slow growing but may recur as
higher-grade tumors. They can be malignant or nonmalignant
• Grade III: Meet two criteria, i.e., anaplasia and mitotic activity - Malignant and often recur as
higher-grade tumors
• Grade IV: Meet three or four of the criteria, i.e., anaplasia, mitotic activity with microvascular
proliferation, and/or necrosis. These tumors reproduce rapidly and are very aggressive malignant
tumors
7. Histological Diagnosis
• LGG are divided into astrocytomas (nuclear irregularities with fibrillary processes) and
oligodendrogliomas (uniformly rounded nuclei and perinuclear halo (‘‘fried egg’’)
10. ATRX Gene Mutation-
• Recommended but not required for diagnosis of glioma
• Diagnostic value-
ATRX mutation is strongly associated with IDH mutation and always mutually exclusive with 1p19q
co-deletion
ATRX deficiency coupled with IDH mutation is typical of Astrocytoma
Molecular Markers
11. •Other mutations –
•TERT mutation- among IDH wild type LGG it confers a poor prognosis
•BRAF mutation – present in Ganglioglioma , pilocytic astrocytoma and pleomorphic
xanthoastrocytoma
Molecular Markers
14. IMAGING IN LOW GRADE GLIOMA
•MRI with gadolinium contrast is
imaging modality of choice
•MRI - infiltrative, non-enhancing
mass lesion that arises in white matter
and often extends into the cortex.
Hypointense on T1
Hyperintense on T2
15. CT scan :
•For those unable to undergo MRI (implanted
pacemaker, metal fragment, paramagnetic surgical clips)
or Unwilling (because of claustrophobia)
• In CT- LGGs are nonenhancing tumour(poorly defined
area of low attenuation)
•LGG appear as iso or low attenuation, poorly deliniated,
often without contrast enhancement or perilesional
edema
•Calcifications in 10–20% of cases - may be related to
oligodendroglial components
IMAGING IN LOW GRADE GLIOMA
16. MR spectroscopy:
•Assess metabolite within tumor and
normal tissue
•Useful in differentiating tumor and
radiation necrosis
•LGGs demonstrate a decrease in N-
acetyl aspartate (NAA) and creatine
levels and an increase in choline (Cho)
levels
IMAGING IN LOW GRADE GLIOMA
17. Management
Surgery
• The risk of inducing new neurological deficits has tempered enthusiasm for
radical resection.
• However resection of low-grade glioma improves overall survival and
importantly delays the time to malignant progression.
• Early surgery and the widespread adoption of awake craniotomy with
intraoperative functional mapping have revolutionised low-grade glioma
management.
18. Why surgery in LGG?
• Better survival with more EOR
• Histological diagnosis and molecular analysis
• Ameliorated mass effect and intracranial tension
• Ease control of seizures
19. Surgery
• GTR
• STR
• Decompression
• Biopsy only (deep lesions including brainstem, diffuse and/or multicentric
tumor. Stereotactic/open)
20. Adjuvant Treatment
• Surgery alone is not curative in patients with low-grade gliomas,
and additional therapy (radiation and/or chemotherapy) is
ultimately required.
• However, the optimal timing of additional therapy is uncertain
and the decision to proceed with immediate versus delayed
postoperative therapy must be individualized.
22. Factors to Decide Adjuvant Therapy
It is important to recognize, however, that individual risk factors are relative (including the age cut-
off of 40 years and exist on a biological continuum. In addition, there is no single agreed-upon
definition of low versus high risk, and risk has been variably defined across trials
•Tumor crossing midline
•Neurological deficits
•Absence of 1p/19q-
codeletion
•Astrocytic histology •IDH mutation status
•> 40 years
•Large preoperative tumour size > 4
cm
•Incomplete resection
24. P < 0.001
P = 0.872
Early radiotherapy of 54 Gy in fractions of 1·8 Gy
Vs.
RT Deferred radiotherapy until the time of progression
25. As the time to clinical or radiological progression is typically long, a “wait and see”
policy can be defended for younger patients presenting with seizures only - until the
time of radiological or clinical progression
In patients with focal deficits, signs of high intracranial pressure, or cognitive deficits,
adjuvant treatment should be initiated without delay
Treatment should consist of a resection as extensive as possible. If the site and extent of
the tumour prevents meaningful resection, a biopsy is needed to obtain histological proof
of malignancy
Irradiation can then be recommended for most patients
This study shows that immediate post-operative irradiation in patients with
LGG increases the median PFS by 2 years, without affecting OS
28. 343(91%) eligible and evaluable patients
Follow-up : At least 50 months (Median F/U = 74 months)
No significant difference in terms of overall survival (58% for the low-dose arm and 59% for
the high dose arm) or the progression free survival (47% and 50%)
N=379
Postoperative / Post Biopsy Irradiation
45 Gy in 5 weeks Vs. 59.4 Gy in 6.6 weeks (1.8 Gy/#)
Quality-controlled RT
The EORTC trial 22844 did not reveal the presence of radiotherapeutic dose-
response for patients with LGG for the two dose levels investigated with this
conventional setup
34. With a median follow-up of 11.2 years, RT followed by PCV
showed a median OS of 13.3 years versus 7.8 years (P = 0.003)
for RT alone.
RTOG 9802
35. Risk Factors in RTOG 9802
• >/=40 yrs; Subtotal resection or biopsy (High Risk)
• For <40 yrs and GTR (Low risk) , factors associated with a poorer prognosis for
progression-free survival (PFS):
1. Preoperative tumor diameter ≥ 4 cm;
2. Astrocytoma/oligoastrocytoma histological type
3. Residual tumor ≥ 1 cm
36. Conclusions from RTOG 9802
•Post-hoc correlative analyses of the RTOG 9802 trial identified molecular alterations in
high-risk low-grade glioma patients who benefited from adjuvant PCV
•High-risk patients with IDH mutations regardless of co-deletion status benefited from
adjuvant radiation followed by chemotherapy
•IDH wild-type, high-risk, LGGs have poor outcomes similar to GBM, requiring more
aggressive treatment regimens, and should be considered for clinical trial enrollment
• Molecular stratification is essential in choosing the appropriate treatment strategy
• Inclusion of adjuvant chemotherapy in high-risk diffuse gliomas improves overall survival
37. • Procarbazine - 75mg/m2 per oral daily
• Lomustine - 110mg/m2 per oral
• Vincristine - 1.4mg/m2 i.v.
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 To 8 week cycles, Total
6 cycles (Adjuvant)
PCV Regimen
39. RTOG 0424 - Single Arm Phase 2 Trial
•RTOG 0424:
–The 3-year OS rate is 73.1%
–The 5-year OS rate was 57.1%
–MST has not yet been reached
•Pignatti ( Historical control):
–The 3-year OS rate was 54%
40. RTOG 0424 - Single Arm Phase 2 Trial
High-risk diffuse glioma
54 Gy RT in 30 fractions with concurrent and adjuvant TMZ
Overall median survival of 8.2 years (95% CI, 5.6 to 9.1 years)
• High-risk patients were defined as having 3 or more of EORTC established risk factors
•Results showed improved efficacy compared with prior historical controls of RT alone (median follow-up
of 9 years)
• Due to varying definitions of “high-risk” diffuse gliomas between clinical trials, additional studies are
needed to determine the optimal chemotherapy regimen.
•Molecular and genomic analyses of RTOG 0424 confirmed that MGMT promoter methylation status
does not appear to add significant prognostic value beyond IDH mutation and 1p/19q status.
41. Recommendations for Follow-up
• No formal clinical trials that define the optimal frequency for follow-up after treatment
• Follow-up with FLAIR or T2-weighted MRI is the standard of care
•Follow-up recommendation - clinical evaluation with particular attention to neurological
function, seizures and corticosteroid use
• Patients should be tapered off steroid use as early as possible
• Laboratory tests are not indicated unless the patient is
corticosteroids or anti-epileptic drug
receiving chemotherapy,
•MRI and Mini–Mental State Examination (MMSE) after the completion of therapy →
every 3–4 months for 1 year → every 6 months for 2 years → every year thereafter until
tumor progression is recommended
