2 - Low Grade Glioma
2 - Low Grade Glioma
2 - Low Grade Glioma
LOW GRADE GLIOMA
Overview:
‐Most common presentation is seizure (also a positive prognostic factor)
‐Also present with H/A and weakness
Molecular Factors:
‐High Ki67 and mutant p53 is associated with worse outcome.
‐LOH 1p and 19q are associated with better outcome and response to chemo.
‐Surprising given that they code for tumor suppressor genes
General Rules:
‐Low grade glioma: GTR + observation and treat on progression. Never go higher than 50.4Gy.
‐EORTC is currently investigating low dose temozolomide but its role is not yet defined.
‐Be aware that diffuse astrocytoma (WHO II) is poorly circumscribed and often transforms to
anaplastic astrocytoma (WHO III) in up to 80%.
Molecular Issues:
‐Ki67 >3% is bad
‐Aneuploid is worse then diploid
‐Mutant p53 is bad
‐LOH 1p and 19q are good (seen in 56% of oligodendro, 33% of oligoastro, and 5% of astro)
‐13y vs 11y survival for oligodendro
‐11y vs 7y survival for oligoastro
‐MGMT (methylguanine methyltransferase) is a DNA repair enzyme, repairing damage induced
by alkylating agents. High levels have worse outcomes.
‐MGMT promoter methylation results in decrease of MGMT enzyme, and thus is a favorable
prognostic factor (in trial of RT + temozolomide, 2yOS 48% vs 14%).
‐VEGF positivity is favorable as well.
Which images to treat with?
‐Most will treat with T2 (if you have to guess use this one).
‐Edema is covered as part of the GTV.
‐Radiologic classification:
‐Type I is well circumscribed, no edema (only type safe to treat with T1 images)
‐Type II has nodules that enhance with some edema.
‐Type III has diffuse infiltration without clear nodules.
Prognostic Factors:
‐Age >40y, astrocytoma histology, tumor >6cm, tumor crossing midline, neurologic deficits
‐High‐risk group = 3+ factors above (4y median survival)
‐Low‐risk group = 0‐2 factors above (8y median survival)
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Why observe?
‐RTOG 9802 conducted an observation on 111 low risk pts, post GTR:
‐5y PFS 78% for oligodendro <4cm and 5y PFS 34% for astro >4cm
‐EORTC 22845 randomized between observation (RT at progression) vs immediate RT with 54Gy.
‐5y PFS 55% vs 35%, OS 7.4y vs 7.2y
‐Arguments for early treatment have been made and EORTC 22845 showed less seizures in the
treated group (41% vs 25% @ 1y) and in another series (Reichenthal), malignant transformation
appears lower in treated group, but this was not true in the EORTC trial.
Extent of the Surgery:
‐Multiple series have shown that the extent of resection correlates with better survival.
‐The most recent was published by Leighton with both Astrocytomas and Oligoastros (230 pts):
‐GTR and extensive STR were better than STR (82% vs 64% 5y survival)
Dose to Give:
‐There are 2 RCTs indicating that 45 to 50.4Gy is a reasonable dose to give with no
demonstrable advantage in terms of LRC or OS with higher doses 59.4‐64.8Gy.
‐EORTC 22844 (Karim): 45Gy vs 59.4Gy; OS 58% vs 59%
‐NCCTG/INTG (Shaw): 50.4Gy vs 64.8Gy; OS 73% vs 68% (p=NS & OS is even higher in
the low dose arm!)
‐Treat with 50.4Gy using T2 weighted MRI and 2cm margin. 95% of failures will still occur within
the treatment fields.
Chemotherapy: NOT used except in a study setting.
‐RCT of CCNU was negative. Adjuvant PCV results are pending.
‐Temozolomide (alkylator) is being tested but response rate is on the order of 15% and 1p
status may indicate a better response.
Favorable Low Grade Glioma Variants:
‐Pilocytic astryocytoma (80% 10yOS)
‐Use a smaller margin because well circumscribed (1cm)
‐Associated with Rosenthal fibers
‐Oligodendroglioma
‐Associated with “fried‐egg” appearance under microscope
‐Pleomorphic xanthoastrocytoma
‐Ganglioma, Dysembryoplastic neuroepithelial tumors, Central neurocytoma
‐Subependymal giant cell astrocytoma (this is considered cured after surgery)
How do you differentiate recurrence from necrosis?
1. Re‐operation (biopsy)
2. Growth (seen on serial imaging)
3. PET scan?
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RT Planning:
‐Pre‐RT Consultations: Endo, audiometry, neuro‐ophtho
‐Simulation:
‐Position: Supine
‐Head position: Neutral or flexed
‐Immobilization: Thermoplastic mask
‐Fiducial markers and laser positioning
‐CT with contrast and 3 mm slices
‐Post‐operative T2 MRI fusion
‐Volumes for WHO I pilocytic astrocytoma:
‐GTV = Enhancing lesion on T1 + gadolinium
‐CTV = GTV + 1cm
‐PTV = CTV + 0.5cm
‐Volumes for WHO II oligo/astrocytoma:
‐GTV = Lesion on T2/FLAIR MRI post‐operatively
‐CTV = GTV + surgical cavity + 2cm
‐PTV = CTV + 0.5cm
‐Fields: 3‐5 fields including non‐coplanar beams if necessary
‐Energy: 6MV
‐Wedges, MLCs, tissue compensators and blocks as necessary
‐OAR:
‐Optic nerve/chiasm <50Gy
‐Retina <45Gy
‐Lens <10Gy
‐Brain total <45Gy, partial <60Gy
‐Brainstem <54Gy
‐Ear (acute serous otitis) <30Gy
‐Ear (chronic serous otitis) <55Gy
‐Lacrimal glands <30Gy
‐Parotid <26Gy
‐Skin epilation <30Gy
‐Skin ulceration <50Gy
‐OAR in SRS:
‐Optic nerve/chiasm <8Gy
‐Visual pathways <12Gy
‐Brainstem <12Gy
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‐Side Effects:
Acute:
‐Scalp erythema and dermatitis
‐Alopecia
‐Fatigue
‐Somnolence
‐Headache
‐Nausea and vomiting
‐Otitis externa
Late (> 3mo):
‐Somnolence (Mainly subacute)
‐Impaired cognitive function
‐Worsens at 3‐4 mo, then improves between 6 to 12 mo
‐Decreased learning ability, short term memory and problem‐solving
‐Brain necrosis (1‐3%)
‐Can cause mass effect
‐Cataracts
‐Retinopathy
‐Endocrine abnormalities (hypothyroid, hypopituitary)
‐Alopecia
‐Subcutaneous fibrosis
Side‐Effects of Treatment (from Gunderson):
‐Neuropsych: difficulties with memory, language, visuospatial, frontal lobe function
‐Fatigue, mood changes
‐5% will have a decline in MMSE
‐Fractions >2Gy may be detrimental
‐Radionecrosis is on the order of <5% as long as the dose does not exceed 65Gy
‐Reduction of IQ in children
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Summary: Low Grade Glioma
Stage Treatment
JPA (WHO I) Maximal Safe Resection Æ
‐If GTR Æ Observation
‐If STR Æ Observation vs RT (50.4Gy) vs SRS (depends on location, symptoms)
Astrocytoma, Maximal Safe Resection Æ
oligoastro, or 1. Observation (serial MRI Æ RT 50.4Gy only on progression)
oligodendro (WHO II) ‐Only if GTR, <40yo, oligodendro histology, & good function
2. Immediate post‐op RT to 50.4Gy
‐No survival benefit, but delays time to relapse and ↓ seizures
Childhood Maximal Safe Resection (GTR or STR) Æ
astrocytoma, 1. Observation (serial MRI Æ RT only on progression)
oligoastro, or 2. Adjuvant chemo may prolong DFS & delay need for RT
oligodendro
Baseline Survival Statistics: 2yOS: 5yOS: Median Survival:
Astrocytoma: 50% 35% 5y (low‐grade)
Oligodendroglioma: 80% 65% 10y (low‐grade)
‐Age >40y, astrocytoma histology, tumor >6cm, tumor crossing midline, neurologic deficits
‐Low‐risk = 0‐2 factors above (8y MS) ‐High‐risk = 3+ factors above (4y MS)
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