Grade 2/3 Flashcards
What is the ASTRO recommendation for Grade 2 Oligo with low risk features?
Close surveillance with MRI surveillance q6mo
Evidence:
EORT 22845 “non believers trial”
- No OS benefit to immediate adjuvant RT
RTOG 9802ph II component
- 5yr PFS 70% in low risk oligo group
What is the definition of a “high risk” Gr2 glioma (oligo or astro)?
Any of the following:
age >40years
Tumour size >4-6cm
Tumour crosses midline
Refractory seizures
Presurgical neurological symptoms from tumour
Subtotal resection or biopsy only
What did the EORTC 22845 study “non believers trial” assess and what were the key results?
Randomized patients with LGG after surgery to early RT vs observation with RT at progression
– Early (vs delayed) RT improved PFS and decreased seizure rate (25% vs. 41% at 1 year), but did not improve OS (median OS was comparable at 7.2 years and 7.4 years, respectively.)
* 65% patients in observed arm eventually received RT
* Malignant transformation equal between arms 70%
* QOL not studied (?relationship between time to progression and neurocognitive deterioration)
* Lack of OS benefit used by some to justify deferring RT until progression for patients with highly favorable prognostic features, minimal known disease, careful continued observation
What were the results of the RTOG 9802 Phase II component?
Patients with low-risk (ie, gross total resection and age <40 years) grade 2 glioma (both Oligo and Astro) underwent close surveillance without immediate adjuvant therapy.
Treatment was given only if radiographic or clinical progression occurred. Gross total resection was defined as <1 cm residual disease on magnetic resonance imaging (MRI).
The 5-year PFS after close surveillance for the entire cohort was 48% whereas it was 70% for the favourable subgroup of oligodendroglioma, tumor <4 cm, and <1 cm of residual disease.
Significant correlation between amount of residual tumor on imaging and recurrence
What did the EORTC 22844 “Believers Trial” show?
Randomized LGG patients after surgery to 45 Gy in 25 fx vs. 59.4 Gy in 33 fx
– No difference in 5-yr OS or PFS with dose escalation
What was the result of the Phase III component of RTOG 9802?
Phase III component randomized high-risk Gr2 Glioma pts to RT alone vs. RT followed by 6 cycles PCV
– Addition of PCV to RT almost doubles OS in high-risk patients (13.3years vs 7.8 years)
* Greatest effect size in oligodendroglioma patients (no 1p19q data)
* Patients with IDH1 mutation significantly higher OS
results of EORTC 22033-26033
Patients with ≥ 1 high risk feature randomized to RT alone vs. dose-dense TMZ alone
– No significant difference in PFS for LGG treated with RT alone vs. TMZ alone
– HR QOL and global cognitive function did not differ in LGG pts treated with RT alone vs. TMZ alone
– Median PFS 39 mos (TMZ alone) and 46 mos (RT alone) far less than median PFS of 10.4 years (RT + PCV) in RTOG 9802
Result of NCCTG/RTOG/ECOG
Randomized LGG patients (95% grade 2) after surgery to
50.4 Gy in 28 fx vs. 64.8 Gy in 36 fx
- No difference in 5-yr OS with higher rate of radiation
necrosis in high dose arm (5% vs. 2%)
Result of RTOG 0424
Single arm phase II high-risk LGG (at least 3 high-risk features) treated with RT with concurrent daily TMZ followed by 12 cycles of monthly TMZ
– 3-yr OS 73.1% compares favorably to historical rate of 54%
– Later analysis of MGMT data (Bell et al) : MGMT promoter methylation independent prognostic biomarker of high-risk, low- grade glioma treated with TMZ and RT
Describe suitable volumes for grade 2-3 glioma
GTV = surgical cavity + T2/Flair + enhancement onT1gad
CTV = GTV + 1.5cm margin. Respect anatomical boundaries
PTV = CTV +3mm
If a grade 3 glioma displays EGFR amplification, +7/–10 cytogenetic signature, or TERT promoter mutation, is this a grade 3 glioma?
No
As per 2021 WHO classification it is a GBM
What is the criteria distinguishing grade 2 and 2 IDH mutant astroctyoma?
Mitotic activity
What features would promote a grade 2 oligo to a grade 3?
substantial mitotic activity, microvascular proliferation, or necrosis.
homozygous deletion of CDKN2A/B
Is an IDH-mutant diffuse astrocytoma, grade 4, a GBM
No- under 2021 WHO classification this is a separate entity
Management of high risk grade 2 Oligodendroglioma
Immediate adjuvant RT with either sequential or concurrent/sequential chemotherapy
Management of grade 3 oligodendroglioma
Immediate adjuvant RT with sequential or concurrent/sequential chemo
Management of grade 3 astrocytoma
Immediate adjuvant RT 59.4Gy with sequential 12mo TMZ
(CATNON study showed OS for adjuvant but not concurrent TMZ)
Management of low risk gr2 astroctyoma?
Close surveillance alone
(conditional recommendation)
Management of high risk gr2 astroctyoma
immediate adjuvant RT with sequential or sequential/concurrent CT
What dose is recommended for Gr2 Oligo or Astrocytoma
54GY/30#
A systematic review and meta-analysis concluded that moderate doses of 45 to 55 Gy appear to be as effective as higher doses (5900-6500 cGy) for patients harboring grade 2 glioma.23
Dose for Gr 3 Oligo
54GY/59.4Gy
30-33#
Dose for Gr 3 Astro
59.4/33#-60Gy/20#
What is the epimediology of gr2 astrocytoma
Age group 20-40
Natural hx of grade 2 astrocytoma
Median OS 6-8 years
Slow growing
Majority (80%) of recurrences transform (50% to G3 and 30% to G4)
Subtype of grade 2 astrocytoma
Fibrillary
Gemistocystic
Protoplasmic
Macroscopic appearances of Gr 2 Astro
Relatively well defined
Spongy/gelatinous appearance
calcifications in 20%
Microscopic appearances of Gr 2 Astro
(Kurt notes)
Well differentiated fibrillary astrocytes
Cellularity moderately increases
Moderate nuclear atypic
Often loose microcytic background
Mitotic activity is generally absent
What are the molecular features of Gr2 Astrocytoma /Diffuse Astrocytoma
IDH mutant
1p19q intact
ATRX loss
TP53 mutation
What is the most common IDH mutation in Diffuse Astrocytoma/Gr2
IDH1 R132H
What is the IHC pattern for Gr2/Diffuse Astrocytoma
IDH1/IDH2 mutation specific stain +
ATRX -
p53 +
GFAP +
Ki67 usually <4%
What mutation is mutually exclusive with 1p19q codeletion? is this required for diagnosis of Astrocytoma?
ATRX loss is mutually exclusive with 1p19q codeletion
ATRX loss is characteristic but not diagnostic for DA
Significance of Gemistocytic Astrocytoma?
- Variant of IDH mutated astrocytoma
- high risk of malignant transformation
- treat as Gr3
-Micro: large densely packed gemistocytes - Poorer prognosis than usual DA, median OS <4 years
What are the defining molecular features of oligodendroglioma?
IDH1 or IDH2 mutation
1p/19q codeletion
What is the IHC pattern of oligo
MAP2 +
S100 +
SOX10 +
OLIG2 +
usually IDH1 R132H +
Intact ATRX
wild type p53
What are the macro features of oligo
Typically soft, well defined, greyish pink mass
Typical imaging appearance of Oligo
CT: hypodense/iso-dense , well demarcated mass, cerebral hemisphere location, calcification common
MRI: often T2 hyper intense, T1 hypotense
Contrast enhancement is uncommon and is a/w more aggressive course
Micro appearances Oligo
Moderately cellular
Diffusely infiltrating
Monomorphic round nuclei with artifactual perinuclear Halos “fried egg” appearance,
surrounded by delicate branching capillary network “chicken wire”
Microcalcifications and cystic degeneration common
Ki67<5%
Prognostic factors based on Pignatti JCO 2002
Age >40
Astrocytoma histology
Tumour >6cm in size
Tumour crossing mideline
Pre-op neuro deficit
low risk = 2 or less (Med OS 7.7yr)
high risk = 3 or more (Med OS 3.6years)
What are the treatment options for a grade 2 glioma with high risk features
Maximal safe debunking alone
Surgery + Adj RT
Surgery + Adj TMZ
Surgery + ADj RT + ADJ PCV
Surgery + adj RT +adj TMZ
Describe the EORTC 22845 non believer trial and results
Randomised to early RT after surgery (54Gy) vs RT on progression in G2 and G1 incomplete resection (ie NO gr3)
Early RT improves PFS and seizure control in low grade glioma
But No OS difference
What is the rationale for surgery alone in low grade glioma?
EORTC 22845 non believers trial shows no OS benefit with adjuvant RT
What is the rational for adj RT after surgery in low grade glioma?
EORTC 22845 non believer trial
Improves PFS and reduced incidence of seizures at 1 year with adjuvant RT
What did the EORTC 22844 believers trial show?
Low grade glioma randomised to low dose (45GY/25#) vs high dose (59.4Gy/33#)
No difference in OS or PFS between arms
What did the RTOG 9110 study show?
Patients with low grade glioma randomised to low dose (50.4Gy/28#) or high dose (64.8Gy/36#)
No difference in OS but higher rate of radiation necrosis in higher dose group
Summarise the evidence for current dose used in gr2 glioma
EORTC 22844 and RTOG 9110 did not show improved OS or PFS with doses 59.4Gy-64.8Gy compared with 45Gy-50.4Gy.
RTOG 9110 did show increased rates of radio necrosis with higher dose
What did the EORTC 22033-26033/NCIC-CE5 trial test and what were the results?
Randomised to adjuvant RT vs Adjuvant TMZ after surgery for G2 patients with at least 1 high risk feature
Results:
No difference in PFS between RT and TMZ in combined group
However, In IDH mut/non codel group, PFS was improved in the adj RT arm by 20 months
What did the RTOG 9802 phase III trial test and what were the results?
Randomised to Adjuvant RT (54Gy/30#) vs RT + adjuvant PCV (procarbazine, lomustine, vincristine)
Gr glioma but high risk feature (STR or >40yo)
Results:
Improved OS and PFS with RT + PCV compared to RT alone
median OS 13.3 years vs 7.8years)
What did the RTOG 0424 trial test and what were the results?
Single arm Ph2
LG glioma with at least 3 high risk features (>40yo, astro, cross midline, tumour >6cm, prep neuro deficit)
RT 54Gy with concurrent TMZ and 12 cycles adjuvant TMZ (ie, same RT as RTOG 9802, just changing the chemo)
compared with historical control of RT alone
Results: improved OS with RT + TMZ (3yr OS 73% vs 54%)
Radiologic features of gr3 Astroyctoma
CT
- regions of hypo density with mass effect
- variable enhancement
MRI
- T1: hypo intense compared to white matter
- T2: generally hyperintense
- T1 C+ (gad): very variable but usually some contrast present
- presence of enhancement differentiates Gr3 from Gr2 on imaging
- ring enhancement suggests central necrosis (GBM) rather than Gr3
Macro of Gr 3 Astro
Gelatinous/spongy
Same as Gr 2
Microscopic features of Gr 3 Astro
Fibrilliary astrocytes with loose microcytic background (same as gr2)
Focal or diffuse anaplasia, significant proliferative activity, more nuclear atypic than gr2 and higher cellularity
Increased mitotic activity
By definition- no necrosis and no microvascular proliferation (or else would be GBM)
Microscopic features of Gr3 Oligo
Round nuclei with Perinuclear halos “fried egg” , surrounded by “chicken wire” delicate branching capillary network
Shows focal or diffuse anaplasia, brisk mitotic activity, sometimes marked atypia
(Can see microvasc proliferation and spontaneous necrosis without it being GBM, as long as Oligo molecular features are present)
What is the treatment paradigm for Gr 3 glioma
Surgery - maximal safe resection
Radiotherapy - 59.4Gy/33#
Chemo-
PCV (EORTC 26951)
TMZ (CATNON- adj TMZ in AA improves OS)
PCV vs TMZ (Codel)
Side effects of PCV
Myelosuppression
- neutropenia 30-50%
- Thrombocytopenia 20-40%
- Anaemia 5-10%
Peripheral neuropahty 6-10%
Nausea 5-10%
Hepatotoxicity 5%
Skin tox 5%
What did the EORTC 26951 trial assess?
Results?
Randomised G3 Oligo to
RT alone (59.4Gy/33#) vs Rt + adjuvant PCV (6c x 6weekly)
RT + PCV improved OS and PFS with largest benefit seen in the 1p19q codel group
(Median PFS 13.1yr vs 4.2yr)
What did the RTOG 9402 trial assess?
Results?
G3 AO and AA randomised to RT alone 59.4Gy/33# vs neoadj PCV (4c x 6weekly) + RT
PFS and OS did not differ between groups for combined AO and AA,
but for 1p19qcodel group OS and PFS significantly better in the PCV arm (OS double)
What did the CATNON/EORTC 26053 trial assess and results?
1p19q non codel Gr3 glioma randomised with 2:2 factorial design
RT alone
RT + concurrent TMZ
RT + adj TMZ
RT + concurrent TMZ + adj TMZ
OS and PFS benefits seen with adj TMZ but not concurrent TMZ
RTOG 9813
Details?
results:
Gr 3 Astroctyoma
Randomised to RT + TMZ vs RT + Nitrosourea
Median OS 3.9/3.8 years
G3 tox significantly higher in NU arm
Details of Codel trial?
Population 1p19q co-del G3 Glioma
4 arms:
RT alone - arm now closed
RT + adj PCV
RT + con/adj TMZ
TMZ alone - arm closed due to inferior OS/PFS on interim analysis
