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Grade 2/3 Flashcards

1
Q

What is the ASTRO recommendation for Grade 2 Oligo with low risk features?

A

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

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2
Q

What is the definition of a “high risk” Gr2 glioma (oligo or astro)?

A

Any of the following:

age >40years

Tumour size >4-6cm

Tumour crosses midline

Refractory seizures

Presurgical neurological symptoms from tumour

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3
Q

What did the EORTC 22845 study “non believers trial” assess and what were the key results?

A

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

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4
Q

What were the results of the RTOG 9802 Phase II component?

A

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

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5
Q

What did the EORTC 22844 “Believers Trial” show?

A

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

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6
Q

What was the result of the Phase III component of RTOG 9802?

A

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

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7
Q

results of EORTC 22033-26033

A

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

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8
Q

Result of NCCTG/RTOG/ECOG

A

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%)

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9
Q

Result of RTOG 0424

A

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

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10
Q

Describe suitable volumes for grade 2-3 glioma

A

GTV = surgical cavity + T2/Flair + enhancement onT1gad

CTV = GTV + 1.5cm margin. Respect anatomical boundaries

PTV = CTV +3mm

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11
Q

If a grade 3 glioma displays EGFR amplification, +7/–10 cytogenetic signature, or TERT promoter mutation, is this a grade 3 glioma?

A

No
As per 2021 WHO classification it is a GBM

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12
Q

What is the criteria distinguishing grade 2 and 2 IDH mutant astroctyoma?

A

Mitotic activity

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13
Q

What features would promote a grade 2 oligo to a grade 3?

A

substantial mitotic activity, microvascular proliferation, or necrosis.
homozygous deletion of CDKN2A/B

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14
Q

Is an IDH-mutant diffuse astrocytoma, grade 4, a GBM

A

No- under 2021 WHO classification this is a separate entity

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15
Q

Management of high risk grade 2 Oligodendroglioma

A

Immediate adjuvant RT with either sequential or concurrent/sequential chemotherapy

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16
Q

Management of grade 3 oligodendroglioma

A

Immediate adjuvant RT with sequential or concurrent/sequential chemo

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17
Q

Management of grade 3 astrocytoma

A

Immediate adjuvant RT 59.4Gy with sequential 12mo TMZ
(CATNON study showed OS for adjuvant but not concurrent TMZ)

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18
Q

Management of low risk gr2 astroctyoma?

A

Close surveillance alone
(conditional recommendation)

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19
Q

Management of high risk gr2 astroctyoma

A

immediate adjuvant RT with sequential or sequential/concurrent CT

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20
Q

What dose is recommended for Gr2 Oligo or Astrocytoma

A

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

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21
Q

Dose for Gr 3 Oligo

A

54GY/59.4Gy
30-33#

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22
Q

Dose for Gr 3 Astro

A

59.4/33#-60Gy/20#

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23
Q

What is the epimediology of gr2 astrocytoma

A

Age group 20-40

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24
Q

Natural hx of grade 2 astrocytoma

A

Median OS 6-8 years
Slow growing
Majority (80%) of recurrences transform (50% to G3 and 30% to G4)

25
Q

Subtype of grade 2 astrocytoma

A

Fibrillary
Gemistocystic
Protoplasmic

26
Q

Macroscopic appearances of Gr 2 Astro

A

Relatively well defined
Spongy/gelatinous appearance
calcifications in 20%

27
Q

Microscopic appearances of Gr 2 Astro
(Kurt notes)

A

Well differentiated fibrillary astrocytes
Cellularity moderately increases
Moderate nuclear atypic
Often loose microcytic background
Mitotic activity is generally absent

28
Q

What are the molecular features of Gr2 Astrocytoma /Diffuse Astrocytoma

A

IDH mutant
1p19q intact
ATRX loss
TP53 mutation

29
Q

What is the most common IDH mutation in Diffuse Astrocytoma/Gr2

A

IDH1 R132H

30
Q

What is the IHC pattern for Gr2/Diffuse Astrocytoma

A

IDH1/IDH2 mutation specific stain +

ATRX -
p53 +
GFAP +

Ki67 usually <4%

31
Q

What mutation is mutually exclusive with 1p19q codeletion? is this required for diagnosis of Astrocytoma?

A

ATRX loss is mutually exclusive with 1p19q codeletion

ATRX loss is characteristic but not diagnostic for DA

32
Q

Significance of Gemistocytic Astrocytoma?

A
  • 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
33
Q

What are the defining molecular features of oligodendroglioma?

A

IDH1 or IDH2 mutation

1p/19q codeletion

34
Q

What is the IHC pattern of oligo

A

MAP2 +
S100 +
SOX10 +
OLIG2 +

usually IDH1 R132H +
Intact ATRX
wild type p53

35
Q

What are the macro features of oligo

A

Typically soft, well defined, greyish pink mass

36
Q

Typical imaging appearance of Oligo

A

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

37
Q

Micro appearances Oligo

A

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%

38
Q

Prognostic factors based on Pignatti JCO 2002

A

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)

39
Q

What are the treatment options for a grade 2 glioma with high risk features

A

Maximal safe debunking alone

Surgery + Adj RT

Surgery + Adj TMZ

Surgery + ADj RT + ADJ PCV

Surgery + adj RT +adj TMZ

40
Q

Describe the EORTC 22845 non believer trial and results

A

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

41
Q

What is the rationale for surgery alone in low grade glioma?

A

EORTC 22845 non believers trial shows no OS benefit with adjuvant RT

42
Q

What is the rational for adj RT after surgery in low grade glioma?

A

EORTC 22845 non believer trial

Improves PFS and reduced incidence of seizures at 1 year with adjuvant RT

43
Q

What did the EORTC 22844 believers trial show?

A

Low grade glioma randomised to low dose (45GY/25#) vs high dose (59.4Gy/33#)

No difference in OS or PFS between arms

44
Q

What did the RTOG 9110 study show?

A

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

45
Q

Summarise the evidence for current dose used in gr2 glioma

A

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

46
Q

What did the EORTC 22033-26033/NCIC-CE5 trial test and what were the results?

A

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

47
Q

What did the RTOG 9802 phase III trial test and what were the results?

A

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)

48
Q

What did the RTOG 0424 trial test and what were the results?

A

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%)

49
Q

Radiologic features of gr3 Astroyctoma

A

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

50
Q

Macro of Gr 3 Astro

A

Gelatinous/spongy
Same as Gr 2

51
Q

Microscopic features of Gr 3 Astro

A

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)

52
Q

Microscopic features of Gr3 Oligo

A

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)

53
Q

What is the treatment paradigm for Gr 3 glioma

A

Surgery - maximal safe resection

Radiotherapy - 59.4Gy/33#

Chemo-
PCV (EORTC 26951)
TMZ (CATNON- adj TMZ in AA improves OS)
PCV vs TMZ (Codel)

54
Q

Side effects of PCV

A

Myelosuppression
- neutropenia 30-50%
- Thrombocytopenia 20-40%
- Anaemia 5-10%

Peripheral neuropahty 6-10%
Nausea 5-10%
Hepatotoxicity 5%
Skin tox 5%

55
Q

What did the EORTC 26951 trial assess?

Results?

A

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)

56
Q

What did the RTOG 9402 trial assess?

Results?

A

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)

57
Q

What did the CATNON/EORTC 26053 trial assess and results?

A

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

58
Q

RTOG 9813
Details?
results:

A

Gr 3 Astroctyoma
Randomised to RT + TMZ vs RT + Nitrosourea

Median OS 3.9/3.8 years

G3 tox significantly higher in NU arm

59
Q

Details of Codel trial?

A

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

CNS (9 decks)

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