updated management of low grade gliomas including WHO 2016 classification and molecular markers

1. Management in low
grade gliomas
Dr Pallavi Kalbande
MD Radiation Oncology
MGIMS Sewagram

2. Low grade glioma
o Slow growing tumours
◦ Divided as
◦ Pilocytic
Astrocytoma (grade I)
DNET (Dysembryoplastic Neuroepithelial Tumor)
◦ Non pilocytic
Fibrillary Astrocytoma
Diffuse Infilterating astrocytoma
Oligodendroglioma

3. WHO grade Histology Imaging Outcome
I
(usually
paediatric)
Low
proliferation
Discrete Possibility of cure
after surgery
80% 10 year survival
II
Mostly in adults
Often present
with seizures
Nuclear atypia
Infiltrative few
mitoses
Non-enhancing
Hyperdense on T2
FLAIR Infiltrative, ?
oedema
Median survival 5-10
years
Can transform to
high grade

4. T1W T2W Constrast
key features on imaging

5. Facts
50% to 75% of WHO grade II gliomas transform to high
grade glioma within 6 to 7 years of diagnosis
LGGs are primarily reported in the frontal lobes (44%),
followed by the temporal (28%) and parietal (14%)
domains
Interestingly, LGGs originating in the cerebellar region are
associated with a better prognosis than those originating
supratentorially

6. Molecular markers
TP53 mutations
Common in diffuse Astrocytomas and are mutually
exclusive from 1p/19q co-deletions
1p/19q Deletions
50-70% Oligodendroglial tumors
Loss of 1p or both 1p/19q may predict chemosensitivity
and predicts prolonged survival

7. IDH 1 mutations
60-90% of LGG
Associated with improved survival
May help differentiate:
gliosis vs tumor or
pilocytic tumors vs grade II astrocytoma
Molecular markers

8. Good prognostic markers
o 1p19q co-deletion
o MGMT methylation
o IDH1 mutation

9. Updated WHO
classification(2016)
o For grade II and Grade III glioma
Diffuse astrocytoma
• IDH-mutant
• gemistocytic astrocytoma IDH mutant
• IDH-wildtype
• NOS
•Oligoastrocytoma NOS
•Oligodendroglioma
• IDH-mutant, 1p19q co-deleted
• oligodendroglioma NOS

11. Initial management
Seizures:
◦ levitiracetam, lacosamide, topirimate, lamotrigine
Edema:
◦ Steroids, dexamethasone 10 mg stat then 8 mg BD
Obstructive Hydrocephalus:
◦ may require surgery and perhaps placement of a
“shunt” to bypass the blockage and lower the
pressure

12. Definitive treatment
Small and
asymptomatic
Grade I
Symptomatic
grade I or Grade II
Follow up
(active
monitoring)
Maximal Safe
resection
Symptomatic
Inoperable
Radioherapy

13. Prognostic factors (Pignati etal
EORTC 22844 and 22845)
1. Age >40
2. Symptomatic (not just seizure activity)
3. Enhancement
4. >6cm
5. Crossing the midline
6. Astrocytic (IDH wt and TERT mutated particularly poor)
>2 factors MS = 3.2 years
≤2 factors MS = 7.7 years
• If >2 of above, definitely consider doing something

14. What is the post-op
status?
Oligodendroglioma Astrocytoma
Age < 40
yrs and
GTR
Follow up
Yes No
Post op RT
50.4Gy/30# or
54Gy/30#
6 cycles of
adjuvant PCV
Watch and
wait

15. Newer approaches

16. Principals of Surgery
 Greater extent of resection improves OS and
seizure control
Gross total resection
Maximal safe resection
Maximizing tumour resection recommended over
simple debulking
Stereotactic biopsy
uncommon, it remains a reliable first step for
cases in which the diagnosis is uncertain

17. Radiotherapy

20. Radiotherapy
Right fronto-parietal LGG imaged with CT and co-registered T2w MR sequence
(GTV). Include peritumoral odema
1.5cm
0.5cm

21. Planning
Three beam arrangements with wedges coplaner or non coplaner most
commonly used

22. Chemotherapy
1p/19q loss predicts response-in almost all pts
Pts with 1p/19q intact LGO, LGOA, LGA less
likely to respond to chemotherapy
PCV regimen (6 weekly cycle)
◦ Lomustine 100mg/m2
◦ Procarbazine 100 mg/m2 oral from D2 – D10
◦ Vincristine 1.5 mg/m2

24. Follow up
MRI brain
 Every 3-6 months upto 3-5 yrs
Then annually

25. Progression after RT
o Resurgery (If resectable)
o Chemotherapy (Unresectable disease)
o Reirradiation with SRS/FSRT (Small recurrences)
o Newer targeted agents under trial

26. Evidence

27. Radiotherapydose RTOG Ph-III
randomized study
ShawJCO2002; 20:2267-2276

28. Radiotherapy dose
RTOG Ph-III randomized study
Necrosis more with higher RT dose
211 pts from 1986-1994
Median follow-up: 76 months
Age >18 years with biopsy
proven supratentorial lesions
Histology (WHO Grade I and II)
Excluded: pilocytic
astrocytoma with gross total
resection
RT- 50.4 Gy vs 64.8 Gy
ShawJCO2002; 20:2267-2276

29. EORTC 22844: Ph-III study

30. Karim IJROBP 1996; 36: 549-56
EORTC 22844: Ph-III study
379 pts
Median follow-up:74m
Age 16-65 years with biopsy
proven supratentorial lesions
Histology (WHO Grade I and II):
QOL worse with higher RT dose

31. EORTC 22845
Randomized phase III
RT Dose (54Gy/30#) Immediate RT vs RT at
Progression
Improved median progression free survival (5.3 yrs vs
3.4 yrs)
Better seizure control rates No difference in Median
survival (7.4yrs vs 7.2 yrs)
No difference in rate of malignant transformation.

32. Early RT Vs No RT
EORTC 22845 PFS

33. Overall survival

34. Long term results

35. High dose per fraction
EORTC 22844 & 22845
At 6 yr follow up:
1.8-2 Gy/fr RT: No impact on cognitive function
>2 Gy/fr: Higher decline in memory domain
At 12 yr follow up:
Cognitive function decline in both 1.8-2 Gy/fr & >2Gy/fr RT
However, impact of High dose per fraction on cognitive function
reduced
Van den Bent Lancet 2005

36. Progression to high grade
EORTC 22845
issue At 12 yr follow up:
Progression to high grade:
RT arm: 50%
No RT arm:51%
No different is progression to high grade with & without RT
Van den Bent Lancet 2005

37. RTOG 9802
Buckner et al

38. RTOG 9802
Buckner et al
Adjuvant chemotherapy
Grade 2 glioma (any subtype)
High risk > 40 years
54Gy in 30 fractions +/- 6 x PCV q8 weekly
Improved overall survival with addition of PCV
Median: 13.3 vs 7.8 years
10 year OS: 60% vs 40%, HR 0.59, p=0.003
Improved progression free survival with PCV
10 year PFS: 21% vs 51%
Largest benefit in oligodendroglioma NEJM April 2016

39. Progression & transformation
LGG may progress without transformation:
Increase in tumour size without transformation to
High grade
- No contrast enhancing
- Low perfusion
- MR spectro: No Choline peak
- Need to treat as low grade glioma

40. LGG may progress with
transformation:
Increase tumour size &
transformation to high grade
- Contrast enhancing (Patchy)
- Higher perfusion
- MR spectro: Choline peak
- Need to treat as High grade
glioma
Progression & transformation