High grade glioma

Epidemiology
GBM: 12-13,000 cases per year
Grade III glioma: 3-4000 cases per year
Cranial RT is a risk factor
Incidence increases with age

Pathology
Anaplastic astrocytoma: no necrosis; fewer mitoses; less cellular; less pleomorphic
Anaplastic oligodendroglioma: perinuclear halos ("fried egg cells"); chicken wire appearance
GBM/Grade IV: necrosis, microvascular proliferation, high mitotic index, pleomorphic

Primary vs. secondary GBM
Primary: de novo, older patients, rapid development.  Associated with EGFR receptor, PTEN, p16 deletions
Secondary: arises in the context of prior lower grade tumor, younger patients; may have better prognosis but unknown if this is due to a lead-time effect.  Associated with p53 mutation, LOH at 19q, PDGFR, DCC.
Both types are associated with LOH at 10q, MDM2, Rb mutations

MGMT
DNA repair enzyme which demethylates O6-methylguanine
Repairs damage induced by temozolomide ... So mutated MGMT is FAVORABLE
In the EORTC temozolomide trial (PMID 19269895) MGMT mutation status was the strongest predictor of response to temozolomide.

Anaplastic oligodendroglioma
Characteristically associated with 1p19q deletion which greatly improves prognosis
RTOG 9402 (PMID 16782910) randomized patients with pure oligo or mixed OA tumors to RT alone vs. RT + PCV chemotherapy.  All patients with 1p19q deletion had improved OS.  No overall survival benefit was seen with the addition of PCV, but a PFS benefit to the addition of PCV was seen in the 1p19q deleted subgroup.

EORTC 26951 (PMID 16782911) was an identical randomization (RT +/- PCV) and showed similar results (improved OS in all 1p19q deleted patients; no OS improvement with chemo but a PFS improvement with chemo was seen in the whole group.  Interestingly the 1p19q deleted group did not have a significantly improved PFS with chemo).

Clinical presentation
Most common symptoms are headache, seizure, focal neuro deficit, cognitive decline
MRI shows enhancing heterogeneous mass typically with extensive edema and central necrosis

RTOG RPA for malignant glioma
Histology (AA vs. GBM)
Age (cutoff 50 years)
Mental status
KPS (cutoff at 70)
Duration of symptoms (less than three months is worse)

Long history of unsuccessful treatments
1) Dose escalation higher than 60Gy (although there appears to be dose response at 60 vs. 45Gy)
2) Hyperfractionation
3) SRS boost
4) Brachytherapy
5) Hypoxic radiosensitizers

Current standard
Maximum surgical debulking
Temozolomide has phase III proven OS benefit: 75mg/m2/day during RT then 150-200mg/m2/day afterwards; correct consolidation/maintenance dose remains under investigation
This regimen increases OS (27 vs 11% at 2 years, 10 vs 2% at 5 years) compared to RT only

RT technique
RTOG recommendations: edema +2cm to 44Gy then enhancement/residual tumor to another 16Gy