Low-Grade Glioma Flashcards
Low-grade gliomas (LGGs) account for what % of all primary brain tumors?
∼10% of all primary brain tumors are LGGs.
Is there a racial predilection for LGG?
Yes. Whites are more commonly affected than blacks (2:1).
What are the histologic subtypes of LGGs?
Histologic subtypes of LGG (WHO 2016 update):
Grade I: pilocytic astrocytoma, subependymal giant cell tumor
Grade II: diffuse astrocytoma (fibrillary, protoplasmic, gemistocytic) including isocitrate dehydrogenase (IDH) mutant/wildtype; oligodendroglioma, IDH mutant/1p19q co-deleted; and oligoastrocytoma
What 4 pathologic features determine glioma grading?
Necrosis Atypia Mitotic figures Endothelial proliferation (Mnemonic: NAME or AMEN)
Which subtype of diffuse astrocytoma has the worst prognosis?
The gemistocytic subtype tends to de-differentiate and has the worst prognosis. Some prefer to treat it like a high grade glioma.
Where anatomically does pilocytic astrocytoma most commonly present?
Most commonly presents in the PF (80% cerebellar, 20% supratentorial).
What pathologic feature is characteristic of pilocytic astrocytoma?
Rosenthal fibers are characteristic of pilocytic astrocytoma.
Where do grade II LGGs most commonly present?
Grade II LGGs most commonly present in the supratentorium.
What is the median age of Dx for pilocytic astrocytoma vs. other LGG?
The median age for pilocytic astrocytoma is 10–20 yrs and for grade II LGG is 30–40 yrs.
What genetic changes are important prognostic factors in LGG?
In LGG, LOH 1p19q and IDH mutations portend a better survival. p53 mutation indicates poorer survival and time to malignant transformation.
IDH1 and IDH2 mutations are strongly associated with better prognosis.
What genetic change is prognostic in oligodendroglioma?
LOH 1p19q is prognostic in oligodendroglioma and is present in over 50% of cases. Associated with sup OS (MS 10 yrs in del 1p/19q vs. 3 yrs in intact)
and PFS. (Jenkins RB et al., Cancer Res 2006)
What is the characteristic pathologic appearance of oligodendroglioma?
“Fried egg” appearance (round cells with nuclear halo) is characteristic of oligodendroglioma.
Where do most oligodendrogliomas occur in the brain?
Most oligodendrogliomas occur in the hemispheres (80%).
Anaplastic transformation from LGG to HGG occurs in what % of pts?
∼70%–80% of pts with LGG will undergo anaplastic transformation (based on EORTC 22845).
What chromosome is affected in NF-1, and with what type of gliomas is it associated?
NF-1 is a result of a mutation on the long arm of chromosome 17 (NF1/neurofibromin tumor suppressor gene) and is associated with optic/intracranial gliomas
What chromosome is affected in tuberous sclerosis, and with what glioma is it associated?
Tuberous sclerosis is a result of a mutation on chromosome 9 (TSC1 tumor suppressor gene) or chromosome 16 (TSC2 tumor suppressor gene)and is
associated with subependymal giant cell astrocytoma.
What syndrome is associated with gliomas and GI polyposis?
Turcot syndrome is associated with gliomas and polyposis.
With what Sx do LGGs most commonly present?
Seizures (60%–70%, better prognosis) > HA, focal neurologic Sx
What is the 5-yr OS of LGG?
The 5-yr OS is 60%–70%.
What is the workup for suspected glioma?
Suspected glioma workup: H&P, basic labs, and MRI brain
How should tissue be acquired for Dx?
Tissue should be acquired by max safe resection (per the NCCN), otherwise by stereotactic Bx.
What is the typical MRI characteristic seen in LGG?
On MRI, LGGs appear hypointense on T1, are nonenhancing with gadolinium, and show T2 prolongation.
What is the typical MRI appearance of pilocytic astrocytoma?
Well-circumscribed, cystic mass, intensely enhancing solid mural nodule
What % of nonenhancing lesions are grade III gliomas?
∼30% are grade III gliomas (65% are LGG).
What feature has been associated with oligodendrogliomas on imaging?
Calcifications are a prominent feature on imaging of oligodendrogliomas
What is suggestive of a malignant tumor on MR spectroscopy?
Increased choline (cell membrane marker), low creatine (energy metabolite), and low N-acetyl-aspartate (a neuronal marker) are suggestive of malignancy on MR spectroscopy.
What is the staging of LGG?
There is no formal staging for LGG.
What are the 5 negative prognostic factors for LGG as determined by EORTC 22844 and 22845?
Negative prognostic factors per the EORTC index: 1. Age >40 yrs 2. Astrocytoma histology 3. Tumors ≥6 cm 4. Tumors crossing midline 5. Preop neurologic deficits (Pignatti F et al., JCO 2002)
What is the general Tx paradigm used for LGGs?
LGG Tx paradigm: max safe resection → observation if low risk (≤40 yo and GTR) or adj RT +/– PCV chemo if high risk (>40 yo or STR).
What prospective data support initial observation over adj RT in LGG (early vs. delayed)?
EORTC 22845 (“Non-Believers Trial”) randomized 314 LGG pts to early RT vs. delayed RT until time of progression. Concluded early RT lengthens PFS (5.3 yrs vs. 3.4 yrs) and seizure control (25% vs. 41%) but does not impact OS. (Van den Bent MJ et al., Lancet 2005)
What adj and salvage chemo regimens are typically used in LGG?
Chemo agents used in LGG:
- TMZ
- BCNU/CCNU (carmustine/lomustine)
- PCV (procarbazine/CCNU/vincristine)
What RT dose is typically used for LGG?
LGG is commonly treated to 50.4–54 Gy (1.8 Gy/fx)
A complete resection can be achieved in what proportion of pts with LGGs?
Appx one-third of pts with LGGs have a GTR.
Within what timeframe should postop MRI be obtained for pts with LGGs? Why is it needed?
Postop MRI should be done within 48–72 hrs of Sg to assess for residual Dz/extent of resection.
In LGG, how are the RT Tx volumes defined, and what margins are typically used?
Per RTOG1072/ECOG E3F05:
GTV = cavity + T2/FLAIR + enhancement
CTV = GTV + 1 cm
PTV = CTV + 0.5 cm
In what clinical circumstances can adj RT be considered for LGGs?
- For pts >40 yo or with STR per RTOG 9802
- For pts with 3 of 5 high-risk features per the EORTC index (above).
No LOH 1p19q or IDH mutation are also adverse features that may be considered.
What % of LGG pts undergoing initial observation in EORTC 22845 eventually required salvage RT?
In EORTC 22845, 65% of pts in the observation arm rcvd subsequent salvage RT.
What proportion of pts do not need salvage RT when observed after surgical resection for LGG?
Per EORTC 22845, appx one-third of pts will not require salvage RT.
In EORTC 22845, how did the OS after progression compare in the adj vs. observation arms?
Survival after progression was better in initially observed pts, most of whom rcvd salvage RT. OS after 1st recurrence was 3.4 yrs vs. 1 yr (SS).
Is there prospective evidence to support dose escalation with adj RT for LGG?
No. Dose escalation in LGG has been evaluated in 2 RCTs, neither of which showed a benefit:
- EORTC 22844 randomized 343 pts to adj RT 45 Gy vs. 59.4 Gy. There was no difference in 5-yr OS (58%–59%) or PFS (47%–50%). (Karim AB et al., IJROBP 1996)
- INT/NCCTG randomized 203 pts to adj RT 50.4 Gy vs. 64.8 Gy. There was no difference in 5-yr OS (65%–72%). 92% of failures were in-field. (Shaw EG et al., JCO 2002)
Is adj therapy needed after GTR or STR for pilocytic astrocytoma in adults?
No. Brown et al. prospectively followed 20 young (<47 yo) adult pilocytic astrocytoma pts s/p GTR, STR (6 pts), or Bx (3 pts). 20-yr OS and PFS in GTR pts was 100%. 20-yr OS and PFS for STR was 100% and 83%.
(Neurooncol Pract 2015)
Is there a benefit of chemo with RT for LGGs with high-risk features?
RTOG 9802 stratified pts into low risk (age <40 yrs s/p GTR) and high risk (age >40 yrs or STR/Bx only). High-risk pts were randomized to adj RT alone (54 Gy) vs. RT + PCV. Outcomes were better in the chemo arm and were SS after long-term f/u (10-yr OS: 40% vs. 60%; PFS: 21% vs. 51%). Benefit to actuarial PFS and OS were apparent after 2 and 4 yrs, respectively. (Buckner et al., NEJM 2016)
In RTOG 9802, what were the 5-yr OS and PFS for low-risk pts observed after GTR?
In RTOG 9802, low-risk pts (<40 yo s/p GTR) were observed and had 5-yr OS of 93% and PFS of 48%. (Shaw et al., J Neurosurg 2008)
Is there a role for TMZ in the initial Tx of LGG?
Results of 2 trials are preliminary:
1. Intergroup EORTC 22033–26033 randomized 477 high-risk LGG pts (>1 of: age >40, progressive Dz, tumor ≥5 cm, tumor crossing midline, neurologic Sx) to adj RT vs. adj TMZ. Overall there was no difference in
PFS or OS at 4 yrs. In exploratory analyses, pts with IDH mutations/1p19q noncodel had better PFS with RT compared to TMZ. IDH-wt and IDHmt/codel pts saw no PFS difference b/t the 2 arms. (Baumert BG et al.,
Lancet Oncol 2016)
2. RTOG 0424 is a phase II study that enrolled high-risk LGG pts (3 of 5 EORTC features) and treated with RT (54 Gy) + concurrent TMZ then adj TMZ. Preliminary results show a 3-yr OS rate of 73%, which is higher than
historic controls. The 3-yr PFS was 59.2%, however, 43% of pts had G3 adverse events. (Fisher BJ et al., IJROBP 2015)
For pilocytic astrocytoma, what is the estimated 10-yr and 20-yr RFS in pts treated with GTR alone?
10-yr and 20-yr RFS is 100% in pilocytic astrocytoma pts treated with GTR alone. (Brown et al., Neurooncol Pract 2015)
In pts with oligodendroglioma/mixed oligodendroglioma, what is the median OS for those +/- LOH for 1p19q?
With LOH 1p19q: median OS ∼13 yrs
Without LOH 1p19p: median OS ∼9 yrs
How does RT affect QOL in the Tx of LGG?
QOL in LGG is impacted by Sg, RT, chemo, and seizure meds. Based on the EORTC 22844 dose-escalation study, higher-dose RT was significantly associated with fatigue/malaise and insomnia and ↓ emotional functioning.
(Kiebert GM et al., Eur J Cancer 1998)
Does RT predispose LGG lesions to malignant transformation?
No. RT is not associated with an ↑ rate of malignant transformation. In EORTC 22845, there was a 70% transformation rate in both the adj and observation arms.
What is the NCCN recommended radiographic surveillance frequency for LGG post Tx?
The recommended imaging frequency post Tx is MRI q3–6mos for 1st 5 yrs, then annually. (NCCN 2018)
What is the constraint for the optic chiasm in conventional fractionation vs. single fraction SRS?
Chiasm is commonly constrained to 54 Gy in
1.8–2 Gy/fx and 8 Gy in a single fx.
What is the cause of somnolence syndrome after brain RT?
Somnolence syndrome is thought to be caused by demyelination.
