Low-Grade Glioma

Updated by Andrew J. Bishop

BACKGROUND

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:

Grade I: pilocytic astrocytoma, subependymal giant cell tumor

Grade II: (fibrillary, protoplasmic, gemistocytic), astrocytoma, oligodendroglioma, and oligoastrocytoma

What 4 pathologic features determine glioma grading?

Necrosis

Atypia

Mitotic figures

Endothelial proliferation

(Mnemonic: NAME or AMEN)

Which subtype of grade II glioma 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 does pilocytic astrocytoma most commonly present?

Most commonly presents in the posterior fossa (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 isocitrate dehydrogenase (IDH) mutations portend a better survival. p53 mutation indicates poorer survival and time to malignant transformation.

What genetic change is prognostic in oligodendroglioma?

LOH 1p19q (50%–70%) is prognostic in oligodendroglioma. Associated with superior OS 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 is the genetic mutation 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 and is associated with optic/intracranial gliomas.

What is the genetic mutation in tuberous sclerosis, and with what glioma is it associated?

Tuberous sclerosis is a result of a mutation on chromosome 9 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-year OS of LGG?

The 5-yr OS is 60%–70%.

WORKUP/STAGING

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 maximal 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.

TREATMENT/PROGNOSIS

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 for GTR or STR with stable Dz; reserving RT or chemo for progression/recurrence.

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?

Chemos used in LGG:

1. Temozolomide (TMZ)

2. BCNU/CCNU (carmustine/lomustine)

3. 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?

Approximately 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 surgery 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 2 clinical circumstances can adj RT be considered for LGGs?

1. For pts s/p STR/Bx only and with Sx

2. 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 received subsequent salvage RT.

What proportion of pts do not need salvage RT when observed after surgical resection for LGG?

Per EORTC 22845, approx one-third of patients 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 received salvage RT. OS after 1^st 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:

1. 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)

2. 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 adjuvant therapy needed after GTR or STR for pilocytic astrocytoma in adults?

No. Brown et al. prospectively followed 20 adult pilocytic astrocytoma pts s/p GTR, STR (6 pts), or Bx (3 pts). 5-yr PFS was 95%. (IJROBP 2004)

Is there a benefit of chemo with RT for LGGs with high-risk features?

This is controversial. RTOG 9802 stratified pts into low risk (age <40 yrs s/p GTR) and high risk (age >40 yrs or STR/Bx only). Low-risk pts were observed. High-risk pts were randomized to adj RT alone (54 Gy) vs. RT + PCV. Outcomes were better in the chemo arm but did not reach SS (5-yr OS: 63% vs. 72%; PFS: 46% vs. 63%). For pts living 2 years, the probability of an additional 5-yr survival favored RT + PCV (74% vs. 59%, p = 0.02), suggesting a possible delayed benefit. (Shaw EG et al., JCO 2012)

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 94% and PFS of 50%. (Shaw EG et al., ASCO 2006)

Is there a role for TMZ in the initial Tx of LGG?

Results of 2 trials are preliminary:

1. EORTC 22033 randomized high-risk LGG pts (3 of 5 EORTC features) to adj RT vs. adj TMZ. No clear benefit of TMZ in PFS or OS. RT remains standard of care. Results need further maturation.
(Baumert BG et al., ASCO 2013)

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 adjuvant TMZ. Preliminary results show a 3-yr OS rate of 73%, which is higher than historic controls
(Fisher BJ et al., ASCO 2013)

For pilocytic astrocytoma, what is the estimated 10-yr RFS in pts treated with GTR alone?

10-yr RFS is ~95% in pilocytic astrocytoma pts treated with GTR alone. (Watson GA et al., Semin Radiat Oncol 2001)

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

(Jenkins RB et al., Cancer Res 2006)

TOXICITY

How does RT affect QOL in the Tx of LGG?

QOL in LGG is impacted by surgery, 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 commonly used RT dose constraint for the chiasm with fractionated RT vs. SRS?

The chiasm is commonly constrained to 54 Gy in 1.8–2 Gy/fx and 8 Gy in a single fx.

What is the commonly used RT dose constraint for the cochlea?

The cochlea is commonly constrained to a mean dose of 30–35 Gy in 1.8–2 Gy/fx.

What is the commonly used RT dose constraint for the brainstem with SRS?

The brainstem is commonly constrained to 12 Gy in a single fx.

What is the cause of somnolence syndrome after brain RT?

Somnolence syndrome is thought to be caused by demyelination.

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