Radiation Oncology: A Question-Based Review

Low-Grade Glioma

John P. Christodouleas and Shiao Y. Woo

image Background

Low-grade gliomas (LGGs) account for what % of all primary brain tumors?

~15% 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 2 classes of LGGs?

Noninfiltrative (WHO I) and infiltrative (WHO II)

What are the histologic subtypes of LGGs?

Histologic subtypes of LGG:

1.     Grade I: juvenile pilocytic astrocytoma (JPA), subependymal giant cell tumor

2.     Grade II: diffuse (fibrillary, protoplasmic, gemistocytic), pilomyxoid astrocytoma (PMA), pleomorphic xanthoastrocytoma, oligodendroglioma, oligoastrocytoma

What 4 pathologic features determine glioma grading?

1.     Necrosis

2.     Atypia

3.     Mitotic figures

4.     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 JPA most commonly present?

JPA most commonly presents in the posterior fossa (80% cerebellar, 20% supratentorial).

What pathologic feature is characteristic of JPA?

Rosenthal fibers are characteristic of JPA.

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 JPA vs. other LGG?

The median age for JPA is 10–20 yrs and for grade II LGG is 30–40 yrs.

What genetic change is an important prognostic factor in LGG?

In LGG, p53 mutation is an important prognostic factor (poorer survival and time to malignant transformation).

What is the natural Hx of PMA?

PMA tends to occur in infants (10−18 mos), mostly in chiasmatic-hypothalamic regions. It is an atypical JPA with a higher rate of CSF dissemination and recurrence.

What genetic change is prognostic in oligodendroglioma?

LOH 1p + 19q (50%−70%) is prognostic in oligodendroglioma.

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.

Can you have mitoses in LGGs?

Yes. If the tumor is small, even a single mitosis upgrades it to at least WHO III (anaplastic). However, if the tumor is large, a single mitosis may not upgrade it to a high-grade histology.

With what Sx do LGGs most commonly present?

Seizures (60%−70%, better prognosis) > HA, focal neurologic Sx

image 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 max safe resection (per the NCCN), otherwise by stereotactic Bx.

What is the typical MRI characteristic seen in LGG?

On MRI, LGGs appear hypodense on T1, are nonenhancing with gadolinium, and show +T2 prolongation.

What is the typical MRI appearance of JPA?

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).

Is there a need for seizure prophylaxis in pts with LGG?

Yes. Per the American Academy of Neurology, prophylactic anticonvulsants are necessary in pts with a Hx of seizures.

What is the min oligodendroglioma component needed histologically to classify a tumor as a mixed oligoastrocytoma?

According to the most recent WHO classification, there is no consensus on a standard cutoff to classify mixed tumors (prior cutoff was 25%).

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.

image 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, reserving RT for recurrence.

What adj and salvage chemo regimens are typically used in LGG?

Chemos used in LGG:

1.     Temozolomide (TMZ)

2.     BCNU/CCNU

3.     PCV (procarbazine/CCNU/vincristine)

What RT dose is typically used for LGG?

LGG is commonly treated to 50.4–54 Gy.

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 time frame 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?

1.     Initial PTV: preop T2 volume + 0.5−1 cm

2.     Boost PTV: postop T1 + 0.5−1 cm

3.     Alternatively, postop T2 (or FLAIR) + 2 cm to 54 Gy with 3D-CRT can be used (per RTOG 9802).

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)

What prospective data support initial observation over adj RT in LGG?

EORTC 22845 randomized 290 LGG pts to surgery alone vs. surgery + adj RT. NTR in 42%, debulking in 20%, and Bx only in 38%. PFS favored adj RT (5-yr PFS 35% vs. 55%, median PFS 3.4 yrs vs. 5.3 yrs), but there was no significant difference in OS (7.2−7.4 yrs). (Van den Bent MJ et al., Lancet 2005)

What % of LGG pts undergoing initial observation in EORTC 22845 eventually required salvage RT?

In EORTC 22845, 65% of pts in the observation arm rcv subsequent salvage RT.

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

Per EORTC 22845, approx ⅓ of patients will not require salvage RT.

In EORTC 22845, how did the OS after 1st recurrence compare in the adj vs. observation arms?

Survival after 1st recurrence was better in initially observed pts, most of whom rcv salvage RT. OS after 1st recurrence was 3.4 yrs vs. 1 yr (SS).

Which study suggested that doses >53 Gy improved outcomes in LGG?

Shaw et al. retrospectively reviewed the outcomes of 126 LGG pts treated +/− varying doses of RT. Pts receiving >53 Gy had an 18% OS advantage at 10 yrs vs. pts receiving <53 Gy (J Neurosurg 1989). More recent prospective studies (EORTC 22844 and the NCCTG LGG study) do not support a benefit of doses above 45−50.4 Gy.

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)

What evidence is there to support observation after GTR or STR for pilocytic astrocytoma in adults?

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 × 6. Outcomes were better in the chemo arm but did not reach SS (5-yr OS: 63% vs. 72%; PFS: 46% vs. 63%). Pts who lived >2 yrs had significantly improved PFS and OS (↓ risk of death by 48%) with chemo, suggesting a possible delayed benefit. (Shaw EG et al., ASCO abstract 2006)

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 abstract 2006)

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

Results of 2 trials are not yet available:

1.     EORTC 22033 is randomizing high-risk LGG pts (3 of 5 EORTC features) to adj RT vs. adj TMZ. Results have not yet been reported.

2.     RTOG 0424 is a phase II study that enrolled high-risk LGG pts (3 of 5 EORTC features) and treated with adj 54 Gy RT + TMZ. This study is closed to accrual (results pending).

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

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

In pts with oligodendroglioma/mixed oligoden-droglioma, what is the median OS for those +/+ LOH for 1p19q?

1.     With LOH 1p19q: median OS ~13 yrs

2.     Without LOH 1p19p: median OS ~9 yrs

(Jenkins RB et al., Cancer Res 2006)

image 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 50–54 Gy in 1.8−2 Gy/fx and 8 Gy in a single fx.

What is the commonly used RT dose constraint for the inner ear?

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

What is the commonly used RT dose contraint for the brain stem with SRS?

The brain stem 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.