Low-grade gliomas

What is the significance of TERT promoter mutation

Among IDH-wt LGG it confers a poor prognosis

What is the significance of 1p/19q codeletion?

Defining feature of oligodendroglioma, favorable prognosis

What are the characteristic features of oligodendroglioma?

-Calcifications -Frieg egg cells -1p/19q codeletion

What margins should you use for RT?

-GTV including FLAIR/T2 changes + 1.5 cm for CTV, another 3-5 mm for PTV -If pediatric, CTV 5 mm plus PTV

What is the general radiation paradigm for low grade glioma?

-High risk pts should undergo adj chemoRT; RTOG 9802 established CRT as standard of care for high risk pts -Dose of 45 to 54 Gy are acceptable (RTOG 9802 and 0424 used 54 Gy; European trial E3F05 used 50.4)

What is the general treatment paradigm for low grade glioma?

-Maximal safe resection -Postoperative MRI -Low risk pts may be observed, whereas high risk patients are typically recommended adj CRT

What are the median OS for the low grade gliomas?

-Oligodendoglioma, IDH mutant and 1p/19q codeleted - Med OS >10 yrs -Diffuse astrocytoma, IDH-m, ATRX loss and TP53 mutation, 1p/19q intact- Median OS >10 yrs -Diffuse astrocytoma, IDH-wt - Med OS 5 yrs -Oligoastrocytoma - median OS <7 yrs

What were the results of RTOG 0424 (Fischer 2015)?

-Phase II, low grade glioma and 3 or more risk factors (age >40, astrocytoma, crosses midlines, size 6 cm, preop neuro function status >1) SATAN criteria -54 Gy plus TMZ concurrent and adj -3 yr OS 73% (improved from historical control 54%) -Median OS not yet reached -3 yr PFS 59% -Grade 3 toxicity 43%, Grade 4 10% -Conc: 3 yr survival with temodar is improved over historical control

What is the significance of IDH1 and IDH2 mutations

-Present in majority of WHO grade II gliomas, favorable prognosis relative to IDH-wt

What were the results of the Nonbelievers trial (EORTC 22845, Karim 2002, van den Bent 2005)?

-RCT 311 pts, WHO grade I-II s/p surg; Post op 54 Gy vs obs (RT given at recurrence) -5 yr PFS improved in RT - 55% vs 35% -1 yr seizures improved - 25% vs 41% -5 yr OS no diff - 66% vs 68% -Median OS unchanged 7.4 yrs vs 7.2 yrs -Rate of malignant transformation NO DIFF - 72% vs 66% (NS) -No diff in cognitive deficits -Conc: RT improves PFS and seizure outcomes but not OS; Also, malignant transf not different

What were the results of RTOG 9802 (Shaw 2008, Buckner 2016)?

-RCT 365 pts, WHO grade II astrocytoma, oligoastrocytoma or oligodendroglioma -Low risk pts (age <40 and GTR) observed; High risk (>40 or <40 and STR) received 54 Gy RT alone vs 54 Gy w/ adjuvant PCV x6 cycles -10 yr PFS improved w/ PCV in high risk group - 51% vs 21% -10 yr OS 60% vs 40% -Median OS improved from 13.3 yrs vs 7.8 yrs -On subanalysis, benefit for oligo and IDH1 mutant but not astrocytoma; Not enough pts for IDH1 wt -Conc: Addition of PCV to RT improves survival in high risk LGG

What were the results of EORTC 22033 study on TMZ vs RT (Baumert 2016, Reijneveld 2016)?

-RCT 477 pts, Age >40, progressive mass, new or worsening neuro sx, intractable seizures -RT 50.4 Gy vs dose dense temodar -PFS w/ RT 46 mos vs 39 mos (NS) -If IDH-m/noncodel, RT had longer PFS; no diff in PFS w/ IDH-m/codel and IDH-wt tumors -Median OS not reached -No diff in HRQoL or global cognitive function -Conc: no significant diff in PFS between radiation and TMZ; MOS not reached

What were the results of Believers trial (EORTC 22844, Karim 1996)?

-RCT, 343 pts; WHO grade I-II disease s/p surgery -Postop 45 Gy vs 59.4 Gy (shrinking fields) -No difference in OS (59%) or PFS (49%) -On analysis, prognostic variables (SATAN): Size >6cm, Age >40, Tumor crossing midline, Astrocytoma, Neuro deficits -Conc: No diff in high vs low dose

What were the results of the INT/NCCTG dose escalation trial (Shaw 2002)?

-RCT, WHO I-II s/p surgery, randomized to postop 50.4 Gy vs 64.8 Gy -No diff in 5 yr OS (72% low dose vs 64%) -More grade 3-5 toxicity w/ high dose -Favorable prognostic factors: age <40, oligo histo -Conc: high dose has more necrosis and no improvement in outcome

What is the general chemo paradigm for low grade glioma?

-RTOG 9802 looked at RT followed by adj PCV (procarbazine, CCNU (lomustine), vincristine) x6 cycles -RTOG 0424 (phase II) looked at RT w/ concurrent and adj TMZ for 12 mos -Both are commonly used but level I evidence (RTOG 9802) only exists for PCV

What are the classic features of pilocytic astrocytomas?

-Rosenthal fibers -Enhances on MRI due to degenerative hylanization of blood vessels -Usually posterior fossa in kids

What are the SATAN criteria for glioma at risk of recurrence and what trial are they from?

-Size >6cm, Age >40, Tumor crossing midline, Astrocytoma, Neuro deficits -Believers trial (EORTC 22844, Karim 1996)

What are the Pignatti high risk factors for low grade gliomas?

1) Age >40 2) Astrocytoma histology 3) Tumors >6 cm 4) Tumor crossing midline 5) Preoperative neurologic symptoms

What is the significance of TP53 and ATRX mutation?

Characteristic of IDH-mutated astrocytomas -ATRX is mutually exclusive from 1p19q codeletion -Less favorable prognosis than 1p/19q

What is the general prognosis for LGG?

Pure oligo - OS 14 yr Low grade astro 5 yr 0-2 SATAN - 8 yr 3-5 SATAN - 4 yr

What is the significance of MGMT methylation?

Role in LGG is less clear, but it has been associated with improved postrecurrence survival in presence of TMZ

What is the most common presenting symptom of low grade glioma?

Seizure (>80% of LGG, compared to 70% and 50% in anaplastic and GBM respectively)