High grade gliomas

Question 1

What % of primary CNS tumors are malignant?

Answer 1

∼35% of primary brain tumors are considered malignant.

Question 2

In adults, what is the most common malignant CNS neoplasm?

Answer 2

∼80% of CNS neoplasms in adults are glioblastoma (GBM), which constitutes 20% of all primary tumors. ∼26,000 new malignant primary brain tumors are diagnosed annually in the United States.

Question 3

What are the WHO classifications for high-grade CNS tumors?

Answer 3

WHO III: anaplastic astrocytoma (AA)/anaplastic oligodendroglioma (AO)/anaplastic oligoastrocytoma (AOA)
WHO IV: GBM

Question 4

What are some common genetic changes seen in malignant brain tumors?

Answer 4

↑ EGFR (50%) and phosphatase and tensin homolog (PTEN) mutation (30%–40%)

Question 5

What are the initial genetic changes associated with primary vs. secondary GBM?

Answer 5

Primary: ↑ EGFR/MDM2 amplification/LOH 10/p16 loss
Secondary: p53 mutation → LGG → LOH 19q/p16 loss → AA → LOH 10, DCC → 2nd GBM; IDH mutation is also very common in secondary GBM

Question 6

What % of GBMs are multicentric?

Answer 6

<5% of GBMs are multicentric.

Question 7

What are the 4 pathologic characteristics used for astrocytoma grading?

Answer 7

Nuclear Atypia, Mitoses, Endothelial proliferation, and Necrosis
(Mnemonic: AMEN)

Question 8

What is the defining pathologic characteristic of GBM?

Answer 8

Necrosis

Question 9

What is the Cushing triad, and what does it represent in brain tumors?

Answer 9

HTN, bradycardia, respiratory irregularity. It represents ↑ ICP.

Question 10

With what Sx do high-grade gliomas (HGGs) most commonly present?

Answer 10

HA (especially in the morning, 50%), seizures (20%), focal neurologic dysfunction, and mental status change

Question 11

What are the common imaging characteristics of HGGs on MRI?

Answer 11

Hypodense on T1, gadolinium enhancing, T2 enhancing, and + T2 FLAIR (edema)

Question 12

What is the MS for LGG vs. HGG?

Answer 12

Low grade: pure oligodendroglioma: 10 yrs; oligoastrocytoma: 7 yrs; AO: 5 yrs
High grade: AA: 3 yrs; GBM: 14 mos

Question 13

What are the most important factors used for the recursive partitioning analysis (RPA) stratification?

Answer 13

Age 50 yrs, histology (AA or GBM), KPS of 70, MS changes, and Sx ≥3 mos
(Curran WJ et al., J Natl Cancer Inst 1993)

Question 14

What is the MS of a pt with RPA classes I–II, III–IV vs. V–VI?

Answer 14

MS by RPA class:
Classes I–II: 40–60 mos (3–5 yrs)
Classes III–IV: 11–18 mos (1–1.5 yrs)
Classes V–VI: 5–9 mos

Question 15

Under what RPA classes can GBM fall?

Answer 15

GBMs fall under classes III–VI:
Class III: <50 yo, KPS 90–100
Class IV: <50 yo, KPS <90 or >50 yo, good KPS
Class V: >50 yo, KPS <70 but no change in MS
Class VI: KPS <70 and MS change

Question 16

On what is the current modified RPA based?

Answer 16

Outcomes with TMZ (Mirimanoff RO, JCO 2006)

Question 17

What is the 4-yr OS and MS for RT + TMZ vs. RT alone for the adapted RPA groups for malignant gliomas (per Mirimanoff RO, ASTRO 2007 update)?

Answer 17

Overall survival: class III (<50 yo, PS 0): 28.4% vs. 6.4%; class IV: 11.3% vs. 3.3%; class V (>50 yo, Mini-Mental State Examination <27, Bx only): 6% vs. 1%
Median survival: class III: 21 mos vs. 15 mos; class IV: 16 mos vs. 13 mos; class V: 10 mos vs. 9 mos

Question 18

What additional factors did the European Nomogram (European GBM Calculator) investigate for stratification purposes?

Answer 18

MGMT methylation status and extent of resection; only MGMT, age, PS, and MS were prognostic (Gorlia T et al., Lancet Oncol 2008).

Question 19

What is MGMT, and why is it important?

Answer 19

MGMT is a DNA repair enzyme that removes alkyl groups from the O6 position of guanine. When methylated the MGMT gene is inactive and therefore, there is no ability to repair the damage caused by TMZ = chemosensitive. Methylated MGMT leads to increased OS regardless of the type of Tx.

Question 20

What is the mechanism of action of TMZ?

Answer 20

Oral agent that crosslinks DNA (alkylating).

Question 21

When should anticonvulsants be started for patients with LGG/HGG`?

Answer 21

Anticonvulsants should be started only if the pt is symptomatic or has a Hx of seizures.

Question 22

What is the impact of resection extent in HGGs?

Answer 22

Data suggest that the extent of resection correlates with improved outcomes. (Sanai N et al., Neurosurgery 2008; Stummer W, Lancet Oncol 2006)

Question 23

What is the Tx paradigm for AA and GBM?

Answer 23

AA Tx paradigm: Sg → RT to 56–59.4 Gy + TMZ or procarbazine, CCNU/lomustine, vincristine (PCV)
GBM Tx paradigm: Sg → RT to 60 Gy + TMZ → TMZ × 6 mos

Question 24

What is the dose of TMZ, and how is it administered/scheduled?

Answer 24

Oral pill; 7 days/wk at 75 mg/m2 concurrent with RT → 1-mo break → 6 cycles of adj TMZ at 150–200 mg/m2 given 5 days of every 28 days

Question 25

With the current Tx paradigm for HGG, what additional pharmacologic therapies are often necessary?

Answer 25

Steroids, proton pump inhibitors, and PCP prophylaxis

Question 26

Which early GBM studies demonstrated significant (doubled) survival with RT vs. supportive care and helped RT become a standard component of Tx?

Answer 26

GBM studies showing significant survival benefit:
1. BTSG 69–01 (Walker MD et al.): randomized to observation, BCNU(carmustine), WBRT, and BCNU + WBRT. There was no difference b/t WBRT vs. WBRT + BCNU, but RT was better than no RT. (J Neurosurg
1978)
2. BTSG 72–01 (Walker MD et al.): Randomized to MeCCNU (semustine), RT alone, BCNU + RT, and semustine + RT. MS 3–6 mos without RT, 9–12
mos with RT. (NEJM 1980)
3. Scandinavian Glioblastoma Study Group (SGSG) (Kristiansen K et al.): 45 Gy + bleomycin vs. 45 Gy vs. observation: MS 10.8 mos vs. 10.8 mos vs. 5.2 mos (SS). (Cancer 1981)

Question 27

Which randomized study supports the use of RT vs. best supportive care for the elderly with GBM?

Answer 27

French data (Keime-Guibert F et al.): pts >70 yo, KPS ≥70, to 50.4 Gy vs. observation. MS improved with RT: 6.7 mos vs. 3.9 mos. There was no difference in QOL or cognition. (NEJM 2007)

Question 28

What studies support the use of hypofx in elderly GBM pts with a poor KPS?

Answer 28

Roa W et al. (JCO 2004), Bauman GS et al. (IJROBP 1994), Malmström A et al. (Lancet Oncol 2012), and Roa W et al. (JCO 2015) suggest feasibility of hypofx. The 1st 3 trials looked at hypofractionated courses vs. standard
fractionation in pts >60–65 yrs or with poor KPS and showed hypofx was as good as or better than standard fractionation in terms of OS. Dose fractionation schemes included 40 Gy in 15 fx (Roa), 30 Gy in 10 fx (Bauman), and 34 Gy in 10 fx (Malmström). The 4th trial compared 25 Gy in 5 fx with 40 Gy in 15 fx, demonstrating noninferiority.

Question 29

Which study suggested that WBRT is not required (i.e., that limited-field RT is sufficient) in the Tx of HGGs?

Answer 29

BTCG 80–01 (Shapiro WR et al., J Neurosurg 1989): prospective RCT, 510 pts, WBRT to 60 Gy vs. WBRT to 43 Gy → CD to 60 Gy. There was no difference in survival in the RT arms. This study also demonstrates that BCNU single agent is equivalent to a multiagent regimen

Question 30

What evidence supports current RT volumes being used in the Tx of HGGs?

Answer 30

Hochberg FH: CT correlation with postmortem tissue, CT abnl + 2-cm margin encompassed tumor extent by 83%. Recurrence by imaging also occurred within 2 cm of the margin in primary Dz in 90% of cases. (Neurology 1980)
Kelly PJ: correlated imaging (MRI + CT) with stereotactic Bx in untreated gliomas. The study found that isolated tumor cells extended at least as far as T2, suggesting that T1 enhancement is equivalent to GTV and a +T2 is
equivalent to subclinical Dz. (J Neurosurg 1987)

Question 31

What evidence supports the current RT dose of 60 Gy used for HGGs?

Answer 31

Combined analysis of 3 BTSG trials (Walker MD, IJROBP 1979): 4 doses (<45 Gy, 50 Gy, 55 Gy, and 60 Gy). MS was 4 mos, 7 mos, 9 mos, and 10 mos, respectively. MRC data (Bleehen NM et al., Br J Cancer 1991): RCT, 474 pts, 45 Gy vs. 60 Gy (no chemo). MS was 9 mos vs. 12 mos.

Question 32

Is there evidence for a dose-escalation benefit beyond 60 Gy in HGGs?

Answer 32

No. There is no evidence for a dose-escalation benefit.
In RTOG 7401, there was no benefit for 70 Gy vs. 60 Gy in >600 pts. (Chang CH, Cancer 1983)
Chan JL et al. escalated the dose to 90 Gy without survival benefit. Of those who failed at 90 Gy, 91% failed in-field. (JCO 2002)

Question 33

Is there evidence supporting RT hyperfx for GBM?

Answer 33

No. RTOG 8302: >700 pts, randomized phase I, 64.8 vs. 81 Gy bid. There was no benefit. RTOG 9006 also showed no benefit.

Question 34

Is there a benefit to radiosurgery boost for HGGs?

Answer 34

No. RTOG 9305 showed no benefit and higher toxicity. (Souhami L et al., IJROBP 2004)

Question 35

Before the TMZ data, was there any benefit to CRT for HGGs?

Answer 35

Yes. This was shown by evidence from 2 large meta-analyses: The MRC Glioma Meta-analysis Trialist Group showed a small improved median PFS (7.5 mos vs. 6 mos) with chemo, reduced risk of death by 15%, and ↑ 1-yr OS by 6%. There was no RT dose–response with less or more than 60 Gy. (Stewart LA et al., Lancet 2002)

Question 36

What is the evidence that supports the current gold standard in GBM Tx with TMZ?

Answer 36

EORTC/NCIC data (Stupp R et al., NEJM 2005 and 5-yr update Stupp R et al., Lancet Oncol 2009): 5-yr OS 10% (+ TMZ) vs. 2% (– TMZ), MS 14.6 mos (+ TMZ) vs. 12 mos (– TMZ). Benefit in all groups including ages 60–70. In pts with methylated MGMT there is a PFS benefit to TMZ + RT vs. RT alone.

Question 37

Which modified RPA class did TMZ + RT not benefit significantly (per Mirimanoff RO et al., JCO 2006)?

Answer 37

Class V. MS per RPA: class III, 17 mos; class IV, 15 mos; and class V, 10 mos. The only significant benefit of TMZ + RT vs. RT alone was in classes III–IV.

Question 38

What is the role of MGMT methylation in terms of response to Tx with HGGs?

Answer 38

Greater response to TMZ + RT in those with methylated MGMT (Hegi ME et al., NEJM 2005; Mirimanoff RO, ASTRO 2007): 4-yr OS unmethylated (RT alone vs. RT + TMZ): 0% vs. 11% and methylated 5% vs. 22%, all SS

Question 39

What data supports the use of TTFs as maintenance therapy in GBM?

Answer 39

Stupp et al., JAMA 2015 compared adj TMZ and TTFs vs. TMZ alone in pts receiving the Stupp regimen for newly diagnosed GBM. Median OS was improved in the TTF group (20.5 mos vs. 15.6 mos).

Question 40

How are TTFs achieved and what is the proposed mechanism of action?

Answer 40

They are achieved via transducer arrays on scalp (worn >18 hrs/day) and are thought to interfere with organelle assembly/cell division.

Question 41

What are the options for recurrent GBM?

Answer 41

TMZ, bevacizumab, reirradiation to ∼35(10) Gy (Fogh SE et al., JCO 2010), radiosurgery, brachytherapy (GliaSite), Gliadel, TTFs or clinical trial

Question 42

What are the approved uses of Gliadel?

Answer 42

FDA approval: recurrent Dz with re-resection improved survival advantage 31 vs. 23 wks. (Brem H et al., Lancet 1995)
In newly diagnosed adj setting: MS was 13.9 mos vs. 11.6 mos. (Westphal M, Neurooncol 2003)

Question 43

What are the general guidelines for RT target volume delineation in GBMs?

Answer 43

RTOG:
Initial volume (46 Gy): GTV1 = T1/tumor bed + T2/FLAIR, CTV1 = GTV1 + 2 cm
Boost volume (14 Gy): GTV2 = T1/tumor bed, CTV2 = GTV2 + 2 cm. PTV adds 0.5 cm to all CTVs. Postop imaging (with MRI fusion) should be used for target delineation.
Alternative MDACC technique with SIB (Chang et al., IRJOBP 2007): GTV = T1/tumor bed, CTV = GTV + 2 cm. PTV 50 = CTV + 5-mm dose to 50 Gy in 30 fx, PTV 60 = GTV + 5-mm dose 60 Gy in 30 fx

Question 44

Which study showed similar survival outcomes with adj RT vs. adj chemo with PCV or TMZ in WHO III gliomas (AA)?

Answer 44

German NOA-04 study (Wick W et al., JCO 2009): same PFS/OS for all arms (RT alone or 2 chemo agents alone). Good predictors: extent of resection, oligo component (oligodendroglioma or oligoastrocytoma), IDH1 mutation, MGMT promoter hypermethylation, 1p19q codeletion. Toxicity: grades 3–4 hematologic toxicity was significantly higher for PCV than for TMZ.

Question 45

Which study investigated sequential PCV → RT vs. RT alone in oligodendroglial tumors?

Answer 45

RTOG 9402/INT-0149 (Cairncross G et al., JCO 2006; Cairncross G et al., JCO 2013): AO or AOA s/p resection randomized to PCV × 4 → RT 59.4 Gy vs. RT alone. No median OS benefit. There was improved median PFS (8.4 yrs vs. 2.9 yrs) with chemo. Pt with 1p19q codeletion (unplanned subgroup analysis) had improved median OS with PCV vs. RT alone (14.7 vs. 7.3 yrs).
PCV increased toxicity.

Question 46

Which recent study investigated sequential RT → BCNU vs. RT alone in AA? What did it find?

Answer 46

EORTC 26882 (Hildebrand J et al., Eur J Cancer 2008): no OS or PFS difference

Question 47

What study tested the role of adj PCV after RT in oligodendroglial tumors?

Answer 47

EORTC 26951 (Van den Bent MJ et al., JCO 2006; Van den Bent MJ et al., JCO 2013): With long-term f/u OS better with RT + PCV (24.3 mos vs. 13.2 mos). 1p19q deleted pts did better. There was no long-term difference in QOL after PCV.

Question 48

What phase III study investigated the efficacy of combining RT with either TMZ or nitrosourea in anaplastic gliomas?

Answer 48

RTOG 9813 (Chang S, Neurooncol 2008): Study closed early with 201 pts enrolled. Showed increased toxicity with BCNU vs. TMZ.

Question 49

What studies are investigating the role of TMZ in AO/AOA?

Answer 49

NCCTG N0577 (CODEL): pts with 1p19q codeletion randomized to RT + PCV vs. RT + TMZ → TMZ vs. TMZ × 12 cycles.
EORTC 26053 (CATNON): anaplastic gliomas without 1p19q del 2 × 2 randomization RT vs. RT + TMZ then observation vs. adj TMZ. Interim results presented at ASCO 2016 showed sup 5-yr OS with RT + TMZ
(56%) vs. RT alone (44%).

Question 50

What is the Tx paradigm for gliosarcoma?

Answer 50

Gliosarcoma Tx paradigm: treat like GBM (Sg → RT + TMZ → TMZ)

Question 51

Which study tested dose-intensified TMZ after TMZ + RT?

Answer 51

RTOG 0525 (Gilbert M et al., ASCO 2011). This study randomized pts after TMZ + RT (after a 1-mo break) to TMZ on days 1–21 vs. standard days 1–5
for up to 12 cycles (max) depending on the response. Prelim results showed more toxicity in dose-dense arm and no difference in OS or PFS. Final data
are pending as are neurocognitive and QOL results.

Question 52

What ongoing phase III studies looked at bevacizumab in the upfront setting for GBM?

Answer 52

RTOG 0825 (Gilbert M et al., ASCO 2013): all treated with RT + TMZ then randomized to concurrent bevacizumab vs. placebo. Preliminary results
show no OS or PFS benefit, but bevacizumab arm had worse QOL, cognitive function, and Sx burden.

AVAglio (Gilbert MR et al., NEJM 2014): all treated with RT + TMZ then randomized to bevacizumab vs. placebo. No OS benefit. Longer PFS 10.7 mos with bevacizumab vs. 7.3 mos with placebo.

Question 53

What is the radiographic appearance of radionecrosis?

Answer 53

Central hypodensity, ring enhancement, edema, and low PET avidity (occurs >6 mos post-RT)

Question 54

What was the grade 3–4 toxicity rate from the Stupp R et al. trial (NEJM 2005) for the RT + TMZ arm? What main toxicity was noted?

Answer 54

7%; mostly hematologic from TMZ (thrombocytopenia and

lymphocytopenia)

Question 55

What does the f/u entail after RT for HGGs?

Answer 55

MRI 2–6-wks post-RT, then q2–4mos for yrs, then q6mos; weekly labs (blood counts) while on TMZ (NCCN 2018)

Question 56

What % of HGG recurrences are local?

Answer 56

80%–90% of HGG recurrences are local.

Question 57

What % of pts may show pseudoprogression after RT + TMZ?

Answer 57

Up to 50% (Taal W et al., Cancer 2008)

Question 58

Does MGMT promoter methylation status influence the incidence of pseudoprogression in HGGs?

Answer 58

Yes. MGMT methylation status increases the incidence of pseudoprogression after TMZ + RT. (Brandes AA et al., JCO 2008)