Treatment/Prognosis

Question 1

What is the MS for LGG vs. HGG?

Answer 1

Low grade: pure oligodendroglioma: 10 yrs; oligoastrocytoma: 7 yrs; AO: 5 yrs

High grade: AA: 3 yrs; GBM: 14 mos

Question 2

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

Answer 2

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 3

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

Answer 3

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 4

Under what RPA classes can GBM fall?

Answer 4

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 5

On what is the current modified RPA based?

Answer 5

Outcomes with TMZ (Mirimanoff RO, JCO 2006)

Question 6

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 6

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 7

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

Answer 7

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

Question 8

What is MGMT, and why is it important?

Answer 8

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 9

What is the mechanism of action of TMZ?

Answer 9

Oral agent that crosslinks DNA (alkylating).

Question 10

When should anticonvulsants be started?

Answer 10

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

Question 11

What is the impact of resection extent in HGGs?

Answer 11

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

Question 12

What is the Tx paradigm for AA and GBM?

Answer 12

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 13

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

Answer 13

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 14

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

Answer 14

Steroids, proton pump inhibitors, and PCP prophylaxis

Question 15

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

Answer 15

GBM studies showing significant survival benefit:

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)

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)

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 16

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

Answer 16

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 17

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

Answer 17

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 18

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

Answer 18

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 19

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

Answer 19

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 20

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

Answer 20

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 21

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

Answer 21

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 22

Is there evidence supporting RT hyperfx for GBM?

Answer 22

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 23

Is there a benefit to radiosurgery boost for HGGs?

Answer 23

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

Question 24

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

Answer 24

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 25

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

Answer 25

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 26

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

Answer 26

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 27

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

Answer 27

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 28

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

Answer 28

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 29

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

Answer 29

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

Question 30

What are the options for recurrent GBM?

Answer 30

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

Question 31

What are the approved uses of Gliadel?

Answer 31

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 32

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

Answer 32

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 33

What is the Tx paradigm for gliosarcoma?

Answer 33

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

Question 34

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

Answer 34

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 35

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

Answer 35

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 36

Side effects of TTF

Answer 36

Itchy skin

Question 37

Karnofsky Performance Status Criteria

Answer 37

100-80: able to carry on normal activity and work, no special care needed
70-50: unable to work; able to live at home and care for most personal needs, varying amount of assistance needed
40-10 unable to care for self; requires equivalent of hospital level care
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