Steven H. Lin and Shiao Y. Woo
What % of primary CNS tumors are malignant?
~40% of primary brain tumors are considered malignant.
In adults, what is the most common malignant CNS neoplasm?
~85% of CNS neoplasms in adults are glioblastoma multiforme (GBM), which constitutes 20% of all primary tumors.
What are the WHO classifications for high-grade CNS tumors?
1. WHO III: anaplastic astrocytoma (AA)/oligodendroglioma/oligoastrocytoma
2. WHO IV: GBM
What are some common genetic changes seen in malignant brain tumors?
↑ EGFR (50%) and PTEN mutation (30%–40%)
What are the initial genetic changes associated with primary vs. secondary GBM?
1. Primary: ↑ EGFR/MDM2 amplification/LOH10/p16 loss
2. Secondary: p53 mutation → low-grade glioma (LGG) → LOH 19q/p16 loss → AA → LOH 10, DCC → 2nd GBM
What % of GBMs are multicentric?
<5% of GBMs are multicentric.
What are the 4 pathologic characteristics that define GBM?
Pseudopalisading necrosis, vascular proliferation, ↑ mitotic rate, and pleomorphic nuclei
What is the Cushing triad, and what does it represent in brain tumors?
HTN, bradycardia, respiratory irregularity. It represents ↑ ICP.
With what Sx do high-grade gliomas (HGGs) most commonly present?
HA (especially in the am, 50%), seizures (20%), focal neurologic dysfunction, and mental status change
What are the common imaging characteristics of HGGs on MRI?
Hypodense on T1, gadolinium enhancing, T2 enhancing, and +T2 FLAIR (edema)
What is the MS for LGG vs. HGG?
1. Low grade: pure oligodendroglioma: 10 yrs; oligoastrocytoma: 7 yrs; anaplastic oligodendroglioma (AO): 5 yrs
2. High grade: AA: 3 yrs; GBM: 14 mos
What are the most important factors used for the RTOG recursive partitioning analysis (RPA) stratification?
1. Age 50 yrs, histology (AA or GBM), Karnofsky performance status (KPS) of 70, MS changes, and Sx greater or less than 3 mos
(Curran WJ et al., J Natl Cancer Inst 1993)
What constitutes RPA class III pts?
Age <50 yrs, AA with poor MS, or GBM with good KPS
What defines RPA class VI pts?
Any histology with KPS <70 and altered MS
What is the MS of a pt with RPA class I–II, III–IV vs. V–VI?
MS by RPA class:
1. Class I–II: 40–60 mos (3–5 yrs)
2. Class III–IV: 11–18 mos (1–1.5 yrs)
3. Class V–VI: 5–9 mos
Under what RPA classes can GBM fall?
GBMs fall under classes III–VI:
1. Class III: <50 yo, KPS 90–100
2. Class IV: <50 yo, KPS <90 or >50 yo, good KPS
3. Class V: >50 yo, KPS <70 but no change in MS
4. Class VI: KPS <70 and MS change
On what is the current modified RPA based?
Outcomes with temozolomide (TMZ) (Mirimanoff RO, JCO 2006)
What is the 4-yr OS and MS for the adapted RPA groups for malignant gliomas (per Mirimanoff RO, ASTRO 2007 update)?
1. Overall survival: class III (<50 yo, performance status [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%
2. Median survival: class III: 21 mos vs. 15 mos; class IV: 16 mos vs. 13 mos; class V: 10 mos vs. 9 mos
What additional factors did the European Nomogram (European GBM Calculator) investigate for stratification purposes?
MGMT methylation status and extent of resection; only MGMT, PS, and MS were prognostic (Gorlia T et al., Lancet Oncol 2008)
What is MGMT, and why is it important?
MGMT is a DNA repair enzyme that removes alkyl groups from the O6 position of guanine (when methylated/inactive, it leads to longer survival).
When should anticonvulsants be started?
Anticonvulsants should be started only if the pt is symptomatic or has a Hx of seizures.
What is the impact of resection extent in HGGs?
Recent data suggest that the extent of resection correlates with improved outcomes. (Sanai N et al., Neurosurgery 2008)
What is the Tx paradigm for AA and GBM?
1. AA Tx paradigm: steroids, then surgery → RT to 60 Gy +/− TMZ
2. GBM Tx paradigm: surgery → RT to 60 Gy + TMZ (GBM)
What is the dose of TMZ, and how is it administered/scheduled?
Oral pill; 7 days/wk at 75 mg/m2 (for 5 days 30 minutes prior to RT) → 1-mo break → 6 cycles of adj TMZ given 5 days monthly 150–200 mg/m2.
With the current Tx paradigm, what additional pharmacologic therapies are often necessary?
Steroids, proton pump inhibitors, and PCP prophylaxis
Which early GBM studies demonstrated significant (doubled) survival with RT vs. supportive care and helped RT become a standard component of Tx?
GBM studies showing significant survival:
1. BTSG 69-01 (Walker MD et al., J Neurosurg 1978): randomized to observation, BCNU, WBRT, and BCNU + WBRT. There was no difference between WBRT vs. WBRT + BCNU, but RT was better than no RT.
2. Scandinavian Gliobastoma Study Group (SGSG) (Kristiansen K et al., Cancer 1981): 45 Gy + bleomycin vs. 45 Gy + observation: MS 10.8 mos vs. 10.8 mos vs. 5.2 mos (SS)
What randomized study supports the use of RT vs. best supportive care for the elderly with GBM?
French data (Keime-Guibert F et al., NEJM 2007): pt >70 yo, KPS >70, to 50.4 Gy vs. observation. MS improved with RT: 29.1 wks vs. 16.9 wks. There was no difference in QOL or cognition.
What studies support the use of hypofractionation in elderly GBM pts with a poor KPS?
Roa (JCO 2004) and Bauman et al. (IJROBP 1994) suggest feasibility of hypofractionation (40 Gy in 15/fx or 30 Gy in 10/fx) in GBM pts with poor PS (>60 yo, KPS <50). There was no difference in outcome compared with standard fractionation.
What study suggested that WBRT is not required (i.e., that limited-field RT is sufficient) in the Tx of HGGs?
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.
What evidence supports current RT volumes being used in the Tx of HGGs?
1. Hochberg FH, Neurology 1980: 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.
2. Kelly PJ, J Neurosurg 1987: 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.
What evidence supports the current RT dose of 60 Gy used for HGGs?
1. 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.
2. 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.
Is there evidence for a dose escalation benefit beyond 60 Gy in HGGs?
No. There is no evidence for a dose escalation benefit.
1. In RTOG 7401, there was no benefit for 70 Gy vs. 60 Gy in >600 pts.
2. Chan et al. escalated the dose to 90 Gy without survival benefit. Of those who failed at 90 Gy, 91% failed in-field. (JCO 2002)
Is there evidence supporting RT hyperfractionation for GBM?
No. RTOG 8302: >700 pts, randomized phase I, 64.8 vs. 81 Gy bid. There was no benefit. RTOG 9006 also showed no benefit.
Is there a benefit to radiosurgery boost for HGGs?
No. RTOG 9305 showed no benefit or higher toxicity.
Before the TMZ data, was there any benefit to CRT for HGGs?
Yes. This was shown by evidence from 2 large meta-analyses.
1. 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. (Lancet 2002)
2. Fine meta-analysis also showed improved MS 12 mos vs. 9.4 mos. (Cancer 1993)
What is the evidence that supports the current gold standard in GBM Tx with TMZ?
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)
Which modified RPA class did TMZ + RT not benefit significantly, per Mirimanoff RO et al., JCO 2006?
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.
What is the role of MGMT methylation in terms of response to Tx with HGGs?
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
What are the options for recurrent GBM?
TMZ alone, re-irradiation to ~36 Gy (Combs SE et al., BMC Cancer 2007) +/− TMZ, radiosurgery, brachytherapy (Gliasite), Gliadel, or clinical trial
What is the dose used for Gliasite in GBM? What is the radioisotope used?
60 Gy to 5–10 mm at a dose rate of 50 cGy/hr (Chan TA, IJROBP 2005); I-125
What are the approved uses of Gliadel?
1. FDA approval: recurrent Dz with re-resection improved survival advantage 8 mos vs. 6 mos. (Brem H et al., Lancet 1995)
2. In newly diagnosed adj setting: MS was 13.9 mos vs. 11.6 mos. (Westphal M, Neurooncol 2003)
What are the general guidelines for RT target volume delineation in HGGs?
1. Initial volume (46 Gy): GTV1 = T1 + T2/FLAIR, CTV1 = GTV1 + 1.25 cm
2. Boost volume (14 Gy): GTV2 = T1/tumor bed, CTV2 = GTV2 + 0.75 cm. PTV adds 0.5 cm to CTVs. Postop imaging (with MRI fusion) should be used for target delineation.
Which recent study showed similar survival outcomes with adj RT vs. adj chemo with procarbazine/lomustine/vincristine (PCV) or TMZ in WHO III gliomas (AA)?
German NOAH-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. Toxicity: grade 3–4 hematologic toxicity was significantly higher for PCV than for TMZ
Which study investigated sequential PCV → RT vs. RT alone in oligodendroglial tumors?
RTOG 9402/INT-0149 (Cairncross G et al., JCO 2006): no OS benefit. There was improved PFS with chemo but at significant toxicity cost. 1p19q deletion conferred better outcomes.
Which recent study investigated sequential RT → BCNU vs. RT alone in AA? What did it find?
EORTC 26882 (Hildebrand J et al., Eur J Cancer 2008): no OS or PFS difference
What study tested the role of adj PCV after RT in oligodendroglial tumors?
EORTC 26951 (Van den Bent MJ et al., JCO 2006): same OS but prolonged PFS. 1p19q deleted pts did better. There was no long-term difference in QOL after PCV.
What ongoing phase III study is investigating the efficacy of combining RT with either TMZ or nitrosourea in anaplastic gliomas?
RTOG 9813 is investigating RT with TMZ or nitrosourea.
What study is investigating the use of upfront TMZ + RT in AO?
RTOG 0131. Pts are treated with neoadj TMZ for 6 mos → TMZ and concurrent RT. An interim report suggests that combination therapy with TMZ + RT is well tolerated and that the response correlates with 1p19q deletion status.
What is the Tx paradigm for gliosarcoma?
Gliosarcoma Tx paradigm: treat like GBM (surgery → RT + TMZ)
What ongoing study is testing dose-intensified TMZ after TMZ + RT?
RTOG 0525. This study is randomizing the 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.
What is the radiographic appearance of radionecrosis?
Central hypodensity, ring enhancement, edema, and low PET avidity (occurs >6 mos post-RT)
What was the grade 3–4 toxicity rate from the Stupp et al. trial for the RT + TMZ arm? What main toxicity was noted?
7%; mostly hematologic from TMZ (thrombocytopenia)
What does the follow-up entail after RT for HGGs?
MRI 1 mo post-RT, then q2mos; weekly labs (blood counts) while on TMZ
What % of HGG recurrences are local?
80%–90% of HGG recurrences are local.
What % of pts may show pseudoprogression after RT + TMZ?
Up to 50% (Taal W et al., Cancer 2008)
Does MGMT promoter methylation status influence the incidence of pseudoprogression in HGGs?
Yes. MGMT methylation status increases the incidence of pseudoprogression after TMZ + RT. (Brandes AA et al., JCO 2008)