1. Jonathan Klein PGY3, Radiation Oncology University of Toronto
High Grade Gliomas: Case Presentation and Summary of Evidence for Radiation Therapy Management
Jonathan Klein
PGY3, Radiation Oncology
University of Toronto

2. Case #1
Mr. A
64M presents to ER with two weeks of dizziness and “things on my left side look funny”.
Feels he veers to the left side when walking.

3. Workup
History
Physical

4. Workup History Physical Characterize symptoms: OPQRST
General: headache, seizures, N/V, syncope, cognitive Δ
Focal: weakness, sensory loss, aphasia, visual Δ
Family history
PMHx/Meds/allergies
Physical

5. Workup History Physical Characterize symptoms - OPQRST
General: headache, seizures, N/V, syncope, cognitive Δ
Focal: weakness, sensory loss, aphasia, visual Δ
Family history
PMHx/Meds/allergies
Physical
CNS: GCS, CNII-XII, gait, strength, DTRs, Babinski
Screening CVS, lung, abdomen exam

6. Imaging MRI with gadolinium is preferred modality
Relevant imaging findings for contouring
T1 with gadolinium: enhancing cavity
T2/FLAIR: edema and enhancement

7. Workup

8. Imaging

9. Histology 4 criteria (AMEN) : # Criteria 0 1* 2 3-4 Grade I II III IV
nuclear Atypia
Mitosis
Endothelial proliferation
Necrosis
# Criteria 0 1* 2 3-4
Grade I II III IV
*1 criterion = atypia for Grade II

10. Staging
AJCC TNM Staging System not used

11. Staging
GBM can be primary or secondary (10%)

12. Prognosis Prognosis by classification
Oligodendroglial component is positive prognostic factor

13. Prognosis
Curran, JNCI, 1993
Recursive partitioning analysis to retrospectively analyze 1578 patients with high grade glioma
3 RTOG studies testing RT +/- Chemo
Results
<50yo: histology most important prognostic factor
>50yo: KPS most important prognostic factor
Mental status differentitated poor KPS group
Conclusion: Older and poor KPS do worse
Curran et al. J Natl Cancer Inst May 5;85(9):

14. Lamont ED, Christakis NA. Survival estimates in advanced cancer.
In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2013.

15. Prognosis By recursive partitioning analysis (RPA)
Curran et al. J Natl Cancer Inst May 5;85(9):

16. Management
Referred to Neurosurgery
What should they do?

17. Surgery NO RCTs have studied Standard: Attempt at gross resection
Surgery vs not
Total vs subtotal resection
Standard: Attempt at gross resection
Not always possible
Location
Critical structures

18. Surgery Simpson, Int J Radiat Oncol Biol Phys, 1993
Review of 3 RTOG trials: 643 patients with GBM
Improved survival with more resection
Surgery: Biopsy Partial Total
% of patients: 17% 64% 19%
MS (months):
Simpson JR et al. Int J Radiat Oncol Biol Phys May 20;26(2):

19. Surgery Lacroix, J Neurosurg, 2001
Retrospective review, 416 patients with GBM
Improved survival with total resection (>98%)
Surgery Partial (<98%) Total (>98%)
MS (months)
Predictors of survival
Age, KPS, extent of resection, degree of necrosis, pre-op MRI enhancement
Lacroix M, et al. J Neurosurg Aug;95(2):190-8.

20. Back to Case Patient taken to OR
Resection attempted, but 2.4cm segment of tumour remains

21. Management
Referred to Radiation Oncology
What should we do?

22. Radiation Walker, J Neurosurg, 1978
Phase III, 303 patients with anaplastic glioma
Surgery then randomized to:
RT vs BCNU vs RT+BCNU vs Obs
MS (mo)
Showed no benefit from chemo
RT = 50Gy WBRT + 10 Gy boost
BCNU = carmustine 80mg/m2 x days 1-3 every 6-8 weeks
Walker MD et al. J Neurosurg Sep;49(3):

23. Radiation Walker, Int J Radiat Oncol Biol Phys, 1979
Meta-analysis of 3 RCTs
621 patients with Gr. III/IV glioma
Surgery then:
Obs vs 45Gy vs 50Gy vs 55Gy vs 60Gy
MS (mo)
Showed benefit for RT and dose-response relationship
Walker MD, et al.Int J Radiat Oncol Biol Phys Oct;5(10):

24. Radiation
Walker, NEJM, 1980
Phase III, 358 patients with anaplastic glioma
Surgery then randomized to
RT vs RT+BCNU vs RT+Semus vs Semus
Results
No arm significant difference between arms
Conclusion: RT alone remains standard
Walker MD et al. N Engl J Med Dec 4;303(23):

25. Radiation Kristiansen, Cancer, 1981
Phase III, 118 patients with Gr III/IV astrocytoma
Surgery then randomized to:
RT vs RT+Bleomycin vs Obs
MS (mo)
Showed no benefit from chemo
RT = 45Gy WBRT
Bleomycin = carmustine 180mg 3/week, 1hr prior to RT, weeks 1,2,4,5
Kristiansen K et al. Cancer Feb 15;47(4):

26. Radiation Laperriere, Radiother apy + Oncology, 2002
Systematic review of 6 RCTs
Confirmed benefit from post-op RT
Recommended:
Young (< 70 yo)
Treat enhancing tumour + margin (e.g. 2 cm)
Dose: Gy in 1.8-2Gy per fraction
Older with good KPS
Can use short course RT
Older with poor KPS
Can consider supportive care alone
This review did not recommend addition of chemo
Laperierre N et al. Radiother Oncol Sep;64(3):

27. Radiation
So RT is good…
What dose should we give?

28. Radiation Randomized to: Median survival: Subsets:
Nelson, NCI Monog., 1988  RTOG 74-01
626 patients with Gr III/IV astrocytoma
Randomized to:
60Gy* vs vs 60+B** vs 60+C+D***
Median survival:
60Gy: 9.3 months vs Gy: 8.2 months
Subsets:
>60 yo: RT+chemo did not improve survival
40-60 yo: RT+BCNU = 23% 2 year survival vs
RT alone = 8%
*60 Gy WBRT
**60 Gy + carmustine (=BCNU)
***60 Gy + semustine + dacarbazine
Nelson DF et al. NCI Monogr. 1988;(6):

29. Radiation Bleehen, BJC, 1991 474 patients with Gr III/IV astrocytoma
Surgery, no chemo, then randomized to:
45/20* vs 40/20+20/10**
MS (mo)
60/30 improved survival with similar toxicity
*=45/20 to “all known and potential tumour”
**=40/20 as above, then 20/10 to “defined tumour volume
together with a 1 cm margin around it.”
Bleehen NM, Stenning SP. Br J Cancer Oct;64(4):

30. Radiation Scott, Int J Radiat Oncol Biol Phys, 1998 RTOG 9006
712 patients with Gr III/IV glioma
Randomized to carmustine + :
60/30 vs 72/60 (1.2 Gy/# BID)
MS (mo)
72/60 not better for any subgroup
60/30 was better for all patients < 50 yo
Scott CB et al. Int J Radiat Oncol Biol Phys Jan 1;40(1):51-5.

31. Radiation
Should we use SRS?

32. ?SRS? Early series showed promising survival w/SRS Buatti et al., 1995
Int J Radiat Oncol Biol Phys Apr 30;32(1):
Int J Radiat Oncol Biol Phys Jul 15;32(4):
Gannett et al., 1995
Int J Radiat Oncol Biol Phys Sep 30;33(2):461-8.
Masciopinto et al., 1995
J Neurosurg Apr;82(4):530-5.

33. ?SRS? RTOG 9305 Souhami, Int J Radiat Oncol Biol Phys, 2004
RCT, 203 GBM pts all received 60Gy EBRT +carmustine
Randomized to upfront SRS vs no SRS (15-24Gy)
Median survival not different: 13.5 v 13.6 months
SRS not currently standard for GBM
Souhami et al. Int J Radiat Oncol Biol Phys 2004;60:

34. Management Referred to Medical Oncology
Should the patient have chemotherapy?

35. Chemotherapy Stewart, Lancet, 2002 Metanalysis, 12 RCTs, 3004 patients
Hazard ratio for death = 0.85
Chemotherapy group did better
Stewart LA. Lancet Mar 23;359(9311): Review.

36. Chemotherapy
Stewart LA. Lancet Mar 23;359(9311): Review.

37. Chemotherapy Stupp, JCO, 2002 Phase II, 64 patients with primary GBM
RT + Temozolomide
RT: 60Gy/30
TMZ: 75 mg/m2/d x 42d then 200 mg/m2/d for 5d q28d x6 cycles
Median survival = 16 months
OS: 1 yr = 58% ; 2 yr = 31%
Grade ≥3 toxicity = 6%
Good prognosis subsets:
≤50 years old
patients who had debulking surgery
Stupp R et al. Clin Oncol Mar 1;20(5):

38. WAKE UP!!!!
Important Study Alert

39. EORTC 26981 Stupp, NEJM, 2005 (2009 Lancet Oncology update)
Phase III, 573 patients <70 yo with primary GBM
Randomized to
RT alone vs Stupp Phase II protocol:
RT: 60Gy/30
TMZ: 75 mg/m2/d x 42d then 200 mg/m2/d for 5d q28d x6 cycles
Stupp R et al. N Engl J Med Mar 10;352(10):

40. EORTC 26981 88% of patients received full course ChemoRT
40% of patients completed adjuvant Chemo
Grade ≥3 toxicity = 4%

41. EORTC 26981 MS (med) 12.1 mo 14.6 mo PFS (med) 5 mo 6.9 mo
RT ChemoRT
MS (med) mo 14.6 mo
PFS (med) 5 mo 6.9 mo
OS: 2 yr 10% 26%
4 yr 3% 12%
5 yr 2% 10%

42. EORTC 26981 Overall survival curve
Stupp R et al. N Engl J Med Mar 10;352(10):

43. EORTC 26981 Subgroups: Methylated MGMT Unmethylated
Stupp R et al. N Engl J Med Mar 10;352(10):

44. EORTC 26981 Improved response for patients with methylated MGMT gene
Epigenetic silencing of MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents.
Hegi ME et al. N Engl J Med Mar 10;352(10):

45. MGMT Methylation Hegi, NEJM, 2005
206 patients from EORTC trial assessed for MGMT methylation status
MethylMGMT found in 45%
Results
MethylMGMT was a favorable prognostic factor: HR =0.45
For methylMGMT TMZ better than RT: 21.7 vs 15.3 months
For unmethylMGMT, no statistically significant difference
Conclusions
GBM with methylMGMT benefited from TMZ, but unmethylMGMT promoter did not benefit
Hegi ME et al. N Engl J Med Mar 10;352(10):

46. Hegi ME et al. N Engl J Med. 2005 Mar 10;352(10):997-1003.

47. RTOG 0525
Gilbert, ASCO, 2011
RCT, 833 pts > 60 yo with GBM/Gliosarcoma
Test dose-dense TMZ regimen
Randomized to
EORTC RT+TMZ protocol vs
60Gy/30 + daily TMZ followed by 21d adjuvant chemo
Gilbert MR et al. Journal of Clinical Oncology, 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 29, No 15_suppl (May 20 Supplement), 2011: 2006

48. RTOG 0525
Gilbert MR et al. Journal of Clinical Oncology, 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 29, No 15_suppl (May 20 Supplement), 2011: 2006

49. RTOG 0525
Gilbert MR et al. Journal of Clinical Oncology, 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 29, No 15_suppl (May 20 Supplement), 2011: 2006

50. RTOG 0525
Improved response for patients with methylated MGMT continued
No difference in PFS or OS between study arms for either methylated or non-methylated subgroups

51. Ongoing Studies
What is being tested now?
Biologic agents

52. Ongoing Studies RTOG 0837 RTOG 0825 Phase III
RT+TMZ vs RT+TMZ+bevacizumab
Bevacizumab (Avastin) shown effect in RCC,NSCLC,CRC
RTOG 0825
RT+TMZ vs RT+TMZ+cediranib

53. Back to case Patient receives concurrent 60Gy/30 RT
Planned for continuing adjuvant monthly TMZ
Patient returns to clinic 1 month after treatment with MRI
Scan shows increased enchancement of treated tumour cavity
…Now what?
…Did treatment fail?

54. Pseudoprogression Sanghera, Can J Neurol Sci, 2010
Retrospective, 111 patients
GBM or Gr.III with GBM-like radiographic features
Used Stupp RT+TMZ protocol
Pseudoprogression (psP) = no further radiographic progression, without salvage therapy, within 6 months after TMZ+RT
Represent transient increase in vessel permeability and damaged peritumoural BBB
Sanghera P. Can J Neirol Sci Jan;37(1):36-42.

55. Pseudoprogression Results
psP group had stable dexamethasone dose
25% had evidence of early progression, with 32% of these representing psP
Median OS : whole cohort = 56.7 weeks
psP = 125 weeks
true early progression = 36 weeks
Conclusion: Maintenance TMZ should not be stopped on the basis of seemingly discouraging imaging features within first three months after RT/TMZ.

56. Pseudoprogression
Sanghera P. Can J Neirol Sci Jan;37(1):36-42.

57. Pseudoprogression Brandes, JCO, 2008
Cohort, 103 patients with MGMT status
Treated with Stupp TMZ+RT protocol
Results
psP occurs in 91% of methylMGMT +ve GBM vs 41% -ve
+ve methylMGMT and psP each improved survival
Patients more sensitive to treatment more likely to get psP
Brandes AA. J Clin Oncol May 1;26(13):

58. Pseudoprogression Sanghera, Clin Oncol, 2012 Expert consensus on psP
Poor efficacy 2nd line Tx so need to minimize inappropriate withdrawal of adjuvant TMZ
psP unlikely if radiographic progression over 2 mo within 6 mo post-Tx
Sanghera P. Clin Oncol (R Coll Radiol) Apr;24(3):

59. Pseudoprogression
Sanghera P. Clin Oncol (R Coll Radiol) Apr;24(3):

60. Sanghera P. Clin Oncol (R Coll Radiol). 2012 Apr;24(3):216-27.

61. Back to case Patient continues on monthly adjuvant TMZ
Returns for 6 month post-RT appointment and has another MRI
Scan shows clearly increased size of disease
…Now what?

62. Recurrent GBM - RT Median time to recurrence is ~7 months
Re-irradiation trials
Over 300 patients reported
Combs 2005; Nieder 2008; Fogh 2010
Results
6 month PFS: 28-39%
1 year median OS: 26% (range 18-46%)
Source: RTOG 0125 protocol.
May be accessed at:

63. Recurrent GBM - RT Fogh, JCO, 2010 147 patients with recurrent GBM
Treated with stereotactic RT 35/10
Cox analysis performed
Survival improved with:
Younger age
Smaller GTV
Shorter time between diagnosis and recurrence
High RT dose (≥35Gy) showed trend to significance (p = .07).
Survival not improved by:
Surgical resection
Chemotherapy
Source: RTOG 0125 protocol. May be accessed at:
Fogh SE et al. J Clin Oncol Jun 20;28(18):

64. Recurrent GBM - Chemo Phase II chemo trials
Wong ET et al. J Clin Oncol Aug;17(8):
Carson KA et al. J Clin Oncol Jun 20;25(18):
6 month PFS: 15%; Median OS: 6 months
Bevacizumab/other monoclonal Abs studied in ph. II trials
Vredenburgh JJ et al. J Clin Oncol Oct 20;25(30):
32 pts given bevacizumab + irinotecan
6 month PFS: 38%; MS for GBM patients: 9.2 months
Kreisl TN et al. J Clin Oncol 2009 Feb 10;27(5):740-5.
48 recurrent glioblastoma patients received bevacizumab alone
Response rate: 25%; Median PFS: 16 weeks; 6-month PFS:29
Other trials have added bevacizumab to other chemo agents such as low dose TMZ, etoposide, erlotinib, nitrosurea
No improvement in survival shown, but worse toxicity
Source: RTOG 0125 protocol.
May be accessed at:

65. Recurrent GBM - Chemo
Friedman HS et al. J Clin Oncol Oct 1;27(28):
RCT, 167 patients with recurrent GBM in 1st or 2nd relapse
Randomized to
bevacizumab alone 10 mg/kg q2weeks vs
bevacizumab +irinotecan (82 patients)
Results not significant:
Beva alone Beva+irino
6-month PFS: %; %
Median survival: months 9.7 months
Conclusion: No increase in efficacy with irinotecan, but increase toxicity
Source: RTOG 0125 protocol.
May be accessed at:

66. Recurrent GBM - Chemo
Salvage chemotherapy post-bevacizumab failure has 6-month PFS of 2% (Quant 2009).
Recurrent GBM patients should be enrolled on trial whenever possible
Ongoing trials include RTOG 1205:
Randomized Phase II for recurrent GBM
Bevacizumab + RT vs bevacizumab alone
Source: RTOG 0125 protocol.
May be accessed at:

67. Case #2 Mr. B. 80M 2 weeks persistent headache and malaise
Refractory to OTC analgesia
Diagnosed with GBM on imaging
Referred to NeuroSx
Taken to OR for biopsy
Platelets decreasing so procedure abandoned

68. Mr. Z. Referred to Rad Onc for management Work up History Physical
Imaging

70. Mr. Z. What to do? No biopsy, so no tissue diagnosis
Treated as presumed GBM

71. Management Curran, JNCI, 1993
Recursive partitioning analysis to retrospectively analyze 1578 patients with high grade glioma
3 RTOG studies testing RT +/- Chemo
Results
<50yo: histology most important prognostic factor
>50yo: KPS most important prognostic factor
Mental status differentitated poor KPS group
Conclusion: Older and poor KPS do worse
Curran et al. J Natl Cancer Inst May 5;85(9):

72. Management Bauman, Int J Radiat Oncol Biol Phys, 1994
Prospective, 29 patients with GBM
Treated with 30Gy/10 WBRT
Compared with historical radical and supportive care controls
Results
Overall median survival 6 months
Median survival: RT = 10 mos; Supp. care = 1 mo
Improved survival for radical dose if KPS>50
Conclusion: 30/10 reasonable for older patients with poor KPS
Bauman GS et al. Int J Radiat Oncol Biol Phys Jul 1;29(4):835-9.

73. Management Roa W, J Clin Oncol, 2004
RCT, 100 patients with GBM ≥ 60 yo
Randomized to radical RT 60/30 vs short course RT 40/15
No chemo during Tx (some got for recurrence)
Results
Median survival: Radical= 5.1 mos; Short= 5.6 mos
6 months survival: Radical= 44.7%; Short= 41.7%
Short course reduced steroid requirements
Conclusion: Short course reasonable to older patients
Roa W et al. J Clin Oncol May 1;22(9):

74. Management
Roa W et al. J Clin Oncol May 1;22(9):

75. Management Keime-Guibert, NEJM, 2007
RCT, 81 patients with Gr. III/IV astrocytoma
All got surgery
Age ≥ 70 yo and KPS ≥ 70
Randomized to RT 50 Gy vs supportive care alone
Results
Trial stopped early due to superiority
Median survival: RT= 29.1 wks; No RT= 16.9 wks
Survival benefit independent of extent of surgery
No effect on HRQoL or cognition from RT
Conclusion: RT is good for older, good KPS patients
Keime-Guibert et al. N Engl J Med Apr 12;356(15):

76. Management OS

77. Management Muni, Tumori, 2010
Prospective comparison study 45 patients with GBM
Age ≥ 70 yo OR Age and KPS < 70
1:1 split of 30Gy/6 ± TMZ mg/m2 x5d q28d
RT+TMZ No TMZ
Median OS 9.4 mos 7.3 mos
6 mo OS 95% 78%
Median PFS 5.5 mos 4.4 mos
6 mo PFS 45% 22%
Minimal additional toxicity (≥Gr 3 = 46%)
Conclusion: RT+TMZ beneficial for older or poor KPS patients
Muni R et al. Tumori Jan-Feb;96(1):60-4.

78. NOA-08
Wick, Lancet Oncol, 2012
RCT, 412 patients with Gr III/IV astrocytoma
Age ≥ 65 yo AND KPS ≥70
Powered for non-inferiority
Randomized to:
RT 60Gy/30
vs TMZ 100mg/m2 x7d 1wk-on/1wk-off
Wick W et al. Lancet Oncol Jul;13(7):707-15

79. NOA-08 Results Subgroups
Median survival: RT=9.6 mo; TMZ=8.6 mo
P(non-inferiority)=0.033
Event-free survival: RT=4.7mo; TMZ=3.3mo
P(non-inferiority)=0.043
Subgroups
MGMT methylation cohort had improved survival
Median survival: Methylated=11.9mo; Unmethylated=8.2mo
Patients with MGMT methylation did better with TMZ
EFS for +ve methMGMT: RT=4.6 months; TMZ=8·4 months; RT=4·6 [4·2-5·0]),
Patients without MGMT methylation did better with RT
EFS for –ve methMGMT: RT=4.6 months; TMZ=3.3 months
Conclusion: TMZ alone is not inferior to RT for elderly, good KPS patients.
MGMT methylation status can aid decisions.

80. Wick W et al. Lancet Oncol. 2012 Jul;13(7):707-15

81. RT +/- TMZ Malmstrom, Lancet Oncol, 2012
RCT, 291 patients with GBM ≥60 yo
Randomization stratified by centre
TMZ 200 mg/m2 x5d q28d for 6 cycles vs
hypo# RT: 34 Gy/3-4 Gy per fraction vs
standard RT: 60Gy/30
Malmstrom A et al. Lancet Oncol Sep;13(9):

82. RT +/- TMZ Results Overall TMZ better than standard 60Gy RT
median OS: TMZ=8.3 months; 60Gy RT=6.0 month
Standard 60 Gy RT not better than hypo# 34Gy RT
Median OS: 34Gy RT=7.5 mos; 60 Gy RT =6.0 mos p=0.24
TMZ not better than hypo# 34Gy RT
Median OS: TMZO=8·4 mos; 34Gy RT= 7·4 mos p=0·12

83. RT +/- TMZ Subset results Patients > 70 years old
TMZ better than standard RT
HR p<0.0001
Hypo# 34Gy RT better than standard RT
HR p=0.02
Patients receiving TMZ
Methylated MGMT had better median overall survival vs non-methylated MGMT
MethylMGMT = 9·7 months; nonMethylMGMT= 6·8 months p=0·02
Patients receiving RT
No difference between methylMGMT and unmethylMGMT
HR=0·97 p=0·81)

84. All patients 60-70 years older than 70 years
Figure 2 Kaplan-Meier analysis of overall survival in patients randomised across three treatment groups (A) All patients. (B) Patients aged 60?70 years. (C) Patients older than 70 years. TMZ=temozolomide. 34 Gy=hypofractionated radiotherapy. 60 .
Malmstrom A et al. Lancet Oncol Sep;13(9):

85. Back to Case
Mr. B treated with 40Gy/15 RT alone
No chemo