High Grade Gliomas: Case Presentation and Discussion of
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Transcript High Grade Gliomas: Case Presentation and Discussion of
Jonathan Klein
PGY3, Radiation Oncology
University of Toronto
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.
Workup
History
Physical
Workup
History
Characterize symptoms: OPQRST
General: headache, seizures, N/V, syncope, cognitive Δ
Focal: weakness, sensory loss, aphasia, visual Δ
Family history
PMHx/Meds/allergies
Physical
Workup
History
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
Imaging
MRI with gadolinium is preferred modality
Relevant imaging findings for contouring
T1 with gadolinium: enhancing cavity
T2/FLAIR: edema and enhancement
Workup
Imaging
Histology
4 criteria (AMEN) :
nuclear Atypia
Mitosis
Endothelial proliferation
Necrosis
# Criteria
Grade
0
I
1*
II
*1 criterion = atypia for Grade II
2
III
3-4
IV
Staging
AJCC TNM Staging System not used
Staging
GBM can be primary or secondary (10%)
Prognosis
Prognosis by classification
Oligodendroglial component is positive prognostic
factor
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. 1993 May 5;85(9):704-10.
Lamont ED, Christakis NA. Survival estimates in advanced cancer.
In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2013.
Prognosis
By recursive partitioning analysis (RPA)
Curran et al. J Natl Cancer Inst. 1993 May 5;85(9):704-10.
Management
Referred to Neurosurgery
What should they do?
Surgery
NO RCTs have studied
Surgery vs not
Total vs subtotal resection
Standard: Attempt at gross resection
Not always possible
Location
Critical structures
Surgery
Simpson, Int J Radiat Oncol Biol Phys, 1993
Review of 3 RTOG trials: 643 patients with GBM
Improved survival with more resection
Surgery:
% of patients:
MS (months):
Biopsy Partial Total
17%
64%
6.6
10.4
Simpson JR et al. Int J Radiat Oncol Biol Phys. 1993 May 20;26(2):239-44.
19%
11.3
Surgery
Lacroix, J Neurosurg, 2001
Retrospective review, 416 patients with GBM
Improved survival with total resection (>98%)
Surgery
MS (months)
Partial (<98%)
8.8
Total (>98%)
13
Predictors of survival
Age, KPS, extent of resection, degree of necrosis, pre-op MRI
enhancement
Lacroix M, et al. J Neurosurg. 2001 Aug;95(2):190-8.
Back to Case
Patient taken to OR
Resection attempted, but 2.4cm segment of tumour
remains
Management
Referred to Radiation Oncology
What should we do?
Radiation
Walker, J Neurosurg, 1978
Phase III, 303 patients with anaplastic glioma
Surgery then randomized to:
MS (mo)
RT vs BCNU vs
8.1
4.2
RT+BCNU vs Obs
8
3.2
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. 1978 Sep;49(3):333-43.
Radiation
Walker, Int J Radiat Oncol Biol Phys, 1979
Meta-analysis of 3 RCTs
621 patients with Gr. III/IV glioma
Surgery then:
MS (mo)
Obs vs 45Gy vs 50Gy vs 55Gy vs 60Gy
4
3
7
9
10
Showed benefit for RT and dose-response relationship
Walker MD, et al.Int J Radiat Oncol Biol Phys. 1979 Oct;5(10):1725-31.
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. 1980 Dec 4;303(23):1323-9.
Radiation
Kristiansen, Cancer, 1981
Phase III, 118 patients with Gr III/IV astrocytoma
Surgery then randomized to:
MS (mo)
RT vs RT+Bleomycin vs Obs
10.8
10.8
5.2
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. 1981 Feb 15;47(4):649-52.
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: 50-60 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. 2002 Sep;64(3):259-73.
Radiation
So RT is good…
What dose should we give?
Radiation
Nelson, NCI Monog., 1988 RTOG 74-01
626 patients with Gr III/IV astrocytoma
Randomized to:
60Gy* vs 60+10 vs 60+B** vs 60+C+D***
Median survival:
60Gy: 9.3 months vs 60+10Gy: 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):279-84.
Radiation
Bleehen, BJC, 1991
474 patients with Gr III/IV astrocytoma
Surgery, no chemo, then randomized to:
MS (mo)
45/20* vs 40/20+20/10**
9
12
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. 1991 Oct;64(4):769-74.
Radiation
Scott, Int J Radiat Oncol Biol Phys, 1998 RTOG 9006
712 patients with Gr III/IV glioma
Randomized to carmustine + :
MS (mo)
60/30 vs 72/60 (1.2 Gy/# BID)
13.2
11.2
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. 1998 Jan 1;40(1):51-5.
Radiation
Should we use SRS?
?SRS?
Early series showed promising survival w/SRS
Buatti et al., 1995
Gannett et al., 1995
Int J Radiat Oncol Biol Phys. 1995 Apr 30;32(1):205-10.
Int J Radiat Oncol Biol Phys. 1995 Jul 15;32(4):1161-6.
Int J Radiat Oncol Biol Phys. 1995 Sep 30;33(2):461-8.
Masciopinto et al., 1995
J Neurosurg. 1995 Apr;82(4):530-5.
?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;60:853-860.
Management
Referred to Medical Oncology
Should the patient have chemotherapy?
Chemotherapy
Stewart, Lancet, 2002
Metanalysis, 12 RCTs, 3004 patients
Hazard ratio for death = 0.85
Chemotherapy group did better
Stewart LA. Lancet. 2002 Mar 23;359(9311):1011-8. Review.
Chemotherapy
Stewart LA. Lancet. 2002 Mar 23;359(9311):1011-8. Review.
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. 2002 Mar 1;20(5):1375-82.
WAKE UP!!!!
Important Study Alert
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. 2005 Mar 10;352(10):987-96.
EORTC 26981
88% of patients received full course ChemoRT
40% of patients completed adjuvant Chemo
Grade ≥3 toxicity = 4%
EORTC 26981
MS (med)
PFS (med)
OS: 2 yr
4 yr
5 yr
RT
ChemoRT
12.1 mo
5 mo
10%
3%
2%
14.6 mo
6.9 mo
26%
12%
10%
EORTC 26981
Overall survival curve
Stupp R et al. N Engl J Med. 2005 Mar 10;352(10):987-96.
EORTC 26981
Subgroups:
Methylated
MGMT
Unmethylated
Stupp R et al. N Engl J Med. 2005 Mar 10;352(10):987-96.
EORTC 26981
Improved response for patients with methylated
MGMT gene
Epigenetic silencing of MGMT (O6-methylguanineDNA 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. 2005 Mar 10;352(10):997-1003.
MGMT Methylation
Hegi, NEJM, 2005
206 patients from EORTC 26891 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. 2005 Mar 10;352(10):997-1003.
Hegi ME et al. N Engl J Med. 2005 Mar 10;352(10):997-1003.
RTOG 0525
Gilbert, ASCO, 2011
RCT, 833 pts > 60 yo with GBM/Gliosarcoma
Test dose-dense TMZ regimen
Randomized to
EORTC 26981 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
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
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
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
Ongoing Studies
What is being tested now?
Biologic agents
Ongoing Studies
RTOG 0837
Phase III
RT+TMZ vs RT+TMZ+bevacizumab
Bevacizumab (Avastin) shown effect in RCC,NSCLC,CRC
RTOG 0825
Phase III
RT+TMZ vs RT+TMZ+cediranib
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?
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. 2010 Jan;37(1):36-42.
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.
Pseudoprogression
Sanghera P. Can J Neirol Sci. 2010 Jan;37(1):36-42.
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. 2008 May 1;26(13):2192-7.
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). 2012 Apr;24(3):216-27.
Pseudoprogression
Sanghera P. Clin Oncol (R Coll Radiol). 2012 Apr;24(3):216-27.
Sanghera P. Clin Oncol (R Coll Radiol). 2012 Apr;24(3):216-27.
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?
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: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1205
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: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1205
Fogh SE et al. J Clin Oncol. 2010 Jun 20;28(18):3048-53
Recurrent GBM - Chemo
Phase II chemo trials
Wong ET et al. J Clin Oncol. 1999 Aug;17(8):2572-8.
Carson KA et al. J Clin Oncol. 2007 Jun 20;25(18):2601-6.
6 month PFS: 15%; Median OS: 6 months
Bevacizumab/other monoclonal Abs studied in ph. II trials
Vredenburgh JJ et al. J Clin Oncol. 2007 Oct 20;25(30):4722-9.
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: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1205
Recurrent GBM - Chemo
Friedman HS et al. J Clin Oncol. 2009 Oct 1;27(28):4733-40.
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:
6-month PFS:
Median survival:
Beva alone
42.6%;
9.2 months
Beva+irino
50.3%
9.7 months
Conclusion: No increase in efficacy with irinotecan, but
increase toxicity
Source: RTOG 0125 protocol.
May be accessed at: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1205
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: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1205
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
Mr. Z.
Referred to Rad Onc for management
Work up
History
Physical
Imaging
Mr. Z.
What to do?
No biopsy, so no tissue diagnosis
Treated as presumed GBM
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. 1993 May 5;85(9):704-10.
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. 1994 Jul 1;29(4):835-9.
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. 2004 May 1;22(9):1583-8.
Management
Roa W et al. J Clin Oncol. 2004 May 1;22(9):1583-8.
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. 2007 Apr 12;356(15):1527-35.
Management
OS
Management
Muni, Tumori, 2010
Prospective comparison study 45 patients with GBM
Age ≥ 70 yo OR Age 50-70 and KPS < 70
1:1 split of 30Gy/6 ± TMZ 150-200 mg/m2 x5d q28d
Median OS
6 mo OS
Median PFS
6 mo PFS
RT+TMZ
9.4 mos
95%
5.5 mos
45%
No TMZ
7.3 mos
78%
4.4 mos
22%
Minimal additional toxicity (≥Gr 3 = 46%)
Conclusion: RT+TMZ beneficial for older or poor KPS
patients
Muni R et al. Tumori. 2010 Jan-Feb;96(1):60-4.
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. 2012 Jul;13(7):707-15
NOA-08
Results
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.
Wick W et al. Lancet Oncol. 2012 Jul;13(7):707-15
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. 2012 Sep;13(9):916-26.
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
RT +/- TMZ
Subset results
Patients > 70 years old
TMZ better than standard RT
HR 0.35 p<0.0001
Hypo# 34Gy RT better than standard RT
HR 0.59 p=0.02
Patients receiving TMZ
Methylated MGMT had better median overall survival vs nonmethylated 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)
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. 2012 Sep;13(9):916-26.
Back to Case
Mr. B treated with 40Gy/15 RT alone
No chemo