management high grade glioma

1. Management of High grade
Gliomas
Presenter: Dr. Gaurav Kumar

2. WHO grading system
Grade I/II Grade III Grade IV
Atypia + + +
Nuclear pleomorphism - + +
Mitotic activity/Anaplasia - +/- +
Microvascular
proliferation
- +/- +
Necrosis - - +
WHO,2007

3. Malignant glioma
• Grade III and IV – Malignant gliomas
• Glioblastomas approximately 60 to 70%
• Anaplastic astrocytomas for 10 to 15%,
• Anaplastic oligodendrogliomas and Anaplastic
oligoastrocytomas for 10%;

5. Marker Prognostic Predictive
MGMT promoter
methylation
Assoc with longer survival of GBM pts
treated with RT + TMZ.
Predictive for response of GBMs
to TMZ therapy.
IDH1 mutation Assoc with better prognosis. Not predictive for response to
particular type of therapy.
ATRX loss
(mutually exclusive
with 1p19q
codeletion)
Clinical behaviour aggressive but
better prognosis in treated cases
May be predictive for response to
double strand DNA damaging
agents.
1p 19q codeletion Assoc with better prognosis. Predictive for response to
chemotherapy (PCV)
EGFR
overexpression
Aggressive grade III tumors behaves
like GBM (Poor)
Role of TKI debatable
Impact of Molecular Genetics

6. Secondary GBM
• The distinction was first made by Hans-Joachim Scherer in
1940.
• Treatment – no difference
• Prognosis better – in presence of IDH1 mutation
Primary GBM Secondary GBM
EGFR amplification IDH 1 mutation
PTEN mutation P53 mutation
LOH10p LOH1p19q
6

7. from KR Swanson et al J Neurol Sci 216 (2003)1-10

8. Mac Donald Criteria : Response Evaluation
Macdonald DR, J Clin Oncol. 1990

9. Patrick Y. Wen et al Journal of Clinical Oncology, Vol 28, No 11 (April 10),
2010
RANO Criteria : Response Evaluation

10. Prognostic Factors
• Younger age (<40 yrs)
• More extensive tumour resection
• KPS
• MGMT methylation status- Predictive and prognostic
• Mini-Mental State Examination (MMSE) score of 27 or higher
• No corticosteroid treatment at baseline
• IDH-1 mutation in secondary GBM*
• EGFR amplification, maintenance of PTEN, wild-type p53 and
p16 all appear to be associated with improved survival in
patients treated with CRT
Thierry Gorlia et al, The Lancet Oncology, January 2008
*Sumihito Nobusawa et al, Clin Cancer Res 2009

11. Prognostic factors & Correlation with oncological outcomes

12. Standard of Care for Anaplastic Glioma (Grade III)
PS </= 2
Surgery Radiotherapy
Concurrent TMZ
PCV (before/after RT)
Surgery : Max safe resection
RT : 59.4 – 60 Gy/33-30#; Partial Brain
If co-deleted 1p
19q
or

13. Standard of Care for GBM
Age < 70 years
PS </= 2
Surgery
Radiotherapy
Concurrent TMZ
Adjuvant TMZ
Surgery : Max safe resection
RT : 59.4 – 60 Gy/33-30#; Partial Brain
Adjuvant Temozolomide : 6 cycles

14. Mainstay of treatment is Surgery and
radiotherapy.
Adjuvant /Concurrent chemotherapy
improves outcome.

15. SURGERY
Surgical Extent Median Survival
Complete resection 11.3 months
Partial Resection 10.4 months
Only biopsy 6.6 months

16. Radiotherapy
• Role of TMZ in Grade III Glioma without 1p 19q co-deletion
• WBRT vs. Limited-Volume RT
• Optimum timming for RT
• Dose Escalation
• Brachytherapy
• Proton Therapy
• Carbon Ion Therapy
• RT in Elderly
• Role of Bevacizumab
• Recent advances
• Re-Irradiation

17. N = 467
Arm 1: Semustine (MeCCNU) [n=111]
Arm 2: Radiotherapy [n=118]
Arm 3: Carmustine (BCNU) plus Radiotherapy [n=120]
Arm 4: Semustine plus Radiotherpy [n=118]
Data was analysed in 358 patients.
Mean RT dose: 57.3 Gy

18. Results
Semustine
(MeCCNU)
Radiotherapy
Carmustine
(BCNU) plus
Radiotherapy
Semustine plus
Radiotherapy
Median
Survival
(weeks)
24 36 51 42
Survival %
(12 months)
15 34.6 50 36.7
Survival %
(24 months)
7.5 9.7 15.2 12.2

19. J Clin Oncol. 2001 Jan 15;19(2):509-18.
Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant
treatment of high-grade astrocytoma: a Medical Research Council trial.
Medical Research Council Brain Tumor Working Party.
N=674
Trial Groups: 1) RT alone
2) RT followed by adjuvant PCV q6wklyx12 courses
Results: No benefit of adjuvant chemotherapy in high grade Astrocytoma.
Median Survival (mo)
RT Alone (n=339) 9.5
RT + Adj. PCV (n=335) 10

20. CATNON trial
● Phase III trial on role of concurrent and adjuvant TMZ in
anaplastic glioma without 1p 19q co-deletion – Intergroup trial
● Study Arms:
1) RT alone
2) RT + Conc. TMZ
3) RT + Adj. TMZ
4) RT + Conc. TMZ + Adj. TMZ
● Planned Interim analysis:
Adjuvant TMZ Overall Survival
Median % 5 yr
PFS
Median
No (n=372) 41 months 44 19
Yes (n=373) Not reached 56 43

21. Conclusion:
● In this subset 74% patient has known MGMT status, out of
which 42% were MGMT methylated.
● Adjuvant TMZ improves OS in Anaplastic Glioma irrespective
of MGMT status.
● Further follow up required
● Role of IDH mutational status ongoing

22. WBRT vs. Limited-Volume RT
• BTCG 80-01, Randomized trial for postoperative treatment of
malignant glioma.
• N=571
• Patients accured 1982-1983: Randomized to WBRT 60.2 Gy or
WBRT 43 Gy + 17.2 Gy Cone-down boost.
• Conclusion: No difference in survival.
• WBRT + Boost as effective as WBRT
Shapiro WR, J Neurosurg. 1989

23. Survival and Failure Patterns of High-Grade Gliomas
After Three-Dimensional Conformal Radiotherapy
N=34
1. June L. Chan et al, Journal of Clinical Oncology, Vol 20, No 6 (March 15), 2002.
2. Ulrich Oppitz et al Volume 53, Issue 1, Pages 53-57.

24. Functional MRI techniques, MRS, DWI,
PET with new tracers as 11C-methionine
seems to better correlate with tumor
extension
Giuseppe Minniti et al, Radiotherapy and Oncology 2010
• 90% of patients failed in central
and in-field localizations in both
treatment plans, founding no
correlation between edema and
recurrence volumes.
Imaging & Failure

25. Optimum time to start RT
Patients were identified from the Wellington Hospital Pathology Department
database
Delay in receiving radiotherapy after surgery decreases
survival of patients with high grade glioma.

26. Dose Escalation

27. Total no of Patients= 474
Malignant Glioma (astrocytoma)
Arm I (n=156) = 45 Gy in 20 fractions
Arm II (n= 318) = 60 Gy in 30 fractions
No adjuvant chemotherapy

28. Results
● Prolongation of median survival with higher doses of RT
9 months in the 45Gy group to 12 months in the 60Gy
group (P = 0.007).
● Over 80% of patients reported no morbidity from the
radiotherapy, and there was no evidence of increased short-
term morbidity in the higher dose group.
● It was apparent that the survival advantage to the higher dose
was maintained even in the poorest prognostic groups.

29. RTOG 9803 (Phase I study)
n=209
Schema:
Phase I (46Gy/23#; all patients)
PTV1 = GTV + 1.5 cm for CTV + 0.3cm PTV margin
Phase II Boost (PTV2 = GTV + 0.3 cm)
Total Dose: 66Gy 72Gy 78Gy 84Gy
* Elective treatment of peritumoral edema not included.
* Carmustine @ 80mg/m² concurrent with RT and adjuvant x 06 cycles q8wkly

30. 66 Gy 72 Gy 78 Gy 84 Gy
Median Survival (mo)
Group I
Group II
11.6
8.2
11.8
12.3
11.8
10
19.3
13.9
Steroid dependency (%)
(3 months)
Group I
Group II
64
71
36
55
50
29
50
50
AcuteToxicity Gr≥3 (%)
Group I
Group II
14
12
4
13
19
9
9
17
Late Toxicity Gr≥3 (n)
Group I
Group II
1/22
0/33
2/23
0/23
2/27
1/35
1/22
0/18
Results
(Group I PTV₂ ≤ 75 cc; Group II PTV₂ ≥ 75 cc)

31. Conclusion:
● Higher doses (>60 Gy) with concurrent chemotherapy is
feasible option in Supratentorial GBM with acceptable late
toxicity, provided volumes are small with smaller margins.
● Group I patients has improved survival with higher doses
Is it Due to higher dose of RT or due to more GTRs in group I ???

32. Dose escalation with stereotactic radiosurgery in
glioblastoma multiforme: Report of RTOG 93-05 protocol
• 203 pts. GBM.
• All pts had surgery.
• Randomized
• 1) SRS followed by EBRT 60 Gy + BCNU (q8w x 6)
• 2) EBRT 60Gy + BCNU, No SRS.
• SRS dose 16-24 Gy, based on size.
• Median F/U 5 yrs. MS 13.5 m (SRS) vs 13.6 m.
• Conclusion: No difference in survival.
Souhami L et al. Int J Radiat Oncol Biol Phys. 2004 Nov.

33. Brachytherapy
• Gliasite brachytherapy - 125I liquid source.
• Temporary high-activity or permanent low-activity iodine 125
(125I) implant.

34. I - 125 Implant
 Sources placed 0.5-1 cm distance
along resection wall.
 Most common indication for
implantation with permanent
sources - recurrent GBM.
 Minimum brachytherapy dose of
45 to 50 Gy with EBRT.

35. Results of brachytherapy
• University of California San Francisco (UCSF)
• Median survival time of 88 weeks in GBM.
• 40% patients of GBM required reoperation and had significantly longer
survival times.
• University of Toronto, 140 patients randomized between 1986 and 1996:
71 to the EBRT plus implant arm and 69 to EBRT only
• Temporary stereotactic 125I implants delivering a minimum peripheral
tumor dose of 60 Gy.
• No survival advantage
Gutin PH et al Int J Radiat Oncol Biol Phys. 1991

36. Brachytherapy of glioblastoma recurring in previously
irradiated territory: Predictive value of tumor volume
• 42 patients with recurrent glioblastomas
• Previous treatments included surgery, external beam
radiotherapy, and chemotherapy.
• Overall survival was 80% at 6 months, 48% at 1 year, and 11%
at 2 years
• Median survival was 50 weeks
• Tumor volume less than 30 cc was associated with a higher
probability of survival
Jean-Marc Simaon et al May 2002

37. GliaSite brachytherapy for treatment of recurrent malignant gliomas
: A retrospective multi-institutional analysis (1)
 N= 95, recurrent grade 3 or
4 gliomas,
 Median age of 51 years,
 Median KPS score of 80
 Previously undergone
resection and EBRT
• Median dose of 60 Gy to an
average depth of 1 cm with a
median dose rate of 52.3 Gy/hr.
• Median survival for all patients
36.3 weeks
• Estimated 1 year survival of
31.1%.
• The median survival was 35.9
weeks for GBM and 43.6 weeks
for those with non- GBM
malignant gliomas.
1.Gabayan AJ et al Neurosurgery. 2006 Apr
2.Welsh J et al, Int J Radiat Oncol Biol Phys. 2007 May
Dose escalation (>100 Gy) with GliaSite (2)

38. Accelerated fractionated proton/photon irradiation to 90
cobalt gray equivalent for glioblastoma multiforme: results
of a phase II prospective trial.
• To assess dose escalation to 90 cobalt gray equivalent (CGE) with
conformal protons and photons in accelerated fractionation
improve local tumor control and patient survival.
• N=23
• The median survival time 20 months, with four patients alive 22
to 60 months post diagnosis.
• 5 to 11 months increase in median survival.
• A dose of 90 CGE in accelerated fractionation prevented central
recurrence in almost all cases.
Fitzek MM et al J Neurosurg. 1999 Aug;91(2):251-60.

39. Phase I/II clinical trial of carbon ion radiotherapy for
malignant gliomas : Combined X-ray radiotherapy,
chemotherapy, and carbon ion radiotherapy
• Treated with combined X-ray radiotherapy (XRT),
chemotherapy, and carbon ion radiotherapy (CRT)
• The treatment involved the application of 50 Gy/25
fractions/5 weeks of XRT, followed by CRT at 8 fractions/2
weeks.
• The carbon ion dose was increased from 16.8 to 24.8 Gray
equivalent (GyE) in 10% incremental steps (16.8, 18.4, 20.0,
22.4, and 24.8 GyE, respectively).
• The median survival time of AA patients was 35 months and
that of GBM patients 17 months (p = 0.0035).
Mizoe JE et al Int J Radiat Oncol Biol Phys. 2007

40. Radiotherapy In the Elderly
• In Elderly patients-cytoreductive
microsurgery, radiation therapy, and
chemotherapy (SS)*.
.
40
*Ewelt C et al, J Neurooncol. 2010
Florence Keime-Guibert et al, nejm,2007
RT+
BSC
BSC
DFS 14.9
wks
5.4
wks
OS 29.1
wks
16.9
wks

41. Radiotherapy in the Elderly

42. Abbreviated Course of Radiation Therapy in Older
Patients with Glioblastoma Multiforme: A Prospective
Randomized Clinical Trial
•age 60 years
or older
• KPS>50.
•N=95
R
A
N
D
O
M
I
Z
A
T
I
O
N
60 Gy in 30 fractions
over 6 weeks
40 Gy in 15 fractions
over 3 weeks
W. Roa et al, JCO,2004

43. GBM in elderly patients: A randomized phase III trial comparing
survival in patients treated with 6-week radiotherapy (RT) versus
hypofractionated RT over 2 weeks versus temozolomide single-agent
chemotherapy (TMZ)
Arm-
A
Arm-
B
Arm-
C
OS 6 7.5 8
R
A
N
D
O
M
I
Z
A
T
I
O
N
•N=342
•age ≥ 60 years
• PS 0-2
•59%-male
•72%- surgery
60 Gy in 2 Gy fractions
over 6 weeks
34 Gy in 3.4 Gy fractions
over 2 weeks
TMZ
(200 mg/m2day 1-5 q 28 days)
A. Malmstrom et al, ASCO 2010

44. Role of Bevacizumab

45. In Recurrent setting
Multicentre phase II,non comparative trial
n=167, KPS=70-100
Treatment Groups:
A= Bevacizumab @10mg/kg q2wkly
B = Bevacizumab @10mg/kg + Irinotecan @ 125mg/m² q2wkly

46. Results

47. Bevacizumab
(n=85)
Bevacizumab + Irinotecan
(n=82)
PFS (6 months) (%) 42 50
ORR (%) 28 38
OS (months) 9.2 8.7
Toxicity (Gr ≥ 3)(%) 46 66
Steroid dependency
Toxicity profile:
Bevacizumab alone: Hypertension - 8.3%
Convulsion - 6%
Hemorrhage – 2.4%
Bevacizumab + Irinotecan: Convulsion - 14%
Neutropenia – 9%
Fatigue – 9%

48. In First line with standard therapy

49. Arm A (n=317)
RT + Conc TMZ + Bevacizumab (added at 4th week)
Maintenance Bevacizumab (Till progression/Unacceptable toxicity) &
Adjuvant TMZ (06 cycles)
Arm B (n=312)
RT + Conc TMZ + Placebo (added at 4th week)
Adjuvant TMZ (6 cycles) + Placebo
Treatment Arms (RTOG 0835)

50. Results

51. Toxicities Grade ¾ (%) During Chemoradiation
BV (n-303) Placebo (n-300)
During Adjuvant therapy
BV(n=260) Placebo (n-233)
Anemia 0.6 0.3 2.3 1.3
Neutropenia 7.3 3.7 10 5
Thrombocytopenia 10.2 7.7 11 11.7
Fatigue 2.3 2.7 13 9
Wound dehiscence 1 0.3 1.6 1
Hypertension 1.3 0.3 4.2 0.9
Thromboembolic disease 4.6 4 7.7
(1- Gr 5)
4.7
Hemorrhage 0 0.3 1.6
(1- Gr5)
0.9
Visceral perforation 0.3 0.3 1.2 0.4
Toxicity profile

52. Conclusion
(In Bevacizumab arm)
● PFS benefit present (10.7 vs 7.3 months)
● No OS benefit
● Severe/life threatening toxicities increased
● Self reported QOL & Cognitive function decline

53. In First line with standard therapy

54. Arm A (n=458)
RT + Conc TMZ + Bevacizumab
Maintenance Bevacizumab (Till progression/Unacceptable toxicity)
&
Adjuvant TMZ (06 cycles)
Arm B (n=463)
RT + Conc TMZ + Placebo
Adjuvant TMZ (6 cycles) + Placebo
Treatment Arms (AVAgilo trial)

55. Results
Bevacizumab Placebo
PFS (months) 10.6 6.2
OS (months) 16.8 16.7

56. QOL & PS Outcome
Bevacizumab Placebo
KPS≥70 maintained (duration in months) 9 6
Glucocorticoids Initiation time (months) 12.3 3.7
QOL deterioration free survival Higher (p<0.001) Lower

57. Toxicity profile
Toxicity Grade ≥ 3 (%) Bevacizumab (n=461) Placebo (n=450)
Grade 5 toxicity 4.3 2.7
Thrombocytopenia 15 9.8
Fatigue 7.4 4.7
Hemorrhage 3.3 1.8
Wound complication 3.3 1.6
Thromboembolic complication 12.6 9.3
Hypertension 11.3 2.2
Proteinuria 5.4 0
Visceral perforation 1.5 0.9

58. Conclusion:
● No Improvement in OS
● PFS improved by 4.4 months
● Maintained/Better QOL and KPS
● Less steroid dependency

59. Tumor treating fields:
New advancement in treating Gliomas

60. ●Tumor treating fields (TT Fields) are low intensity (1 – 2
V/cm), intermediate frequency (100 – 200 kHz)
alternating electric fields administered using insulated
electrodes placed on the skin surrounding the region
of a malignant tumor.
● TTFields were shown to destroy cells within the
process of mitosis (microtubule destruction in
anaphase) via apoptosis, thereby inhibiting
tumor growth.
● TTFields have no effect on non-dividing cells.

62. EGFR vIII targeted peptide vaccine

64. Re-Irradiation

65. ReRT with
Conventional
Fractionation
First
RT
Dose
Interval
(mo)
ReRT
Dose
BED
Cumulative
NTD
(Gy)
Survival Acute
Toxicity
Gr 3/4
Late
Toxicity
Kim et al
(13-AA,07-GBM)
59.4 38 36 181 91 9 Not
severe
Not
severe
Hayat et al (21
glioma)
45 31 30 +
CCNU
163 82 22 Not
severe
NA
Arcicasa et al
(n=24 HGG)
60 14 34.5+
CCNU
180 90 13.7 Not
severe
NA
Nieder et al
(21 GBM,11 AA)
58.5 20 45 175 87 8.5 9% 6%
Veninga et al
(29 AA, 10OD)
50-60 33 46 197 99 6.9 N=1
Severe
edema
5%
Bauman et al
(n=10) HGG
54-72 15.5 18-74 8.3 6%
20%ND
Henke et al
(n=31)
59 NR 20 10.2 6%

66. ReRT with
FSRT
First
RT
Dose
Interval
(mo)
ReRT
Dose
BED
Cumulative
NTD
(Gy)
Survival Acute
Toxicity
Gr 3/4
Late
Toxicity
Shepherd et al
(29 AA, 4 LG)
55 29 35 229 113 11 Not
severe
12%
Cho et al
(15 GM,10 Gr 3)
60 19 37.5 198 99 12 8% 4%
Hudes et al
(19 GBM, 1 AA)
60 3 24(35
AA)
210 max 105 10.5 Not
severe
0%
Lederman et al
(88 GBM)
60 6.3 24 +
Pacli
210 105 7 (9.4
with CT)
Not
severe
8%
Voynov et al
(5 AA, 5 GBM)
59.7 6.3 30 219 109 10.1 NA 10%(40
% N+T)
Grosu et al
(35 GBM,9 AA)
60
(1.8-3)
16 30 219-255 109-
127
6 (11
with CT)
Not
severe
13%
(N+T)
Combs et al
(40 AA)
59.4 34.5 36 190 95 16 Not
severe
Not
severe

67. ReRT with
FSRT
First
RT
Dose
Interval
(mo)
ReRT
Dose
BED
Cumulative
NTD
(Gy)
Survival Acute
Toxicity
Gr 3/4
Late
Toxicity
Combs et al
(53 GBM)
57 10 36 186 94 8 Not
severe
Not
severe
Ernst-Stecken et
al (11 GM,4 AA)
57.7 10 35 237 118 12 Not
severe
0%
Kohshi et al
(11 GBM,14 AA)
60 13 22/8# 172 86 11
(19 with
HBO)
NA 28%
Leing et al
(12 GBM,7 AA,
3 LGG)
55 20 20-45 180-267 90-
133
11 Not
severe
22%

68. Conclusion :
● NTD rather than the Interval is a Limiting factor for necrosis
● NTD cumulative threshold in RT & ReRT for brain necrosis
>100 Gy
*NTD threshold can be increased with decreased volume of ReRT by
FSRT
Re-Irradiation is a feasible option for
recurrent/residual High grade gliomas

69. Thank You

70. Intensity-modulated radiotherapy (IMRT) and conventional three-
dimensional conformal radiotherapy for high-grade gliomas: does
IMRT increase the integral dose to normal brain?
• Equivalent target coverage
• Improved target conformity
• Enabled dose reductions of normal tissues,
Brainstem
 Optic chiasm
 Right optic nerve
 Left optic nerve , p < or = 0.01.
• This was achieved without increasing the total nontarget integral dose by
greater than 0.5%.
• Overall, total integral dose was reduced by 7-10% with IMRT, p < 0.001,
without significantly increasing the 0.5-5 Gy low-dose volume.
Hermanto U et al Int J Radiat Oncol Biol Phys. 2007

71. Intensity-modulated radiotherapy in high-grade gliomas:
Clinical and dosimetric results
• N=58, high-grade gliomas
• A dose of 59.4–60 Gy at 1.8–2.0 Gy per fraction was delivered
• Median follow-up of 24 months
• IMRT resulted in a decreased maximum dose to the spinal cord, optic
nerves, and eye by 16%, 7%, and 15%.
• Dose escalation 80 Gy possible*
• No Survival advantage , Decreased late toxicity.
Ashwatha Narayana et al ,ASCO,2004
*Monjazeb AM et al, Int J Radiat Oncol Biol Phys. 2011