Contemporary management of glioblastoma and high grade glioma in 2020 with radiotherapy and chemotherapy & recent advances in new treatment modality.

1. Adjuvant therapy of high grade
glioma in 2020: Marching ahead.
-Dr. Subhas Pandit
MD(AIIMS), ECMO
Nepalese Society of Neurosurgeons
Webinar Sept 05,2020

2. Content
1. Current Standard of care
2. Radiotherapy aspects
3. Emerging treatment advances
2

3. High Grade Glioma (n=277)
20% of CNS tumors
3

4. Clinically relevant biomarkers
● IDH1/IDH2
■ Primary vs sec.
■ Vaccine target
● MGMT promoter
methylation
■ Response to TMZ
● EGFR Mutation
■ EGFR vIII
4

5. Evolution of treatment
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6. Partial Volume RT = Whole Brain RT
1978 1989
Surgery followed by focal radiotherapy
became the standard of care in 1990s. 6
Addition of Radiotherapy(whole
brain) improves survival

7. Addition of chemotherapy (TMZ)
Stupp R. et al EORTC-NCIC trial
NEJM 2005
Lancet 2009
7
SURGERY

8. Radiotherapy vs combined RT+ TMZ
Survival RT RT+TMZ
Median 12.1
months
14.6
months
2 year 10.9 % 27.2%
5 year 1.9 % 9.8 %
Stupp R. , 5-year analysis of the EORTC-NCIC trial , Lancet 2009
HR : 0.63 (0.53-0.75)
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9. Current standard : Stupp ’s Regimen
● Six weeks of radiotherapy with concurrent oral temozolomide (75mg/m2)
● Radiation dose of 60 Gray in 30 fractions ( 2 Gray /day)
● 6 monthly cycles of adjuvant TMZ after radiotherapy
● 150-200 mg/m2 per day for 5/28 days
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10. MRMT Promotor methylation =
Good prognosis and predictive (TMZ)
MGMT
High
MGMT
Low
Hegi M, NEJM 2005
Apoptosis
Repair
MGMT
methylated
unmethylated
MGMT
Stupp R. Lancet Oncol,2009
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11. Attempt to optimized TMZ dose
● No difference in OS or PFS
● Irrespective of MGMT status
● Toxicity higher in dose dense arm
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12. Temozolamide : 6 vs 12 months ?
● Pooled data from 4 large randomized trials
● Continuing TMZ beyond 6 cycles was not shown to increase overall
survival for newly diagnosed GBM
● MGMT
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13. GBM in elderly ( Treatment options)
● Radiotherapy only: OS 29 vs 17 week. [Keime‐Guibert ,N Engl J Med. 2007]
● Hypofractionated radiotherapy (short course RT)
○ 40 Gy in 15 fractions : Equivalent to standard dose Roa W, JCO 2004
○ 25 Gy in 5 fractions : Equivalent to 40Gy/15# , Roa W, JCO 2015
● Hypofractionated RT + TMZ: (9.3 vs 7.6 months OS); Perry JR, NEJM 2017
● TMZ only : Effective only in Methylated MGMT: NOA-08, Nordic trail , Lancet Oncol 2012
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14. Radiation…..??
● 2D-Radiotherapy
● 3D Conformal Radiotherapy
● Intensity modulated radiotherapy (IMRT)
● Volumetric radiotherapy (VMAT)
● Stereotactic Radiotherapy
● Proton therapy
● Brachytherapy
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15. 2D Planning
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16. 3D-Conformal RT
● Always LINAC Based
● CT-scan based planning (MRI optional)
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17. IMRT / VMAT
Advanced 3D technique
Computer generated highly
conformal plans
Especially useful in tumors near
critical structures like optic
structures,brainstem etc
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18. Principle of Stereotaxy
○ Precisely locate the target
stereotactically using special frames
■ Hold the target still
■ Accurately aim the radiation beam
○ Shape the radiation beam to the target
○ Deliver high radiation dose
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19. Walk-through in RT planning
● Delivered 5 days per week for 6
weeks.
● Typical treatment time 10-15
minutes
● Painless, similar to CT scan but
with masks.
● No radioactive substance is used.
● Side effects are minimal.
● NO NEED TO ADMIT PATIENTS. 19

20. 20
CT Simulation
Individualized Thermoplastic mask –
For precise Positioning & Immobilization.

21. Planning CT
T1 MRI
T2 MRI
Target &
Organs at risk 21

22. 22
CT - MRI fusion for tumor/target delineation
MRI - Better anatomy/pathology for contour
CT - Dose distribution

23. T1 -component
T2 - Edema
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Fused CT-MRI

24. CTV -Clinical
target volume
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25. Dose Distribution
Dose volume histogram
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26. What dose ?
60Gy
<54 Gy
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27. Advances- Hippocampal Sparing IMRT
Gondi et al ,IJROBP 2011
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28. Advances- Scalp Sparing VMAT
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29. Emerging Strategies in GBM
1. Targeted therapy
a. VEGF (Bevacizumab)
2. Tumor treating fields - Mild Electric field to disrupt cell division
3. Brachytherapy
4. Immunotherapy -Stimulate immune cells to recognize and kill tumor
cells.
5. Gene therapy :Phase I/II of VB 111 in Neuro Oncol 2020 May
6. Nobel approaches: Focused Ultrasound , Laser ablation
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30. Bevacuzimab (AVASTIN)
● Endothelial proliferation and neovascularization are hallmark.
● Express high level of angiogenic factors like VEGF
● Phase II trials showed improved PFS in recurrent setting.
● FDA approved for recurrent GBM (2009) .
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31. Gilbert et al NEJM 2014 & Chinoto et al NEJM 2014
Bevacezumab in newly diagnosed GBM
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32. Tumor treating field : EF-14 trial
● Low intensity electric current in scalp eletrode
● RT+TMZ Vs. RT+TMZ+TTF
● Median overall survival: 19.6 mth vs 16.6 months
● 2 year survival : 43% vs 29%
● NCCN Category 1
Stupp R. et al JAMA 2017
32

33. Targeted radioimmunotherapy(COTARA)
Seed Implants
Brachytherapy techniques
Gliasite
33
I 131 basedRadioactive seeds

34. Immunotherapy approaches
Vaccine
Peptide vaccine
[Rindopepimut]
Dendritic cell vaccine
Oncolytic virus therapy
Adaptive T cell therapy
Immune Checkpoint blockade
Nivolumab
Pembrolizumab
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35. The phase II ACT III study reported encouraging
results in June 2015.
The ReACT clinical trial for glioblastoma reported
encouraging results in 2015.
In March 2016 the phase III ACT IV trial was
terminated because it did not increase overall
survival
Rindopepimut is an injectable peptide cancer vaccine targeting a mutant protein called EGFRvIII
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36. Checkpoint Inhibitors - Nivolumab
Conclusion:
Immune checkpoint
inhibition, in its current
state, demonstrates
limited efficacy and
has failed to improve
the survival .
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37. 37

38. Recombinant polio vaccine in recurrent GBM
Early phase clinical data -proof of concept
58 months24 months12 months
N Engl J Med 2018 38

39. 39

40. Conclusion
● Standard of care is Surgery ---> RT/TMZ ---> 6 cycles adjuvant TMZ.
● Many new approaches have failed to improve outcome.
● Some new and promising treatments undergoing clinical trials.
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