Glioblastoma multiforme , Recent advances, Radiotherapy techniques

1. Recent Advances in High Grade
Gliomas (HGG)
Dr Rajesh B
Associate Professor
Department of Radiotherapy
Christian Medical College, Vellore

2. Learning Objectives
• Current management strategy for High Grade Gliomas
• Radiotherapy treatment planning guidelines for High Grade Gliomas
• Chemo irradiation for HGG - How to titrate dose of TMZ during RT
• How to assess response for Gliomas – RANO Guidelines
• Recent advances in RT /chemo for HGG
• Clinical trials which would answer our queries in Future

3. Objectives of Radiation in Malignant Glioma
• Potential for cure
• Prolong survival times with improved quality of life
• Control local infiltration of cancer cells
• Palliation
Overall, the objectives of radiation in the treatment of CNS
malignancies include:

4. Current management
strategies in HGG

5. Treatment Algorithm for management of GBM

7. Radiotherapy treatment
planning guidelines for HGG

8. Simulation Process
• Simulate after removal of Craniotomy Staples / Sutures
• Start RT within 4-6 weeks of surgery
• An immobilization mask is fashioned to reduce motion during and
between fractions.
• The planning CT scan is extended to encompass the head and neck
region (Atleast upto C4 levels) to allow sufficient anatomic areas for
proper image fusion and genera-tion of high- quality digitally
reconstructed radiographs (DRRs) and to permit the introduction of
noncoplanar beams;
• Slice Thickness for CT images – 2.5 - 3mm
• Do MR Fusion for good TV delineation

9. Radiotherapy Volumes for HGG’s
Planning Target Volume (PTV)
- To account for both organ
motion and setup error
- Organ motion in the brain
is minimal (e.g., <1 mm)
- Modify PTV to exclude
normal tissue in areas
where gliomas are unlikely
to infiltrate.

10. Tips for Planning
• Check the critical organ delineation carefully
• Check BEVs
• Avoiding entrance and exit dose to the eye may be a relatively simple
means of preventing not only cataracts but also conjunctivitis and a
dry eye
• Contour the ear canals, as there is now a greater awareness of the risks
of developing otitis externa as well as otitis media
• For tumors located in the temporal lobes, the exit dose to the
parotid gland may bring about xerostomia.
• Always contour Brain tissue outside the PTV as a organ and try to limit
dose to the same as low as achievable.
• Use functional MRI or MRS data if available for planning purposes

11. • RT dose prescription as per RTOG guidelines.
• A clinical judgment was made to modify the
planning target volume to exclude sensitive
structures by presuming that „„natural barriers‟‟
would impede the contiguous spread of tumor
cells.
• As such, the traditional 2–2.5-cm margin was
not added in the direction of the temporal bone.

12. Dose constraints to critical organs

13. Hippocampus contouring
http://www.rtog.org/CoreLab/ContouringAtlases/HippocampalSparing.asp

14. Hippocampus delienation by software
Courtesy : Dr Minesh Mehta

15. Chemoirraditation for HGG

16. ChemoRT schedule
• RT - Five fractions per week
• Prophylactic antiemetics
• PCP prophylactics
• Low dose steroids with H1 blocker
• Weekly blood counts
• Give Temozolomide for a maximum of 49 days and then STOP

17. Dose modification for Concomittant
Temozolomide

18. Dose Level Dose (mg/m2/day) Remarks
-1 100 Reduction for prior toxicity
0 150 Dose during Cycle 1
1 200
Dose during Cycles 2-6 in absence of
toxicity
Toxicity
Reduce TMZ by 1
Dose Level*
Discontinue TMZ
Absolute Neutrophil Count < 1.0 x 109/L (< 1000) See footnote†
Platelet Count < 50 x 109/L (<50,000) See footnote†
CTC Nonhematological Toxicity (except for
alopecia, nausea, vomiting)
CTC Grade 3 CTC Grade 4†
†TMZ is to be discontinued if dose reduction to < 100 mg/m2 is required or if the same Grade 3 nonhematological toxicity
(except for alopecia, nausea, vomiting) recurs after dose reduction.
TMZ=temozolomide; CTC=Common Toxicity Criteria.
Dose modification for Adjuvant
Temozolomide

19. Response Assessment for
HGG

20. RANO Basics
The Revised Assessment in Neuro-Oncology (RANO) criteria was published in
2010, as an update to the existing MacDonald criteria (see references at end)
• Used for assessing disease progression and treatment response in
glioblastoma multiforme (GBM)
References
Print Version:
“Updated Response Assessment Criteria for High-Grade Gliomas: Response
Assessment in Neuro-Oncology Working Group.” Journal of Clinical Oncology.
2010 Apr 10; 28(11):1963-72.
Online Version:
http://jco.ascopubs.org/content/28/11/1963.abstract

21. Image Acquisition
•MRI is the only modality used to assess response and progression
•Minimum sequences required:
– Pre-contrast T1, T2/FLAIR
– Post-contrast T1, with two orthogonal planes (or a volume acquisition)
recommended
•Recommended slice thickness ≤5 mm with no gap
•Additional imaging that may be helpful:
– Diffusion (DWI, ADC)

22. Definitions
Measurable lesions
Contrast enhancing lesions
Minimum size: two perpendicular diameters ≥10 mm
If slice + gap thickness >5 mm, minimum size is 2 times the total
Do not include cavity, cyst, or necrosis in the measurement
Non-measurable lesions
Lesions that are too small (e.g. 12 x 8 mm)
Lesions that do not enhance (seen only on T2/FLAIR)
Lesions with a poorly defined margin

28. Pseudoprogression
• Enhancement that simulates tumor growth, most often caused by radiation
(whole brain or focal)
• Growth of existing lesions or appearance of new lesions within 12 weeks of
completion of radiation therapy may be the result of treatment effects rather
than growth of tumor.
• Clinically the neurological status of the patient would be stable / improved
• Continued follow-up imaging can determine whether initial lesion growth
was true progression or pseudoprogression.
– If lesion continues to enlarge, the initial growth is called true progression
– If lesion stabilizes or shrinks, the initial growth is confirmed as pseudoprogression
• In such cases, the baseline SPD is no longer included when choosing the nadir value
for the purposes of determining when progression occurs
• Diffusion weighted imaging can help distinguish pseudoprogression from
true tumor growth, but its use is still experimental.
• The use of MR perfusion and spectroscopy is also being explored.

29. Recent advances in Chemotherapy &
Radiotherapy management of HGG

30. Positive Phase III Trials Evaluating the Role of
Irradiation, Chemotherapy, or Chemoradiation in the
Treatment of Malignant Gliomas

32. Methylation status as a Prognostic marker

33. Methylation status as a Prognostic marker

34. RTOG-0525- Dose intense Vs Conventional
Schedule in Adjuvant therapy

35. Treatment Plan
ChemoRT:
Focal RT ( 60 Gy /30 #, Conc TMZ 75 mg/m2) followed by 6 cycles of adjuvant TMZ
Adjuvant chemotherapy: (Both arms – six cycles of 28 days)
Group A : Dose Dense - 150 mg/m2 daily days 1 to 7 and 15 to 21 of each cycle
Group B: Metronomic Arm- 50 mg/m2 daily days 1– to 28 of each cycle
Antiemetics / Supportive care inculding Growth factor support at discretion of physician
Maintenance doses of 13-cis-retinoic acid - 100 mg/m2 daily days 1 to 21 of a 28-day cycle till PD.
Dose Dense Vs Metronomic Schedule in
Adjuvant therapy for GBM

36. Control :
Focal RT ( 60 Gy /30 #, Conc TMZ 75 mg/m2)
followed by 6 cycles of adjuvant TMZ
Trial Group:
2 cycles neoadjvuant chemotherapy
ACNU (40 mg/m2/day) and CDDP (40 mg/m2/day) CI 72 hrs Q6 weeks
Followed by RT and Adj TMZ as in control group
Median
survival
Overall survival
1yr 2yr
Control 18.9 m 81.7% 27.8%
Treatment 28.4m 72.4% 50.9%
Study stopped inbetween due to 30% Grade 4
toxicty of the neoadjvuant arm

37. RTOG 9305: Newly Diagnosed GBM
Stereotactic Radiosurgery Phase III Trial
Arm 1
RT – 60Gy / 30 #
BCNU 80mg/m2 D1-3 of RT then
Q8weeks for 6 cycles
Arm 2
SRS followed by
RT – 60Gy / 30 #
BCNU 80mg/m2 D1-3 of RT then
Q8weeks for 6 cycles
SRS Dose
24Gy – Lesion < 2cm
18 Gy- Lesion 2.1 -3 cm
15 Gy – Lesion 3.1-4 cm

38. • For patients with malignant glioma, there is Level I-III evidence that the
use of radiosurgery boost followed by external beam radiotherapy and
BCNU does not confer benefit in terms of overall survival, local brain
control, or quality of life as compared with external beam radiotherapy
and BCNU.
• The use of radiosurgery boost is associated with increased toxicity.
• For patients with malignant glioma, there is insufficient evidence
regarding benefits / harm of using
– radiosurgery at the time progression or recurrence.
– stereotactic fractionated radiation therapy in patients with newly
diagnosed or progressive/recurrent malignant glioma

39. http://njms.umdnj.edu/gsbs/stemcell/scofthemonth/scofthemonth2/braincancer/2.jpg
http://www.medscape.com/viewarticle/578097_3

40. Results of Irradiation of CSC Niches
In the human brain, the 3-5 mm thick lateral periventricular region of the lateral ventricles - the
subventricular zone (SVZ ) - and a subsection of the hippocampal formation - the subgranular layer
( SGL ) – have been shown to harbor normal brain stem cells
These regions are believed to contain specific regions of so-called stem cell niches, which support
neuronal stem cells and keep them in an undifferentiated state .

41. Hypofractionated IMRT with Field in Field
Boost for Newly diagnosed GBM
CT – MRI fusion done ( Post op MRI)
Combination of coplanar and noncoplanar beams
GTV = CE tumor on T1W + Entire resection cavity
CTV = Edema visible on T2-weighted MRI images
TV i = GTV + CTV + 1 cm
TV b = GTV + 0.5 cm
5mm minimum margin to spare critical normal OARs

42. Results of Hypofractionated IMRT
• Median OS – 13.6 months
(Range – 0.9-40.2 months )
• Median PFS – 6.5 months
(Range – 0.9-40.2 months )
• 1yr survival – 57 %
• 2yr survival – 19%
• No difference in OS among dose groups

43. Accelerated Hypo IMRT
with TMZ
• Total of 35 patients ( 74% pats in old RPA Class 5 or 6)
• Patients whose tumors were within 1.5 cm of either the optic chiasm or the
brainstem were not included
• The GTV was defined as the surgical cavity and/or postoperative contrast-
enhancing lesion on MRI fusion.
• The PTV was taken as the GTV plus a 1.5-cm margin. Visible edema outside
the PTV margin was not included in the volume.
• Treatments were delivered with an isocentric technique, often with three or
more non coplanar beams.
• GTV - 60 Gy in 20 daily 3-Gy fractions
– 95–100% isodose line covered the GTV
– 65–70% line encompassed the PTV (40Gy in 20 daily fractions)
• Concomitant TMZ at a dose of 75 mg/m2 daily during hypo-IMRT, followed by
adjuvant TMZ at a dose of 150–200 mg/m2 daily for 5 days every 28 days,
according to the EORTC/NCIC regimen

44. Results of Accelerated HypoIMRT trial
• Median follow-up - 12.6 m.
• 82.8% - completed CRT and
71.4%- received a median of
four cycles of adjuvant TMZ.
• Median OS - 14.4 m
• Median DFS - 7.7 m

45. Elderly GBM – NOA-08 / Methvsalem Trial
(Age >65yrs)
Inclusion criteria: Age >65 yrs
Median Survival:
RT 9.8 mo
TMZ 8.6 mo
Hazard ratio 1.28
(0.94-1.63)
TMZ alone inferior to RT
Unexpected toxicity in elderly

46. Elderly GBM – Nordic Trial (Age >60yrs)
Temozolomide may be an alternative to RT

47. Recursive Partioning Analysis of GBM

48. MRS Study for Volume delineation in
our institute

49. MRS based volume delineation
• Multivoxel MRS was done at various levels on the FLAIR
sequences.
– At levels of enhancing component that contains enhancing lesion
– Surrounding enhancing edema
– Regions with non enhancing edema alone and
– Areas with normal brain.
• Peak parameters for choline, creatine, NAA, lipid and lactate was
estimated on a voxel by voxel basis and the choline-creatine
index (CCI) and Choline-NAA index (CNI) was defined.
• At these image levels, following areas were defined on a voxel by
voxel basis
– Choline Creatine Index of more than 1.5
– Choline NAA Index (CNI) of more than 3
– CNI of 1.5 to 3 and CNI of less than 1 was defined

50. • Areas with CNI more than 3 and those areas with CNI between 1.5 and 3
were defined on a voxel by voxel basis. The parameters defined at
these image levels on which MRS was performed, was extrapolated to
other images of FLAIR MRI on which MRS was not performed.
• The three dimentional MRS volume defining the high risk area
encompassing CNI of more than 3and intermediate risk area
encompassing CNI of 1.5 to 3 was compared with the volume defined
by post Gadolinium T1W and T2W FLAIR sequences.
• Disjoint and conjoint volumes were then defined by comparing the
volumes defined by the MRI alone and combined MRI & MRS. Similar
comparison was made between volumes defined by areas
encompassing CNI less than 1.5 and non enhancing edematous
component on FLAIR MRI.

51. MRI VOLUMES MRS VOLUMES
T1W GTV ( Enhancing component
on T1W image)
CNI of more than 3
T2W GTV (Enhancing component on
T2W FLAIR image)
CNI of 1.5 to 3 and CCI more than 1.5
PTV (GTV + 2.5 cm uniform margin) CNI less than 1.5 + 5 mm
MRS analysis for volume delineation was done later than the MRI and
hence the MRS data was not utilized for treatment of these patients .
Treatment planning of all patients were done as per CT-MRI based
volume delineation.
This study was only a dosimetric study and volumes generated using
MRS was not used to treat these patients

52. Comparison of T2 FLAIR GTV volume (cc) to MRS
defined GTV Volume [Intermediate Risk area (CNI 1.5)

53. Comparison of PTV volume in MRI (GTV T2 FLAIR+2.5
cm) and PTV in MRS (CNI< 1.5+ 5 mm)
Wilcoxon signed-rank test:
Adjusted variance = 96.25
z = 2.803
P = 0.0051

54. Picture below Depicts the
Conjoint T1 GTV Volume
(Blue) of MRI in a patient with
Glioblastoma that is much
less than the corresponding
High Risk Area (Brown) in
MRS seen as disjoint area
The pictures shows the conjoint
and disjoint PTV volumes of
MRI and MRS
MRI defined PTV (dark)
extends into the orbit whereas
the extension is not seen in the
PTV defined by MRS.

55. Clinical trials that would answer
our questions

56. Major ongoing Trials in High Grade Gliomas

57. CATNON: Phase III trial comparing no adjuvant
chemotherapy versus adjuvant therapy until progression
for anaplastic glioma without 1p/19q loss

58. CODEL : Phase III Intergroup Study in Newly Diagnosed
Anaplastic ODG or Anaplastic Mixed Glioma with
Chromosomal cowith co--deletions of 1p and 19q.

59. Trials of anti-angiogenic agents for
newly-diagnosed glioblastomas
• VEGF
– Bevacizumab (RTOG, Roche)
– Aflibercept (VEGF VEGF-Trap) (ABTC)
• VEGFR
– Cediranib (VEGFR, PDGFR)
– Vandetanib (VEGFR, EGFR)
– Sorafenib (VEGFR, PDGFR, Raf)
– XL184 (VEGFR, Met) (Exelixis)
– Pazopanib (VEGFR, PDGFR, cKIT)
• PKCβ
– Enzastaurin (UCSF, multiple)
• Integrins
– Cilengitide (Merck KG)

60. TMZ/RT ±Cilengitide in MGMTmethylated
GBM CENTRIC/EORTC 26071 / 22072

61. BRAIN Study Design – Recurrent GBM
Avastin ± Irenotecan

62. AVAglio study or RTOG-0825

63. • Longest documented GBM patient in Literature -20 yrs
• He had been treated with surgery and partial brain irradiation (59 Gy of 6-
MV photons in conventional fractionation delivered via the shrinking-field
technique).
• The authors speculated that the outcome may have stemmed from the fact
that he had a favorable molecular profile (e.g., methylated MGMT
promoter, PTEN positive, and TP53 positive, which the authors termed
“triple positive” similar to the nomenclature of breast cancer).
• 5 yr survival in GBM from the EORTC-NCIC - 10%, and
• 5 yr survival for pts with favorable prognostic factors ~ 30%

64. Thank You