Treatment Changes Rel To Brain Tumors Dennis Shaw

1. Treatment Related Complications in
Pediatric Brain Tumors
Dennis Shaw
Seattle Children’s Hospital
Univ. of Washington

2. Brain tumor treatment effects
• Treatment effects
• Leukencephalopathy
• Cap. Telangiectasia
• Vasculopathy/moyamoya
• Calcification
• Secondary tumors
• Radionecrosis [RN]
• Pseudoprogression [PsP]
• Pseudoresponse [PR]
• Treatments
• [Surgery]
• Photons [+/- chemo]
• Newer adjuvant chemo-
radiotherapy
• Proton Beam Therapy [PBT]
• Antiangiogenic agents

3. Radiation induced white matter
changes [T2 hyperintensity]
17 y.o. anaplastic ependymoma
Tumor post op 3 yrs post external beam

4. Radiation induced capillary
telangectasia/ microhemmorhages
Medulloblastoma SWI 3 years post XRT

5. Moyamoya 10 years s/p XRT [30.6Gy] for
medulloblastoma
Han 2017

6. Treated at <2 years of age with XRT/chemo
for supratentortial ATRT

7. Extensive Ca++ post XRT
for supratentortial ATRT

8. Post XRT meningioma: 7 years post XRT

9. 14 y.o. High Grade Glioma: XRT with
Temozolomide [TMZ]:
1 month post
radiation +TMZ
Progressive
Disease?
Treatment
Effect?

10. 14 y.o. High Grade Glioma: XRT with TMZ:
Pseudoprogression
1 month post
radiation +TMZ
3m; no further
tumor treatment

11. Treatment effects: PsP, RN, PR
• Distinguishing from progressive/recurrent tumor
[PD] during surveillance imaging:
-Pseudoprogression (PsP)
-Radiation necrosis (RN)
• Impact of:
-Radiation sensitizers [Temozolomide (TMZ)]
-Proton Beam Therapy (PBT)
-Anti-VEGF agents [Avastin]: -pseudoresponse (PR)

12. Radiation Therapy:
adverse effects- classic timing
• 0 3m 6m years- post XRT
Acute
Subacute
Delayed
XRT
(during or shortly after exposure)
symptomatic- increased ICP

13. Radiation Therapy:
adverse effects- classic timing
• 0 3m 6m years- post XRT
Acute
Subacute
Delayed
XRT
(<12 weeks) most w/o
symptoms

14. Radiation Therapy:
adverse effects- classic timing
• 0 3m 6m years- post XRT
Acute
Subacute
Delayed
XRT
(# months-yrs)
often
symptomatic

15. Radiation Therapy:
adverse effects- pathology
• 0 3m 6m years- post XRT
Acute
Subacute
Delayed
XRT
Pathology:
Oligodendrocyte
injury:
Cytokine release
BBB disruption
Endothelial
injury/apopto
sis 
necrosis

16. Radiation Therapy:
adverse effects: PsP, RN
• 0 3m 6m years- post XRT
Acute
Subacute
(Pseudo-
progress)
Delayed
(Radiation Necrosis)
XRT
Local inflam
BBB disruption,
perm 
edema, +gad
Necrosis +gad
edema
[hem/vasc malf]

17. Radiation Therapy:
adverse effects: PsP, RN
• 0 3m 6m years- post XRT
Acute
Pseudo-
progress
Delayed
(Radiation Necrosis)
XRT
Local inflam
BBB disruption,
perm 
edema, +gad
Necrosis +gad
edema
[hem/vasc malf]
most w/o
symptoms

18. Complicating factors:
• Radiation enhancers (TMZ) & Chemotx
‘Chemo-radiotherapy’ = ‘Treatment Effects’
• Proton Beam Therapy
prolonged acute & sub-acute effects
earlier necrosis

19. Radiation Therapy:
adverse effects: classic timing
• 0 3m 6m years- post XRT
Acute
Subacute
(Pseudo-
progress)
Delayed
(Radiation Necrosis)
XRT

20. Chemoradiotherapy:
adverse effects- overlapping time periods
• 0 3m 6m years- post XRT
Acute
Subacute
(pseudo-
progress)
Delayed
(Radiation Necrosis)
XRT
85% with
2 years

21. Treatment effects versus tumor
• 0 3m 6m years
Acute
Subacute
(Pseudo-
progression)
Delayed
(Radiation Necrosis)
XRT
‘Treatment
effects’
Tumor Progression / Recurrence

22. Pseudo-Progression (PsP) and Radiation Necrosis
(RN) vs Tumor/Progressive Disease (PD)
• Histopathology gold standard:
- often not obtained due to morbidity of
surgery.
Pathology not always straight forward:
-Tumor can have necrosis
-Mixed pathology seen [sampling error]
• Often studies presume PsP/RN, PD based on
f/u imaging and clinical
Many studies have been loose in distinguishing
between these entities.

23. Pathology: PsP, RN
• Despite proposed differences in
pathophysiology between PsP and RN:
PsP & RN have many overlapping pathologic
features, and seem to have as such many
similar imaging features, potentially
exploitable to distinguish from PD

24. Limitations of the literature
• Most studies of treatment effects are high
grade glial (HGG) tumors in adults.
• [Small numbers, not prospective]
• Children have different spectrum of
malignant tumors with differing biologic
behavior than adult high grade glioma.
• Reaction to radiation (animal studies suggest
endothelial/oligodendrocyte/microglia
differences between children and adults)

25. ATRT: Gross total resection;
Proton Beam: Radiation Necrosis
Initial tumor 1 year post PBT

26. Incidence of Radiation Necrosis
• Photon radiation necrosis rates in adults:
5% 72Gy, 10% 90Gy [Lawrence 2010]
• Few studies in children:
• Photons;
-Plimpton 2015: n=101, 54-59.4Gy;
5% ‘rad necrosis’ [mean 1.2m post XRT]
-Spreafico 2008 n=49, chemo & PBSC rescue;
HHG 24%, PNET 75% ‘abnormal imaging’
(8m [2-39m) post XRT]
• Proton Beam (PBT):
-Kralik 2015: n=60; 31% rad necrosis
-Sabin 2013: n=17 (young); 47% rad necrosis

27. Incidence of Pseudoprogression
• Up to 20% adults tx with chemoradiotherapy
[TMZ] Brandsma 2008 review

28. Distinguishing treatment effects/
recurrent tumor/progressive disease
• Conventional MRI:
-Timing/relationship to radiation-chemotherapy
-Tumor type: pattern
HGG-infiltrative spread likely vs CSF spread with
many ped tumors
• Advanced MR:
-Diffusion Weighted Imaging
-Perfusion Weighted Imaging:
-MRS

29. Correlation with radiation fields/dose:
10 y.o. with C-M ependymoma;
Cervicomedullary
Ependymoma
f/u 1 year post XRT; new
L-M enhancement

30. Correlation with radiation:
C-M ependymoma
Radiation profile:
enhancement in
maximum radiation zone
Stable 3 months later

31. Distinguishing treatment effects/
recurrent tumor
• Conventional MRI:
-Timing/relationship to radiation-chemotherapy
-Tumor type: pattern
HGG-infiltrative spread likely versus
CSF spread with many pediatric tumors
• Advanced MR:
-Diffusion Weighted Imaging
-Perfusion Weighted Imaging
-MRS

32. 23 month old with Pineoblastoma
1 year post
Proton XRT
FLAIR
T1 gad
Original tumor

33. 2 y.o. with history of Medulloblastoma:
Ventricular surface nodular spread:
Tumor recurrence
ADC
DWI
T1 gad

34. History of Medulloblastoma
14 month
post XRT

35. MRI Pattern (adult High Grade Glioma):
Tumor vs Treatment effects [PsP, RN]
Recurrent Tumor (vs Radiation Necrosis):
Mullins 2005; n=15/27 tumor; adult HGG PBT
-Callosal involvement + multiple foci
+ across midline
+ subependymal spread
[sensitive., specific., PPV, NPV all <78%]
Recurrent Tumor (vs Pseudoprogression)
-Subependymal spread;
sens. 38%; specific 98% [low NPV]
Young 2011; n=63/93 tumor; adult HGG
sens. 42%; specific 89% [low NPV]
Yoo 2015 [distant spread only] n=24/42 tumor; adult HGG

36. Callosal spread + subepend:
7 year old relapse HGG:
s/p resection & Proton Beam Tx

37. Mineralizing microangiopathy
4 month old; ATRT gross total resection
PBT [+thiotepa]
Progressive hemiparesis 6 months post PBT
Treatment/Radiation Injury:
Initial Tumor 3m post PBT. 10m post PBT

38. 3yr; ATRT gross total resection
PBT (+ thiotepa): Treatment/Radiation Injury
Initial Tumor 3m post PBT 7m post PBT

39. Distinguishing treatment effects/
recurrent tumor
• Conventional MRI:
-Timing/relationship to radiation-chemotherapy
-Tumor type: pattern
HGG-infiltrative spread likely vs
CSF spread with many ped tumors
• Advanced MR:
-Diffusion Weighted Imaging
-Perfusion Weighted Imaging
-MRS

40. Diffusion weighted imaging (ADC)
theory:
• Treatment effects = less restricted diffusion
/higher ADC
-Reflecting lower cellularity
RN: necrosis/loss of cells
PsP: BBB disruption/leaking/edema?
• Progress Tumor: high grade tumor = cell dense

41. ATRT: Radiation necrosis: ADC
Tumor at
presentation
1 year post radiation

42. Recurrent tumor: ADC
7 y.o. HGG 2 years post chemoradiotherapy
[PBT]

43. ADC: Treatment effects vs Prog Disease
Hein 2004: adult HGG; n=18, 6/18 Tx effects (n=2
imaged ≤3months post Tx)
• Recurrence: mean ADC = 1.18±0.13X10-3 mm/s2
• Tx effects: mean ADC 1.4±0.17X10-3 mm/s2
• Considerable overlap
•
> .0015 mm/s2 = non tumor
< .0011 mm/s2 = tumor
P< .006

44. Diffusion weighted imaging (ADCratio)
• ADC ratio = ADC lesion /ADC normal contralateral white matter
• Hein 2004: ADC ratio better then ADC lesion
-ADC ratio PD 1.43±.11; Tx effect 1.82±.07 p= <.001
Treatment effect > 1.62 > Progressive Disease

45. RN/PsP vs PD: ADClesion , ADCratio
• Matsusue 2010: (n=10/15 tumor recurrence; mixture
LGG & HGG;); 3/15 MRI ≤6 months post XRT;
-ROI lowest ADClesion/ ADC normal contralateral white matter
-ADCratio > 1.3; sens 9/10, specific 4/5 PsP,RN vs PD.
• Prager 2015: HGG, n=68; 10/68 TX effects;
[8/10=PsP, (<6months post XRT)]
-ADC lesion threshold <0.00149; sens 73.7%, spec 70%= PD
-ADC ratio difference not significant

46. DWI/ADC: Pseudoprogression
early diffusion restriction?
• Young 2011; n=93, adult HGG with worsening
lesion on MRI 2-4 wks post XRT: PsP= 30/93
Qualitative assessment: reported diffusion
restriction: 16/30 of those with PsP
PsP pathophysiology associated with diffusion
restriction?

47. Post. Fossa ATRT 15 months post PBT:
Radiation necrosis (acute?); low ADC
Initially ischemia?

48. DWI/ADC: summary
• High ADClesion (>.0015mm/s2): probably RN/PsP
• Low ADClesion (<.0011mm/s2): probably PD
• ADCratio ? PD < 1.3-1.6 < RN/PsP
• Limitations:
• Low ADC can be seen in RN; (acute/ ischemic
phase?)
• Low ADC may be more common early with PsP
(awaiting further data )

49. Distinguishing treatment effects/
recurrent tumor
• Conventional MRI:
-Timing/relationship to radiation-chemotherapy
-Tumor type: pattern
HGG-infiltrative spread likely vs CSF spread with
many ped tumors
• Advanced MR:
-Diffusion Weighted Imaging
-Perfusion Weighted Imaging
-MRS

50. Perfusion (PWI)
Theory
• Detect microvasculature, angiogenesis
• Tumor: Increased CBV
• RN/PsP: Decreased CBV
• Most studies use DSC; Parametric maps: CBV
• ‘Normalized’ rCBVratio= CBVlesion/CBV nl contralateral WM
• Technique/analysis more difficult, potential issues
with heterogeneity, capillary leak.

51. 7 y.o. HGG 2 years post PBT
Recurrence: rCBV
rCBV= 4

52. PF ATRT: 4m post PBT
Radiation Necrosis (Brainstem)

53. Treatment effect versus progressive
disease: DSC
Matsusue 2010: n=15 [adult HGG+LGG]
- rCBVratio threshold 2.1: PPV 9/10, NPV 4/5
Prager 2015: n=68 [adult HGG]
- rCBVratio ≥ 1.27: sens 86.5%, specific 83.3% PD
- Sub analysis predicting PsP (<6 m post XRT)
- rCBVratio < 1.07: sens 100%, specific 75% PsP

54. Progressive disease versus PsP:
PWI/DSC
• Wan et al 2017 meta analysis;
• 11 studies with 20+ subjects between 2011-
2016 employing DSC
• AUC of the SROC = 0.8899
• ‘good but not excellent diagnostic accuracy’

55. Distinguishing treatment effects/
recurrent tumor
• Conventional MRI:
-Timing/relationship to radiation-chemotherapy
-Tumor type: pattern
HGG-infiltrative spread likely vs CSF spread with
many ped tumors
• Advanced MR:
-Diffusion Weighted Imaging
-Perfusion Weighted Imaging
-MRS

56. MRS: Theory
• Tumor/PD:
Cho [ NAA]
• Treatment effects/Radiation necrosis (RN):
 Cho, NAA [lipid, lac].
• Typically use metabolic ratios; Cr denominator.
• Limitations:
volume averaging [SVS vs MVS]
variable TE employed; peak height vs peak area

57. MRS: 6 y.o. HGG 1 year post PBT
Cho/Cr = 2.8

58. MRS: Recurrent PNET (non enhancing)
Cho/Cr = 2.46

59. MRS: tumor vs RN
• Rock 2002: Cho/Cr > 1.79 = tumor
• Weybright 2005 Cho/Cr > 1.8 = tumor
• Zeng 2007: Cho/Cr > 1.71 = tumor
• Fink 2012: Cho/Cr > 1.5 = tumor
[MVS]

60. MRS: summary
• Cho/Cr: <1.3 = RN
• Cho/Cr > 1.6 -1.8 = PD.
• Limitations:
Volume averaging [multi-voxel preferred]
Overlap:
Intra-tumoral necrosis
Occasionally Cho elevated in RN
Cho elevation possible in PsP

61. Tumor MGMT promoter
methylation status:
• MGMT (O6 methylguanine DNA methyl
transferase) is responsible for repairs of DNA
errors during replication.
• Methylated MGMT promoter =
decreased MGMT production [‘turned off’]
decreased DNA damage repair (--radiation--)
more tumor cell death

62. Tumor MGMT promoter methylation
Brandes 2008 n=50/103 HGG with progressive
enhancement @ 1 month post XRT+TMZ
Pseudoprogression Progressive tumor
Methylated MGMT
promoter
21/23 (91%) 2/23 (9%)
Unmethylated MGMT
promoter
11/27 (41%) 16/27 (59%)
Methylated promoter: incidence Pseudoprogression (and
better response to treatment)
Methylated promoter: early  enhance more likely PsP

63. Pseudoresponse
HGG: Avastin [anti VEGF]
Pre
Avastin
Post
Avastin
Enhancement
 tumor contralateral
hemisphere

64. Pseudoresponse
• Antiangiogenic drugs (anti VEGF) Avastin;
•  enhancement [1-2 days] ‘super steroid’
• ‘Radiologic response’ rates of 25-60%
• ‘interpret with caution’ as often not response
[alters tumor- invasive/non enhancing
phenotype?]
• Enlarging non enhancing T2 abnormality:
evidence of tumor progression

65. Conclusions: PR, PsP, RN,
• Conventional MR:
• Expected pattern of tumor spread:
[CSF spread, Sub-ependymal, CC].
• Mineralization helpful?
• Advanced MR:
• ADC: high=RN [acute RN, PsP?] low=tumor; some
overlap (ADCratio value?)
• rCBV: dec= RN/PsP, inc=tumor; some overlap
• MRS: Cho/Cr: MVS

66. Conclusions: ‘Team Sport’
• Prospective diagnosis of radiation necrosis /
pseudoprogression in children, as in adults
‘remains challenging’
• Imaging interpretation most useful including the
clinical context; collaboration with a
multidisciplinary team:
- XRT (type/dose/margins/timing)
- Chemo-radiotherapy regimen
- MGMT promoter methylation status (HGG)

67. Thank you