An overview on state of the art in tumor assessment in pediatric neuro-oncology. Presented in the Course of advanced images in pediatric oncology 2018 (Madrid - Spain_ and Neuroscience meeting at Great Ormond Street Hospital for Children in London UK

1. “The Elephant in the Room”
felice.d’arco@gosh.nhs.uk

2. “Elephant in the room” is an English-language metaphorical idiom for an obvious
problem that no one wants to discuss, or a condition of groupthink that no one wants
to challenge”
The Elephant in the Room, Banksy, 2006 Barely Legal show, Los Angeles

3.  We need to assess tumor response to therapy in
children
 We need objective, reproducible radiological
measurements for clinical trials
 Current methods of assessment in neuro-oncology
(RANO) are based on adult tumors
 Biological/radiological heterogeneity of pediatric brain
tumorsPediatric brain tumors are unique entities, require
adjustment of imaging criteria and a “one size fits
all” strategy may not be the right approach.
Currently there is no consensus on standards to
define tumor response in children
Radiological Assessment in Pediatric Neuro-Oncology

4. Learning objectives
 Role of contrast enhancement
 Assessment of Pseudoprogression /
Pseudoresponse with advanced MR
techniques
 Assessment of different types of tumors
(DMG, OPG)
 Use of Volumetrics

5. Role of Contrast: Adults
Macdonald Criteria
1990
- Assessment of Adult GBM
- Axial post contrast T1 images
(initially CT post contrast)
- Product of Max perpendicular
diameters
- Nonenhancing tumor not assessed
- Not applicable to low grade (non-
enhancing)
- Effect of treatment
(pseudoprogression/pseudorespon
se

6. Role of Contrast: Adults
RANO 2010
- Measurable lesions: enhancing, ≥ 10 mm
- Axial post contrast T1 images
- Product of Max perpendicular diameters
- Evaulation of non enhancing FLAIR/T2
lesions
- Clinical features considered

7. Complete response
• disappearance of all enhancing
disease (measurable and non-
measurable)
• sustained for at least 4 weeks
• stable or improved non enhancing
FLAIR/T2 lesions
• no new lesions
RANO 2010
Partial response
• 50% or more decrease of all
measurable enhancing lesions
• sustained for at least 4 weeks
• no progression of non-
measurable disease
• stable or improved non enhancing
FLAIR/T2 lesions
• no new lesions
Progression
• 25% of more increase in
enhancing lesions
• increase (significant) in non-
enhancing T2/FLAIR lesions
• any new lesions
Stable disease
• All others: changes less than
50% in decrease or 25 %
increase
RANO criteria are still widely used
in clinical trials in pediatric neuro-
oncology!!

8. Role of Contrast: Children
• Most of the pediatric atrocytomas do not enhance or enhance
inhomogeneously
• Cystic/Necrotic components?
• Tumoral enhancement can vary spontaneously without treatment
and without changes in overall tumor size! (Gaudino et al 2012)

9. Interval development of new areas of contrast
enhancement may correspond to new areas of tumor,
increasing sensitivity in diagnosis of tumor
progression/response
We still need contrast!
D’Arco F, Mankad M, Tamrazi B. in press

10. Assessment of HGG in children: pseudoresponse
and pseudoprogression
Pseudoresponse: a reduction in tumor related contrast enhancement and edema
simulating response to therapy, when the actual lesion actually has remained stable or
even progressed.
Administration of anti-angiogenic therapy
After resection of HGG,
enhancing residuum
posterior to the surgical
cavity
BVZ lesion disappeared
(very good response?!)
1 month after
discontinuation of BVZ,
rapid progression with
edema and new
enhancement

11. Hygino da Cruz Jr et al. AJNR 2011
Diagnosis of Pseudoresponse
- Time: 1-2 days after surgery
and after 12 weeks
- Discrepancy enhancing
component vs FLAIR/T2
- Clinical features considered
- No standard in pediatric
population

12. Pseudoprogression is an increase in lesion enhancement and/or T2
signal related to treatment (Chemo-RT, immunotherapy) rather than true
progression.
N.B: histologically distinct from both true tumor progression as well as other more
delayed changes related to treatment such as radiation necrosis.
1) Acute phase: few days,
transient and reversible
edema
2) Sub-acute phase: few
wks/3 months, increased
enhancement improving
after 6wks (TRUE
PSEUDOPROGRESSION)
D’Arco F, Mankad K, Tamrazi B. in press
3) Radiation Necrosis: >
3 months to years,
irreversible damage
Rate pseudoprogression in pediatric
DMG treated with chemo/RT: 19-24%

13. DDX pseudoprogression vs true progression
Perfusion
11 yo, GBM in right basal
ganglia
D’Arco F, Tamrazi B. in press
- high grade gliomas :vascular
proliferation
- RT induced change: decreased
microvascular density and
capillary perfusion
- Low perfusion in c.e. area:
PsPr

14. New enhancing lesion posteriorly to the resection cavity 1 month
after completion of chemoradiation
Pseudoprogression!
Huang et al. 2015

15. DCE-MRI and ASL: similar results
Courtesy of S. Bisdas UCL -
ASL DSC
K-trans

16. Post-gad T1w ASL Cerebral blood flowCholine PET / T2w
New PET radiotracers may overcome current limitations of FDG-PET
?
Diffuse anaplastic astrocytoma (Grade III) in a 10 y child, F-U under
treatment

17. Multimodality imaging: «hot spot» for biopsy in diffuse anaplastic astrocytoma
Restricted diffusion = high cellularity (ddx with RT induced changes, low grade tumors, normal brain

18. Serial ADC for monitoring: pearls and pitfalls
• ADC values are reduced in high grade neoplasms because of the high cellular
concentration
• Lysis or apoptosis of neoplastic cells, expected during therapy, may result in
increase of the ADC values
• Minimum ADC values in the ROI should be used for surveillance monitoring
ADC
changes to
be
evaluated in
clinco-
radiological
context !
ADC influenced by internal edema in LGG

19. Diffuse Intrinsic Pontine Gliomas (DMG)
Pre-RT
Post-RT
1) Supratentorial white
matter volume decreased
with time: steroid adjuvant
therapy
2) Steroids may have a
substantial effect on lesion
volume changes
3) Normalized DIPG
volume decreased during
combined treatment and
increased shortly after
completion of radiation
therapy
Svolos et al. 2017
RT effect on the tumor or
on the edema??

20. “Anaplastic” areas within the DIPG?
Löbel et al 2011
T2 C+ DWI ADC
CBV

21. Löbel et al 2017
Reduction in volume and signal but stable metabolic profile

22. Assessment of DMG
1) If discrete enhancing lesions are present:
measure them with RANO!
But be aware of pseudoprogression
2) Still measure T2 (area or volume).
But be aware this may represent just edema reduction
(steroids and RT)
3) If focal areas of T2 hypo, high perfusion, low
ADC and or faint enhancement: may be the “real”
tumor
But be aware this is still an hypothesis
4) MRS may represent surrogate of metabolic
profile of the tumor
But no reference values/experimental
5) We have no cure and real improvement under
therapy is controversial: do we need to assess
tumor response in DMGs?

23. Assessment of Optic Pathway Gliomas
o Pediatric OPGs do not enhance homogeneously and enhancement not
indicative of progression/response
o Pediatric OPGs have very slow grow rate overtime (stable disease =
response to therapy)
o OPGs clinico-radiological discrepancy
o Association with NF1 makes things complicated
F-U 9 months
3 year-old
Eur. Radiol. 10, 1076-1078 (2000)
There is no MRI criterion predictive of tumor
growth and prognosis; moreover there is no
correlation between tumor enhancement, internal
structure and the tumor clinical course!

24. Radiological approach to children with
OPGs
o NF1 patients should not be routinely screened with MRI looking for OPGs unless
unexplained visual symptoms are present
o Newly diagnosed OPGs: follow-up scan every 3 months for the first year and then
every 6 months
o New or progressive visual loss and increase in the size: more short follow up (6
weeks)
o Linear measurements on T2/FLAIR sequences (van den Bent et al. 2011): RANO
• Changes in size can be independent from tumor free survival! (Gnekow et
al.2004)
Dodge Classification: location
Stage 1 Stage 2 Stage 3

26. Volumetrics vs RANO
D’Arco et al 2018 Neuroradiology (ePub)
o 14 (20%) of the 70 patients have
showed discordant results
between 2D and Volumetrics in
terms of category of response
to treatment
o Possible differences in clinical
management
o Consider volumetrics when
discrepancy between
subjective analysis and RANO

27. Is there room for advanced techniques?
“In the optic nerves, median FA significantly correlated with
VA with lower FA associated with poorer vision. In the optic
radiations, both lower FA and higher ADC were significantly
associated with poorer vision.”
“DTI is an imaging biomarkers sensitive to micro-structural
damage to the underlying white matter not always visible on
conventional MRI”

28. Assessment of OPG
1) Clinical correlation (vision) is critical
2) Size: RANO T2/FLAIR or Volumetry, location is
important
3) Variation in enhancement do not correlate with
treatment response and/or clinical symptoms
4) Correlation between size and symptoms is
controversial
5) Room for advanced techniques (DTI)

29. Conclusions
 No consensus in evaluation of treatment response in
pediatric neuro-oncology
 RANO still widely used in clinical trials but probably sub-
optimal
 Contrast variation may be misleading
 Different tumors  different assessment
 Clinical correlation/advanced techniques