Molecular Classification, Management and Radiation Techniques

1. MEDULLOBLASTOMA
Presenter: Dr. Rituraj
Upadhyay
Moderator: Dr. Subhash
Gupta
MOLECULAR
CLASSIFICATION
AND MANAGEMENT

2. OUTLINE
■ Introduction, Staging, Classification and Management
■ Evidence, Newer Studies
■ Molecular Classification
■ Radiation Principles andTechniques
■ Recommendations

3. BACKGROUND
■ Medulloblastomas is an embryonal tumor arising in the posterior cranial fossa
■ Median age: 6 years; 20% at < 3years.
■ Comprises 20% of all pediatric brain tumors
■ Annual incidence- 10 children/0.5 adults per million
■ All medullublastomas are assigned WHO grade IV status, equivalent to the
highest grade of histological defined brain tumor malignancy.
■ WHO 2007 classification recognizes
– Classic: 70%

4. Natural History
Arising in the
midline cerebellar
vermis (roof of the
4th ventricle)
Grows into the 4th
ventricle
Fills the 4th
ventricle
Spread around
the 4th ventricle
Invasion of
brachium pontis
Invasion of
ventricular floor
Invasion of brain
stem (33%)
CSF Spread
(33%)
Extra neural spread (7%) : Younger age, males and diffuse subarachnoid disease. M/c - Bone

5. Etiology
■ Majority are sporadic
■ Familial Cancer Syndromes (< 7%): Turcot’s (APC gene -WNT), Gorlin’s (PTCH-SHH),
Li-Fraumani’s (TP53), Rubinstein-Taybi syndromes, Fanconi’s anemia.
■ Loss of chromosome 17p occurs in 50%
■ Inactivation of HIC-1 tumor suppressor gene by hypermethylation
■ Myc amplification
■ Over-expression of ErbB2
■ Previous irradiation

6. Diagnosis - Clinical
■ 80-90% - obstructive hydrocephalus at presentation
Headache & vomiting, papilloedema (60-80%),
6th N palsy, large heads in infants – ‘setting sun’ sign
■ Truncal unsteadiness-50%
■ Head tilt, neck stiffness, nystagmus
■ Psychomotor delays, lethargy, feeding difficulty, weight loss, loss of developmental milestones
■ Acute coma – Hydrocephalus/haemorrhage

7. Neuroimaging
■ CT appearance
– Homogenously enhancing, well-
defined vermian cerebellar mass
– Surrounding vasogenic edema
– Evidence of hydrocephalus
– Cyst formation (59% of cases)
– Calcification - uncommon

8. Neuroimaging
■ MRI features:
– Iso- to- hypointense relative to white matter
(T1 images)
– Hyperintense inT2 weighted images
– Vasogenic edema +
– Spine : enhancing nodules over leptomeninges
(10-30%)
■ Adult Medulloblastomas:
– Poorly defined masses located in the
cerebellar hemisphere
– Cyst like regions are more commonly seen
– Abnormal leptomeningeal enhancement (cf.
Meningioma) – desmoplastic variant

9. Workup
■ Pre-operative MRI brain and spine
■ Post-operative MRI brain- to assess for residue within 72hrs of surgery
■ Lumbar puncture- CSF cytology ( at 10-21 days post-op)
■ Bone marrow, bone scan and other investigations if symptomatic
■ Hormonal profile and Visual assessment should be done at baseline

10. Staging Systems
■ Chang-Harisiadis System: Based on operative findings ( Original – 1969 , Revised -
1977)
■ Laurent staging System (MAPS system): Based on radiological and operative
findings (1985)
■ Langston Classification: Modified Chang's classification to include radiological staging
and excluded internal hydrocephalus / number of internal structures included.
■ Risk group classification:
– PediatricOncology group System
– Halperin System

11. Chang's Staging System
■ T1:Tumor < 3 cm
■ T2:Tumor ≥ 3 cm in diameter
■ T3a:Tumor >3 cm in diameter with
extension producing
hydrocephalus
■ T3b:Tumor >3 cm in diameter with
unequivocal extension into the
brain stem
■ T4:Tumor >3 cm in diameter with
extension up past the aqueduct of
Sylvius and/or down past the
foramen magnum (i.e., beyond the
posterior fossa)
■ M0: No mets
■ M1:Tumor in the CSF
■ M2: Intracranial tumor beyond primary
site (e.g., into the aqueduct of Sylvius
and/or into the subarachnoid space or
in the third or foramen of Luschka or
lateral ventricles.
■ M3: Gross nodular seeding in spinal
subarachnoid space
■ M4: Metastasis outside the
cerebrospinal axis

12. Staging
■ The staging system given Chang was based on radiation oncology
considerations – Chang himself was one.
■ Pre CT era staging criteria – given in 1969
■ Takes the intraoperative findings into account.
■ Brain stem invasion is important prognostic factor in the Chang's
Staging – usually denoted inability to resect grossly.
■ Recent studies –T stage probably doesn't confer a poor prognosis ,
M stage does.
■ Several studies had shown that theT stage of the Chang's system did
not correlate with survival (possible exception of brain stem invasion)
– so replaced by the definition of the post operative residual tumor
volume concept.

13. Staging – Risk Stratification
Average/Standard High
> 3years < 3years
<1.5cm2 residue after surgery >1.5cm2 residue after surgery
M0 M1-4
Classic/Desmoplastic type Large cell/anaplastic type
Complete staging done Incomplete staging

14. Grouping- based on Molecular Pathology
Subtype Age group/
gender
Pathology Cytogenetic abnormality/Mutant gene/
abherrant pathway
Mets at
presentation/
5 YR OS (%)
WNT
(10%)
Older children Classic, very rarely
LCA
6 q-, CTNNB1, DDX3X,
SMARCA4,,MLL2,TP53
WNT signaling
5-10%/
95%
SHH
(30%)
<3years,
>16 yrs
Desmoplastic
/nodular
Classic, LCA
MBEN
9q-, 9p+,3q+,17p-,14q-,10q-
PTCH1&2,SMO,MLL2,, SUFU,
GL1-2 ,TP53, MycN,DDX3X,BCOR
SHH signaling
15-20%/
60-80%
Group 3
(25%)
Infants>
childhood;
males
Classic>LCA 1q+,7+,17q+,18+,8-,10q,17p-
Myc,PVTI,SMARCA4,OTX2
Myc signature
45%/
<50%;
Myc – 70%
Group 4
(35%)
All ages
males
Classic
rarely LCA
4+,7+,17q+,18+,17p-
KDM6A, SNCAIP, CDK6 & MycN
Neuronal signature
40%
70%
Schroeder & Gururangan, Pharmacogenomics & Personalized Medicine 201; 7:43-51.

15. Management Summary
Medulloblastoma
Age < 3 yrs
Gross excision ± Ventriculostomy
Chemotherapy Craniospinal Radiation
+ PF boost
Chemotherapy
High Risk
RT after completing
3 years/relapse
Patient stable
Patient extremely
somnolentHigh dose steroids + MRI
Yes No

16. Adult vs. Paediatric Medulloblastoma
Child Adult
Usual age ~ 4 - 8 yrs Median age ~ 24 - 30 yrs
Shorter clinical History (~ 3 months) Longer history ( ~ 5 months)
Classical type predominates Desmoplastic type relatively
commoner
Median cerebellar syndrome
predominates
Lateral cerebellar syndrome seen
Biologically more agressive Biologically less aggressive
Poorer resectability - median location Greater resectability - lateral location
Higher surgical morbidity and
mortality
Lower surgical morbidity and mortality -
impact of location and age
Poorer RT tolerance Better RT tolerance
Poorer long term survival Better long term survival

17. Pre-surgical Management
■ Most patients will have hydrocephalus.
■ Initially managed medically:
– Moist O2 inhalation (Hypercapnia is however
considered in serious situations as an last ditch
medical measure to reduce ICP)
– Propped up position
– Oral or injectable steroids (Dexa preferred)
– Osmotic diuretics in grave circumstances.
■ VP Shunting is required in majority as they present
with hydrocephalus.
■ Use of filtered shunt reduces incidence of shunt
metastasis.
■ Halperin et al have also described a I125 impregnated
shunt.

18. Operative Considerations
■ Operative Approach: Posterior fossa
craniotomy (ML-SOC)
■ Position: Prone (earlier sitting position
– venous embolism) – “Concorde
position”
■ Tumor mass is often soft, fleshy, and
vascular – characteristically
“suckable”
■ Definitions of resection:
– > 90% : Gross-total or near total
– 51 – 90%: Subtotal resection
– 11 – 50%: Partial resection
– < 10%: Biopsy
■ Factors that preclude a complete
resection include:
– Brainstem invasion, generally of the
floor of the fourth ventricle,
– Adjacent leptomeningeal spread
with coating of the subarachnoid
spaces, and
– Significant supratentorial extension
of the primary posterior fossa mass.

19. Interesting correlates
■ 90% or greater resection is associated with improved survival, at least in children
older than 3 years of age without evidence of tumor dissemination.
– 5 year event-free survival (EFS) was 78% for children with M0 disease and less than
1.5 cm2 residual, compared with 54% for those with larger residual volumes
– Exception is Brainstem involvement : Complete excision is associated with greater
morbidity.
■ Extent of residual tumor on postoperative MRI a more important prognostic factor
thanT stage itself.
■ Lumbar Puncture timing:
– Before Sx: Often C/I due to presence of ↑ICT
– During Sx:Only Cisterna Magna is sampled.
– After Sx: Immediately after operation / 3rd post op week
– However not important for further RT – All patients will receiveCSI irrespective of LP
status!!

20. RADIATION THERAPY
With the possible exception of germ cell tumors, medulloblastomas
are one of the most radiosensitive tumors.

22. Craniospinal Irradiation: History
■ The concept of CSI was advanced by Dr Edith Paterson
(wife of Ralston Paterson).
■ Before this the patients of Medulloblastomas were treated
with posterior fossa or whole brain radiation
■ She advocated the treatment of the entire neuraxis –
bringing the concept of CSI
■ Paterson and Farr reported that with the use of cranio-
spinal irradiation in 27 patient resulted in a 3 yr survival of
65% (Acta Radiologica – 1953) –This was despite surgery in
form of a partial resection / biopsy in all but 1 patient.

23. Rationale for CSI
■ Medulloblastoma is the seminal tumor identified with subarachnoid
dissemination.
■ The impetus for Paterson's study came from the postmortem findings of
metastatic deposits in brain and spinal cord.
■ Landberg et al reviewed serial treatment results (10 year survival) at Sweden:
– 5% after limited posterior fossa irradiation,
– 15% after irradiation to the posterior fossa and spinal canal,
– 53% afterCSI.
■ Reported failures in the subfrontal region additionally indicate the need to
completely encompass the cranial and spinal subarachnoid space

24. RADIATION THERAPY - Evolution
■ Historical controls: No long-term survivors without RT; high recurrence rates
with focal (posterior fossa) treatment.
■ 1980s- craniospinal radiation (35-40Gy) + 50 Gy to posterior fossa (5 Yr
survival of 65%)
■ Attempts to reduce dose, volume and altered fractionation schedules in
average risk patients.
■ 23.4Gy neuraxis dose without chemotherapy- 5 Yr EFS 52% vs 67% (Thomas
JCO 2000)
■ 23.4Gy + concurrent VCR & adjuvant chemotherapy-5Yr EFS -83%.
(Packer JCO 1999)
■ Reducing boost volume ( 54-55.8Gy to tumor bed + margin)- comparable
results to posterior fossa boost.

25. TargetVolume
■ The intent of CSI is to deliver a tumoricidal dose to the primary tumor
and any tumor cells distributed in the CSF or tissue elsewhere in the
nervous system.
■ The volume of irradiation thus includes:
– Entire brain and its meningeal coverings with the CSF
– Spinal cord and the leptomeninges with CSF (laterally to include
meninges till exit of the nerve roots)
– Caudal End of the thecal sac and sacral nerve roots
– Posterior fossa - boost

26. Fields to encompass Target Volume
■ Phase I : Craniospinal radiotherapy (two parallel opposed lateral cranial
fields orthogonally matched with the posterior spinal field to cover the
entire length of the spinal cord)
■ Phase II : Posterior fossa boost (whole posterior fossa irradiation or
conformal boost to tumor bed)

27. EVIDENCE
■ Until the 1990s, the standard of care for patients older than 3 years with
standard-risk disease consisted of postoperative radiotherapy to the
craniospinal axis to a dose of 35 to 36 Gy followed by a boost to the whole
posterior fossa to a total dose of 54 to 55.8 Gy.
■ Both trials showed no benefit to adding chemotherapy to standard CSI 36 GY , though on
subgroup analysis advanced stages did benefit
TRIAL TREATMENT ARMS EVENT FREE
SURVIVAL AT 5YRS
OVERALL
SURVIVAL AT 5
YEARS
SIOP 1 RT vs RT plus concomitant vincristine + adjuvant
chemotherapy ( CCNU ,Vincristine )
48% ( p- NS ) 53% ( p- NS )
CCG 942 RT against RT + chemotherapy ( CCNU ,Vincristine ,
Prednisone )
50% against 59% (
p-NS )
65% ( p- NS )

28. STANDARD- RISK GROUP
■ French SFOP group attempted to reduce RT volume by not irradiating supratentorium, but
results disastrous. <20% EFS at 6 years, with 9/13 failures in supratentorium. CSI is necessary,
despite long-term toxicity
■ Based on these results, POG 8631/CCG 923 attempted to lower CSI alone dose to 23.4 Gy, but
had to be stopped early after showing higher failure rate (67% vs. 52%)
■ SIOP II –Standard risk--Also attempted to lower CSI dose from 35 Gy to 25 Gy, and add adjuvant
chemo. Neither worked, with patients getting post-op adjuvant chemo and low dose CSI doing
particularly badly. High risk patients were randomized to +/- adjuvant chemo, standard 35 Gy
CSI and additional chemo. Adjuvant chemo didn't work here either. 5-year EFS 68% for
standard CSI

29. ■ Most standard risk patients were nevertheless treated with adjuvant chemotherapy despite NO
evidence of benefit. PNET 3 study -----2006 finally demonstrated benefit to EFS (5-year 74% vs.
60%), but no difference in OS. Unfortunately, it also demonstrated a significantly worse health
status in survivors treated with CSI + adjuvant chemo compared to CSI alone
STANDARD- RISK GROUP
TRIAL TREATMENT ARMS EFS AT 5YRS OS AT 5YEARS
HIT 91 Immediate PORT+vincristine f/b CCNU,Vincristine,Cisplatin
Vs Postop chemo ( Ifos+eto+MTX+CDDP+CyA) f/b RT
At 3 yrs, 78% vs 65%
(p- < 0.03 )
NC
CCG
9892-pilot
study
concurrent vincristine and LOW DOSE CSI 23.4 Gy f/b CCNU ,
Vincristine , Cisplatin
80% PFS ( As good as
historical controls
with 35 Gy )

30. ■ Based on these results, low dose CSI 23.4 Gy with concurrent vincristine became
standard in CCG study A9961, and randomization was between two different
chemo arms (CCNU-based vs. cyclophosphamide-based). 5-year EFS was 81%,
and there was no difference between the arms.
STANDARD- RISK GROUP

31. ■ Q- Why CSI dose de-escalation is so important ?
 Long-term effects of CSI
■ Neuro-cognitive dysfunction
 Full posterior fossa RT results in 5 point IQ drop per year for <7 year old and -0.8 points for >7 year
old
 Supratentorial radiation dose is the principal risk factor associated with impaired intellectual
outcome. An approximate 8-point per year decline for children treated with 36 Gy ( Silber etal ,
JCO 1992 )
 Verbal fluency, immediate word list recall, block design, and fine motricity of the dominant hand
were significantly lower in children irradiated at the standard doses than in those irradiated at
reduced doses ( Kieffer-Renaux et al , Dev Med Child Neurol 2000 )
 Even with the reduced radiation dose side effects can still be substantial.An average loss in IQ
scores of over 4 points per year for the first 3 years after treatment by 23.4 Gy. In younger children
(or those with a higher baseline IQ score at the start of treatment) this loss was even more severe.
(Ris MD et al.,JCO 2001 )
 Others- Endocrinologic toxicity , Hearing

34. CURRENT STANDARDOF CARE IN STANDARD RISK MB
Max safe resection →RT with concurrent weekly vincristine → adj chemo (8 6-wk cycles of
cisplatin/CCNU/vincristine). RT is CSI to 23.4 Gy → cone down 1 (CD1) to PF to 36 Gy, then cone
down 2 (CD2) to cavity/residual; or PF to 54–55.8 Gy; or cavity/residual to 54–55.8 Gy (MDACC)

35. HIGH-RISK MB
■ Since both SIOP I and CCG 942 demonstrated benefit for chemo in advanced stage disease,
efforts have been aimed at determining correct sequence and drugs

36. Chemotherapy
■ Indication for CT :
1. As Adjuvant with Surgery in child <3 yrs to delay/avoid RT.
2. In Recurrent /Progressive disease .
3. In patients with Extra cranial mets .
4. High risk Pt. to improve cure rates
5. In avg. risk group to allow reduced RT dose.
■ Non-disseminated, totally resected, desmoplastic tumors in children <
3 years showed long-term survival with chemotherapy alone
(5Yr EFS :77-90% and OS: 85-100%).

38. ■ Assigning patients to one of the two risk groups, however, does not account for
the well observed diversity in response to therapy.
■ Large-scale genomic transcriptome analysis:
– diverse intrinsic genetic and molecular patterns found in tumors
– Resulted in the definition of four molecular subgroups.
– WNT, SHH, Group 3 and Group 4
■ Recognizing the importance of these biological groups ,WHO revised the
classification in 2016 to

39. WNT Subgroup
■ Most uniform pattern of genetic aberrations: Increased activity ofWNT pathway
■ Almost all tumors have classic histology
■ Most of these genes have known interactions with nuclear β-catenin.
■ M/c mutations-
1. Exon 3 of CTTNNB1 gene (90%)
2. Monosomy Chromosome 6
3. DDX3X (50 %)
4. SMARCA4 (26.3 %)
5. TP53 (13.5 %)

40.  CLINICAL CHARACTERISTICS
■ Only 10% of all MB
■ Most rare but have the best prognosis of all MB subtypes
■ Typically occur in older children and adolescents with an equally distributed
gender ratio
■ Typically located in the midline region of the fourth ventricle, and the tumor
often shows brainstem infiltration
■ Metastasis along CSF pathways is relatively rare and encountered in 5–10%
■ 5-year survival rates exceed 90 % ( standard-risk )

41. SHH subgroup ( Sonic Hedgehog )
■ SHH is mainly secreted by the Purkinje cells
in cerebellum and is pivotal for patterning
the midline structures and regulating
granular cell migration and stem cell
proliferation
– SHH ligand binds and inactivates the
transmembrane receptor PTCH1
– Results in releasing the inhibition of
SMO
– SMO acts to activate transcription
factors of the GLI family to express
target genes
– SUFU regulates GLI proteins to inhibit
the SHH pathway

42.  CLINICAL CHARACTERISTICS
■ SHH subgroup accounts for 30% of all MBs
■ Bimodal pattern of incidence is seen , with equal gender ratio
■ Only SHH-MBs may present all of the five major histopathological subtypes,
though classic and desmoplastic subtypes are most common
■ Metastatic dissemination is present in 15–20 %
■ 5-year survival rate is around 75 %.

43. Adult SHH
• PTCH1 alterations
• SMO mutations (14%)
• TERT promoter ( 83%)
Pediatric SHH
• PTCH1 alterations
• ≥ 3 yrs- MYC and GLI2
amplifications
• TP53 mutations
• Infants- SUFU mutations

44. ■ Zhukova etal- Children harbouring TP53 mutation had a 5-year survival of 41 %
compared to 81 % for those without it.
■ Compared to the other subgroups, SHH tumors more frequently recur locally in the
original resection cavity
GOOD
PROGNOSIS
• Adults > children
• TERT promoter mutations ( adults only)
WORSE
PROGNOSIS
• Adults- Metastases, GLI2 amplification,
Ch. 10q deletion
• Pediatric- TP53 mutation, cMET
activation

45. ITS ALL INTHE FAMILY…
■ SHH tumors frequently occur in patients harboring familial syndromes, notably
germline mutations in PTCH1 (NBCCS/Gorlin syndrome),TP53 (Li–Fraumeni
syndrome) and SUFU.
■ These patients require unique screening for secondary malignancies, and genetic
counseling for the family
■ Potential treatment implications---
 Germline PTCH1 mutation– Near universal development of basal cell carcinoma if
radiated
 Li-Fraumeni syndrome - Dismal outcome due to particularly aggressive primary
tumors and the high risk for secondary malignancies in survivors

46. Group 3 MB
■ No distinctive major signaling pathway alteration has been identified.
■ These tumors present a very unbalanced genome with various patterns of
chromosomal and genetic aberrations
■ Alterations seen-
1. Overactivation of oncogenes GFI1A and GFI1B ( 30% )
2. MYC amplification ( 10-20% )
■ Isochromosome17q occurs in ~ 25% of all Group 3 MBs, and it is regarded as a
strong prognosticator for worse outcome.

47.  CLINICAL CHARACTERISTICS
■ Accounts for 25% of all MBs
■ Almost never seen in adults , seen in infants and children with male:female ratio
of 2:1
■ Encompasses a high ratio of LCA histology (40%),especially in infants
■ Metastatic manifestation is present in up to 45 % (Tumor bed typically devoid of
disease at time of recurrence )
■ With a 5-year survival around 50 %, this category has the WORST OUTCOME of
all subtypes

48. Group 4 MB
■ Most common genetic alteration– Isochromosome 17q ( although has not been
proved to have a prognostic role as for Group 3)
■ Most frequent mutation affects the gene KDM6A (13 %)--located on the X
chromosome and encodes for a histone demethylase (H3K27)
■ Amplification of MYCN in ≤ 10%
 CLINICAL CHARACTERISTICS
■ Most common subgroup overall – 35% of all MBs
■ Male:Female- 2-3:1
■ Leptomeningeal metastasis seen in 30-40% patients
■ Intermediate prognosis comparable to SHH group

49. SUMMARY

51. FUTURE RISK STRATIFICATION BASED ON
MOLECULAR SUBGROUPING
■ A risk stratification scheme has been proposed as a guide for the design of
further validation studies and the next generation of clinical trials in children.
■ 4 risk groups have been defined-

52. RISK
GROUP
SURVIVAL INCLUDES:
Low > 90 % • WNT: Non-metastatic, under the age of 16
• Group 4: with loss of chr 11 (1/3
rd ), gain of chr 17( 5%)
Standard 75 – 90 % • SHH: Non-metastatic (except TP53 mutated)
• Group 3: Non-metastatic , No MYC amplification
• Group 4: Non-metastatic, without chr 11 loss
High 50 – 75 % • SHH: MYCN amplification or metastasis
• WNT, Group 4: Metastatic
Very High < 50 % • SHH: TP53 mutated tumors (regardless of mets)
• Group 3: MYC-amplified, metastatic tumors

54. APPROACHING SUB-GROUP BASED
TREATMENT:
■ PNET 5
 SR vs LR acc. to B-catenin status
 LR: reduced dose CSI from 23.4Gy to
18Gy f/b reduced intensity 6 cycles
chemotherapy to confirm higher EFS
 SR: whether concurrent carboplatin
during radiotherapy ( 23.4Gy )
followed by 8 cycles chemotherapy
will improve outcomes
■ SJMB12
 Reduction of CSI dose to 15 Gy in
Average riskWNT patients
 UsingVismodegib as maintenance
therapy in SHH patients
 Addition of pemetrexed and
gemcitabine for select Group 3 and 4
patients

55. SUBGROUP BASEDTARGETTHERAPIES
■ WNT
■ Although the WNT pathway had first been described 30 years ago , agents aimed
to modulate or inhibit points along the pathway only recently entered clinical
trials
■ None of these drugs have been approved for treatment up to now

56. SHH
■ At present , molecular targets for therapy are
best studied for SHH pathway
■ Approaches to modulate SHH signaling have
mainly focused on SMO (smoothened )
inhibition
 Vismodegib
 Sonidegib
FDA approved for basal
cell carcinoma
Vast majority (82%) of adult
patients harbor tumors with
mutations in either PTCH1 or
SMO – will respond to SMO
inhibition
Infant (36%) and childhood (45%)
SHH-MBs frequently have mutations
downstream of SMO, which makes
these tumors intrinsically resistant to
drugs targeting SMO

57. ■ Mechanisms of acquired resistance to SMO inhibitors—
1. Point mutations in SMO
2. Increased PI3K signalling
3. Alternative activation of the RAS-MAPK pathway evading the SHH pathway
■ Combining SMO antagonists with PI3K blocker or GLI inhibitors may be a
strategy to defer the development of resistance

58. ■ Pre-clinical study on pediatric MB cell lines derived from high-risk SHH-TP53-
mutated and MYC-amplified Non-WNT/Non-SHH MB
 RESULTS-
■ Provides first in-vitro evidence of cytotoxic effect ofVandetanib on pediatric MB cell lines
■ Vandetanib in combination with the clinically available PI3K inhibitor GDC-0941 leads to
enhanced cytotoxicity against MYC-amplified and SHH-TP53- mutated MB
■ This study provides a rationale to further evaluateVandetanib in clinical trials for the
treatment of the most aggressive MB variants

59. Group 3 and 4
■ The lack of well-defined genetic drivers and overlap in molecular profiles
between these two groups complicate investigations on drug candidates for
target therapies.
■ In cells overexpressing MYC, the two FDA approved drugs pemetrexed and
gemcitabine were identified to inhibit proliferation.
■ Combined administration of these agents in mouse allografts and xenografts
showed a decrease of tumor growth.
■ It has to be considered that despite being a prevalent characteristic, increased
expression level of MYC is only found in about 10–20 % of patient samples
attributed to Group 3 MBs

60. ■ Evaluated intellectual functioning and implication of limiting radiation exposure in the 4
subgroups of MB
■ Patients treated with CSI received either standard-dose (ie, 30.6 to 39.4 Gy) or reduced-dose
(ie, 18.0 to 23.4 Gy) f/b BOOST to PF/focal conformal boost to 45-55.4Gy
■ Several differentWechsler Intelligence test versions were used
 RESULTS–
■ Intellectual outcomes declined comparably in each subgroup except for processing speed;
SHH declined less than Group 3 (P = .04)
■ SHH had the lowest incidence of cerebellar mutism and motor deficits
■ Limiting CSI dose– beneficial in IQ forWNT/Group 4 , but NOT for Group 3/SHH

61. ■ Q-Why SHH had the lowest incidence of cerebellar mutism and motor deficits
post RT ?
■ ABC transporters not only contribute to
chemotherapy resistance but also play a
functional role in radiation protection
■ These findings suggest that inhibition of
ABC transporters COULD increase the
efficacy of radiation treatment for MB
patients.

62. RADIATION PLANNING:
OVERVIEW
• Localization
• Positioning
– Classical: Prone
– New: Supine
• Immobilization :
– Use of binding tapes:
Simple, cost effective and
easy
– Use customized
thermoplastic devices
• Simulation and Field
Selection:
– Cranial fields: Two parallel
opposing lateral fields
– Spinal fields:
• Conventional SSD: Two
fields
• Extended SSD: One field
may suffice
• Verification and Execution
• Junction Shift

63. POSITIONING
• Prone:
– Better immobilization
– Better extension of the chin & Better Spine alignment
– Direct Visualization of field and junctions
– Uncomfortable, technically difficult to reproduce
• Supine:
– More patient comfort and reproducibility
– Anesthesia access
– Use of a small wedge to support chest and knee rests for spine
straightening.
• Head position:
– Extended: Most common – allows the mandible to move out of the
spinal field
– Flexed: Probably straightens the cervical spine – more homogeneous
dosage.

64. FIELD GAP TECHNIQUE
SSD 1SSD 2
L2 L1S
Hot SpotCold Spot

65. CONVENTIONAL (2 D) PLANNING
• Conventional Simulator
• Initial volume-
– Whole brain to inferior border of C3/4 (for
margin below posterior fossa and
matching of spinal beam avoiding exit
through mouth)
– Spine - C4/5 – S2/3/S4 ( to include
theca & sacral nerve roots as verified
by MRI)
• Single or multiple spinal fields depending
on length.

66. CONVENTIONAL (2 D) PLANNING
• SSD = 100 cm
• Spinal field is simulated first –
easier to match divergence of spinal field
with the cranial field by means of collimator
rotation
• Width - vertebral body + 1 cm to include
the intervertebral foramina , usual width 5 -
7 cm
• After gap calculation, the spinal fields are
simulated.

67. CALCULATION OF FIELD GAPS
• Gap vs No Gap?
• Medulloblastoma being a radiosensitive tumor, small
reduction in dose per fraction or total dose to part of TV,
owing to a gap, may produce significant difference in cell kill
over a fractionated course of CSI, seen as local recurrences
(Tinkler, IJROBP 1995)
• No gap risks overdose at the junction & cervical spine & may
result in disabling late toxicity
• Use of fixed gap ranging from 5 mm - 10 mm.
• A customized gap depending on field length & depth of prescription -
more appropriate
S = ½ L1.d/SSD1 + ½ L2.d/SSD2

68. TARGET VOLUME SPINAL FIELD
• Lateral extent to include the the
transverse processes in their
entirety
• Theory is to include the spinal
subarachnoid space
• This extends to the spinal
ganglia which are situated at
the intervertebral foramina
• Inferior spade field is not
needed – lateral extent of the
thecal sac is defined by the
lateral extent between the two
pedicles.

69. TARGET VOLUME SPINAL FIELD
• Inferior extent:
– Classical : S2 (ending of the thecal sac in
66% patients)
– High: S1 ( termination in 17%)
– Modified: S3 ( termination in 96%)
– To cover filum terminale: S5 ->
unacceptable dose to pelvic organs.
S2 covers 83% of the patients

70. CONVENTIONAL (2 D) PLANNING
• Spinal field-
Superior border at C3-C4
junction such that field is
not exiting through oral cavity
• Mark the divergent boundary of the superior
margin of spinal field (red line) on the lateral
aspect of neck to provide a match line for the
lateral cranial field (blue line)
• Open length of field to a
maximum length and mark
inferior border

71. CONVENTIONAL (2 D) PLANNING
• AP width includes entire
skull with 2 cm clearance
• Superiorly, clearance
to allow for symmetric
field reduction while doing
junction shift
• Inferiorly, the border is
matched with superior
border of spinal field

72. TARGET VOLUME: CRANIUM
The lower border for a conventional
cranial field if used with a block will
result in a miss of the cribriform
plate
Miss will
occur here
This corresponds to the anterior
surface of the greater wing of the
sphenoid

73. TARGET VOLUME CRANIUM:
METHOD 2 • Shielding: SFOP guidelines
are less stringent
• The recommended placement
of block is:
– 0.5 cm below the orbital
roof
– 1 cm below and 1 cm in
front of the lower most
portion of the temporal
fossa
– 1 cm away from the extreme
edges of the calvaria.
– Note the flexion of the
head.
• Customized blocks are better
than MLCs

74. WHY MATCH CRANIO-SPINAL JUNCTIONS?

75. COLLIMATOR – COUCH ROTATION
• Classically described technique.
• Divergence of the spinal field into the cranial field is overcome
with collimator rotation
• Divergence of the cranial fields into the spinal fields is overcome
with couch rotation (rotated so that the foot end moves towards
the gantry)
• Both the rotations are performed during irradiation of the
cranial fields.

76. MATCHING CRANIO-SPINAL JUNCTION:
COLLIMATOR ROTATION
• Cranial field is set up so that caudal field
margin is parallel with the diverging
superior margin of the spinal field
• Collimator angle = tan-1 {½ L1/SSD}
L1 is spinal field length.
 (7 - 10°)

77. MATCHING CRANIO-SPINAL JUNCTION:
COUCH KICK
• To match the diverging cranial fields
with the diverging spinal field the
couch may also be rotated in addition
to the collimator rotation.
Couch angle = tan-1 { ½ L2/SAD}
L2 is cranial field length
~(6°)

78. MATCHING CRANIO-SPINAL JUNCTION:
OTHER TECHNIQUES
– Half beam block
– Asymmetric jaws
– Widen the penumbra so that
abutting fields can be used
without dose inhomogeneity
• Penumbra generators
• Partial transmission blocks
• Wedges
• Beam spoilers
• Vibrating jaws

79. TREATMENT & VERIFICATION
– DRR

80. CRANIO-SPINAL JUNCTION: FIXED VS MOVING
• Owing to lateral scatter of photons & electrons, a gap on skin as
defined by the light beam will be reduced by 1-2mm at depth
(Thatcher, 1989, IJROBP).
• At doses relevant for medulloblastoma, a 5mm overlap at 4 MV
photons can result in 30 to 40% overdose i.e. 14Gy for 36Gy
prescribed dose, which may exceed cord tolerance
(Hopulka, 1993, IJROBP)
• Systematic error during radiotherapy delivery could further lead to an
overlap or gap. Acceptable systematic set up error for CSI is 2 mm
• Concurrent CT recently being used for high risk patients can also
result in long term neurotoxicity.

81. JUNCTION SHIFT
• Moving the junctions / Feathering
smoothes out any overdose or underdose
over a longer segment of cord
• Move either cranially or caudally.
• Cranial inferior jaw is closed & spinal
superior jaw is advanced by the same
distance superiorly (if junction to be
shifted cranially).
• Similarly, lower border of superior spinal
field & superior border of inferior spinal
field are also shifted superiorly,
maintaining the calculated gap between
them.
• Usually shifted by 1 to 2 cm each time.

82. DOUBLE JUNCTION TECHNIQUE
Day of Planning
Day 1: The upper spinal
field is shortened
Day 2: The lower spinal field is
shortened
Upper Spine Lower Spine
Upper Spine
Upper Spine
Lower Spine
Lower Spine
Junction on D 1 Junction on D 2

83. CONVENTIONAL (2 D) PLANNING
Extended SSD technique:
• Entire spinal canal in single field.
• Better homogeneity
• Increase in PDD with increase in SSD.
• Greater total penumbra as compared
to the standard SSD.
• Higher doses to all anteriorly placed
normal structures
• Doses to gonads and thyroid may lead to
sterility, thyroid dysfunction &
carcinogenesis.
• Not routinely recommended.

84. CT SIMULATION- IS IT REQUIRED?
• Helps in
– Virtual simulation of treatment fields without the patient.
– Better definition of critical organs and target volume.
– Graphical overlays of anatomic CT data onto digitally reconstructed radiographs (DRRs) and the viewing
of all fields simultaneously in multiple CT-based planes improve field placement, matching, shielding
accuracy & direct calculation of gap between the fields.
• Conventional Simulator films do not define:
– Terminal location of the thecal sac.
– Relationship between the optic globe and the cribriform plate.
• The cribriform plate may be located below or at the same level as the superior edge of the lens in
50% patients, Shielding the lens – underdosage of the cribriform plate.
• Nearly 25% of all recurrences occur in the supratentorial region.

85. FIELD GEOMETRY - PRONE

86. FIELD GEOMETRY - SUPINE

87. 3D CRT- CSI

88. CRITICAL NORMAL STRUCTURES (OAR)
• Pituitary
• Eyes / Lens
• Cochlea / Inner ear
• Parotid
• Oral cavity
• Mandible
• Thyroid
• Larynx
• Heart
• Lungs
• Oesophagus
• Liver
• Kidneys
• Gonads (Testes / Ovaries)
• Breasts
• Whole Pelvis( marrow)

89. BOOST- 2D PLANNING (POSTERIOR FOSSA)
• Field arrangement - two lateral opposing
fields
• Anterior: Posterior clinoid process (avoid
pituitary)
• Posterior: Internal occipital protuberance
• Inferior: C1-C2 interspace
• Superior: Midpoint of foramen magnum
& vertex or 1cm above the tentorium (as
seen on MRI)

90. IS IT NECESSARY TO TREAT THE
ENTIRE POSTERIOR FOSSA?
Fukunaga IJROBP 1998

91. 3D CRT / IMRT TUMOR BED BOOST
• GTV- Tumor bed on MRI
• CTV = GTV + 15 mm.
• PTV = CTV + 3-5 mm, modified only at sella.
• Immobilization accuracy +/- 3-5 mm.
• 95% of isodose covers 100% of CTV & 95% Of PTV.
• Homogeneity: no > 10% of target volume receives > 110% of boost dose.
• Constraints:
– < 70% Supratentorial brain to receive > 50% boost dose.
– < 80% Left & right cochlea to receive > 80% of boost dose.
– < 50% Pituitary to receive > 30% of boost dose.
– < 10% Left & right optic nerve & chiasma to receive > 50.4 Gy each.

92. CSI WITH NEWER MODALITIES
• IGRT
– Localization and targeting precision verified using KVCT/MVCT acquisition.
• TOMOTHERAPY
– Rotational IMRT: No need for junctions
• IMRT
– Superior dosimetry: Target volume coverage and OAR sparing
– No survival advantage has been demonstrated.
– Higher body integral dose: potential for higher (yet unproven) risk of second malignancies.
• PROTON THERAPY
– Uniform dose distribution to the posterior fossa and spinal cord within the thecal sac.
– Near complete organ sparing - lower probabilities of developing secondary hearing, hormonal defects
– Long term effects of secondary neutron spill - not quantified.

94. RT INDUCED NORMAL TISSUE EFFECTS
Acute Toxicity
• Hair loss
• Vomiting +/- Headache
• Skin reactions especially over ears
• Somnolence
• Hematological toxicity (prophylactic growth factor support is NOT
indicated)
Long term Sequelae
• Neurocognitive & neurophysiological dysfunction
• Endocrine abnormalities
• Growth retardation
• Ototoxicity- particularly with platinum based adj CT
• Cerebrovascular accidents
• Gonadal toxicity & reduced fertility
• Second malignancies

95. FOLLOW UP
• In standard risk :
– First 2 years:
• Brain MRI - every 3 months
• Spinal MRI - every 6 months;
– 2-5 years
• Brain MRI every 6 months
• Spinal MRI every year for 3 yrs.
• In high-risk :
– Brain and spinal MRI - every 3 months for the first 2 years then every 6 months.

96. RECURRENCE
• Relapses occur in nearly 75% of paediatric cases within 2 years.
• Predicted by Collins rule of recurrence=age at diagnosis + 9 months
• Sites
• Post. Fossa
• Supratentorial region including cribriform plate
• Spinal cord
• Ventricular walls
• Diagnosed by neuroimaging or clinical progression
• Treatment at relapse:
– Localized brain recurrence: Surgeryradiation therapy combined
with various chemotherapy schedules.
– Disseminated disease: Chemotherapy or best supportive care including
radiation.

97. SUMMARY OF RECOMMENDATIONS
■ CSI followed by chemotherapy is the standard of care for both average and high-risk children
ages 3 and older
■ Current standard approach:
– Standard risk: Surgical resection  CSI 23.4 Gy at 1.8-Gy/fx with PF boost to 54 Gy
with concurrent vincristine  PCV chemo. DFS ~80%
– High risk: Surgical resection  Post-op CSI 36–39 Gy at 1.8-Gy/fx, with entire PF and
mets >1 cm boosted to 54 Gy with concurrent vincristine PCV chemo. DFS ~60%
■ Infants<3 yrs: Surgery  Intensive chemo. Delay/Reserve RT for salvage
■ Contemporary CSI treatment & planning approach uses MRI and CT simulations (3D RTP).
■ Posterior boost also benefits from 3D-RTP and the use of highly-conformal 3D-CRT or
IMRT techniques.

98. CONCLUSION
■ Over the last 5 years, our understanding of molecular patterns accounting for the
observed clinical heterogeneity of medulloblastomas has dramatically increased
■ Forthcoming clinical trials incorporating subgroup-specific genetic markers into
traditional clinical risk stratification protocols will gradually refine and define the
prognostic and predictive value of molecular profiles in order to brace preventive
and therapeutic interventions
■ It is anticipated that adjuvant treatment modalities selectively adjusted based on
the molecular background of medulloblastomas will improve tumor control and
reduce therapy-induced morbidity and neurological sequalae