1. Management of
Medulloblastomas
Moderator:
?
Department of Radiotherapy
PGIMER, Chandigarh
2. Introduction
Medulloblastomas are the most common type of primary
CNS neoplasm occurring in the posterior fossa in childhood.
These tumors are characterized by:
Young age at presentation
High intrinsic radiosensitivity
Propensity for intracranial spread via the CSF pathways
Potential for metastatic spread
3. History
First described by Harvey Cushing and
Percival Bailey in 1930
At that time this tumor was described
variously – sarcoma, neuroblastoma and
neurocytoma.
Initially described as “spongioblastoma
cerebelli” - a soft, suckable tumor usually
arising in the vermis of cerebellum Harvey Cushing
In 1925, changed name to
medulloblastoma – from “medulloblast” -
a hypothetical multipotent cell
Percival Bailey
4. Incidence
Overall account ~ 7% all brain
tumors
20% of tumors in pediatric age
group
0.4%–1% of all adult central
nervous system tumors
40% of tumors of the posterior
fossa
Medul- Cerebral Cerebellar
1½ – 2 times more common in loblastoma low grade Astrocy-
Astrocy- toma
males. Ependy High grade Brain Stem
moma Astrocy- Glioma
toma
Peak incidence at the age of 5 – Others
6 yrs.
7. Raised ICT Symptoms and signs
Subtle changes in personality, mentation, and/or speech
Infants with open cranial sutures have Irritability, anorexia, failure to
thrive and macrocephaly.
Classic triad of headache, nausea and/or vomiting, and papilledema -
advanced
Torticollis: Cerebellar tonsil herniation
Setting-sun sign
Parinaud Syndrome:
Vertical gaze disturbance
Convergence retraction nystagmus
Light near dissociation of the pupils
Lid retraction (Collier’s sign)
Horizontal diplopia : 6th nerve palsy
8. Other Signs and Symptoms
Ataxia, long-tract signs, or cranial neuropathies
Initial cerebellar dysfunction may be insidious:
Clumsiness, worsening handwriting
Difficulty with hopping or running
Slow or halting speech
Midline cerebellar masses lead to truncal unsteadiness or
increased ICP.
Duration of symptoms : Lesser duration poorer prognosis
(Halperin et al)
9. Adult vs Pediatric Medulloblastomas
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
72% pediatric cases are median in 45% are median in origin and 43%
origin lateral
Biologically more aggressive – more Biologically less aggressive – less
labeling index and less apoptotic labeling index and more apoptotic
index index
Poorer resectability – median location Greater resectability - lateral location
Higher surgical morbidity and Lower surgical morbidity and mortality
mortality – impact of location and age
Poorer RT tolerance Better RT tolerance
Poorer long term survival Better long term survival
10. Medulloblastoma in < 3 yrs
Comprehensive review by Saran et al (IJROBP , 1998)
Accounted for 25% of all pediatric medulloblastomas
Average 5 yr RFS ~ 40% - 45%
Higher frequency of disseminated disease at presentation
Later presentation due to lack of closure of cranial sutures
Lower dose of radiation usually delivered ~ 20% - 25%
reduction
Cranio-spinal dose : 30 Gy at 1.5 Gy per fraction
Posterior fossa dose : Limited to 45 Gy
Difficulty in planning and delivery of RT
Poorer RT tolerance
Unusual HP subtype : ATRT ( Atypical Teratoid/ Rhabdoid
tumor) – associated with very poor prognosis – recently
recognized.
11. Natural History
Arising in the
Grows into the 4th Fills the 4th
midline cerebellar
vermis (roof of the ventricle ventricle
4th ventricle)
Spread around
the 4th ventricle
Invasion of
ventricular floor
CSF Spread
Invasion of brain
(33%)
stem (33%)
Invasion of
brachium pontis
Extra neural spread (7%) : Younger age, males and diffuse subarachnoid disease
12. Extra neural spread
Overall prevalence of extraneural metastasis at 7.1% of
patients - Rochkind et al
Sites:
Bone (77%) - sclerotic (65%), lytic (35%)
Lymph nodes (33%)
Liver (15%)- 4th in case of adults
Lung (11%) - 3rd in case of adults
Muscle (2%)
VP Shunt mets: Rare after incorporation of millipore filter in
the early 1970s
13. Pathology: Gross Appearance
Typically located in midline in the
posterior fossa
Grayish – pink color
Circumscribed with soft, granular
consistency
Small areas of necrosis present.
Calcification uncommon.
Desmoplastic variant: Firmer
appearance and darker color. Also
more common in the lateral
cerebellar hemispheres.
14. Microscopic Appearance
Highly cellular tumor
High N:C ratio
“Carrot shaped” nucleus
Cells arranged in typical
Homer – Wright rosettes
Multiple histological
subtypes
15. Other Variants
Neuroblastic Medulloblastoma
Desmoplastic Medulloblastoma
Medullomyoblastoma
Large Cell Medulloblastoma
16. Origin
Classical :Fetal remnant cells in the external granular layers
of the cerebellum
WHO: Classifies Medulloblastomas under the category of
embryonal neoplasms:
Medulloblastoma
Ependymoblastoma
PNETs
Medulloblastoma
Medulloepithelioma
Ependymoblastoma
PNET
Esthesioneurblastoma
Pineloblastoma
Cerebral Neuroblastoma
17. Neuroimaging
CT appearance
Hyperattenuated, well-
defined vermian cerebellar
mass
Surrounding vasogenic
edema
Evidence of hydrocephalus
Homogeneous contrast
enhancement
Cyst formation (59% of
cases)
Calcification - uncommon
18. Neuroimaging
MRI features:
Iso- to- hypointense relative to white
matter (T1 images)
Hyperintense in T2 weighted images
Enhance following contrast
Heterogeneous enhancement.
Vasogenic edema +
Adult Medulloblastomas:
Poorly defined masses located in
the cerebellar hemisphere
Cyst like regions are more
commonly seen
Abnormal leptomeningeal
enhancement (cf. Meningioma) –
desmoplatic variant
19. Metastatic disease
Leptomeningeal disease:
Spinal cord is the most common site
Most metastases are found along the
posterior margin of the spinal cord –
CSF flow from cisterna magna to
posterior margin of spinal cord
Supratentorial involvement frequently
involves the frontal and subfrontal
regions
Sulcal and cisternal effacement
Ependymal-subependymal
enhancement
Widened tentorial enhancement
Communicating hydrocephalus
20. 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:
Pediatric Oncology group System
Halperin System
21. Chang's Staging System
M1: Tumor in the CSF
T1: Tumor < 3 cm
T2: Tumor ≥ 3 cm in diameter M2: Intracranial tumor
beyond primary site (e.g.,
T3a: Tumor >3 cm in
into the aqueduct of
diameter with extension
Sylvius and/or into the
producing hydrocephalus
subarachnoid space or in
T3b: Tumor >3 cm in the third or foramen of
diameter with unequivocal Luschka or lateral
extension into the brain stem ventricles.
T4: Tumor >3 cm in diameter M3: Gross nodular seeding
with extension up past the
in spinal subarachnoid
aqueduct of Sylvius and/or
space
down past the foramen
magnum (i.e., beyond the M4: Metastasis outside the
posterior fossa)
cerebrospinal axis
22. 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.
24. Risk Grouping
Tait and Evan showed that the risk grouping approach could be utilized
to stratify patients into two risk categories:
Poor risk
Average risk
Several studies had shown that the T 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.
Factors Average Risk Intermediate risk Poor risk
Tumor cells or clumps in Disseminated with
Posterior Fossa, Not
Extent of
CSF; ? Brain stem intracranial or spinal
Disease invading the brain stem involvement disease
Extent of Total ; Near total; <1.5 ? Subtotal; > 1.5 cm Biopsy or minimal
2
cm residual residual resection
2
resection
7 yrs or greater NA 3 yrs or younger
Age
Undifferentiated Differentiated Rhabdoid elements
Histology
? Aneuploid, ? ? C- myc
? Diploid; High
Isochromosome 17q, low amplification, low
Biologic
apoptotic index
apoptotic index apoptotic index
26. 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.
27. Operative Considerations
Factors that preclude a
Operative Approach:
Posterior fossa craniotomy complete resection include:
Position: Prone (earlier sitting Brainstem invasion,
position – venous embolism) – generally of the floor of the
“Concorde position” fourth ventricle,
Adjacent leptomeningeal
Tumor mass is often soft,
spread with coating of the
fleshy, and vascular –
subarachnoid spaces, and
characteristically “suckable”
Significant supratentorial
Definitions of resection: extension of the primary
posterior fossa mass.
> 90% : Total or near total
51 – 90%: Subtotal resection
11 – 50%: Partial resection
< 10%: Biopsy
28. Complications
Operative mortality ~ 1% Post operative mutism:
Morbidity: 25% Typically one to several
days after removal of a
Complications: large midline cerebellar
mass.
Hematoma,
Accompanied by cerebellar
Aseptic meningitis, signs
Cervical instability, Slow recovery of
Pseudomeningocele, spontaneous speech within
1 to 3 months,
Tension pneumocephalus,
Damage to the
Postoperative mutism. -
dentatothalamocortical
Typically seen with
pathways is the underlying
dissections of the vermis
pathophysiologic
(10%)
mechanism
29. 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 than T 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 receive CSI
irrespective of LP status!!
30. Radiosensitivity of Medulloblastoma
With the possible exception of
germ cell tumors, Dq SF2 Gy
Cell Line N D0
medulloblastomas are the most 1.48 135 ~ 100
TX – 7
radiosensitive tumors.
1.62 130 ~ 120
TX – 14
1.5 153
As the table shows the D0 for Case#3
most cell lines will vary between ~180 ~ 110 0.44
DAOY
135 – 180 Gy and this indicates
the intrinsic radiosensitivity of
Large reduction in SF
tumor.
SF2 Gy = 28% (Fertil et al)
Implications:
Radiosensitive and hence high
degree of local control with post
op RT Small reduction in
Errors in treatment delivery will dose
be magnified as dose just at the
threshold is being delivered.
31. 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.
32. 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% after CSI.
Reported failures in the subfrontal region additionally indicate
the need to completely encompass the cranial and spinal
subarachnoid space
33. Target Volume
The intent of CS-RT is to deliver a cancerocidal 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
Lower border of the thecal sac
Posterior fossa - boost
35. Target Volume: Cranium
Miss will
occur here
The lower border for a conventional
cranial field if used with a block will
result in a miss of the cribriform
plate
This corresponds to the anterior
surface of the greater wing of the
sphenoid
36. Target Volume Cranium: Method 2
The 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
37. 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.
38. 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
39. Planning Overview
Localization Field Selection:
Positioning Cranial fields: Two parallel
opposing lateral fields
Classical: Prone Spinal fields:
New: Supine Conventional SSD: Two fields
Immobilization : Extended SSD: One field may
suffice
Use of binding tapes: Verification and Execution
Simple, cost effective and
easy
Use customized
thermoplastic devices
40. Problems in planning
Coverage:
Co60: 37 x 37 cm
LINAC: 40 x 40 cm
Solutions to cover the entire neuraxis:
Treat with multiple fields: Problem of field junction matching
Treat at extended SSD:
Allows single field technique
However simultaneous increase in the PDD occurs –
increased organ dose under spinal field ( PDD ∞ SSD)
Posterior fossa boost : Definition of the upper border
41. Positioning
Prone:
Better immobilization
Better extension of the chin ( reduced dose inhomogeneity in
the mandible)
Visualization of field
Supine: More patient comfort ? Anesthesia access.
Use of a small wedge to support chest – better patient
comfort.
Head position:
Extended: Most common – allows the mandible to move out of
the spinal field
Flexed: Probably straightens the cervical spine – more
homogeneous dosage.
42. Overcoming matching problems
Cranial and Spinal field divergence:
Using half beam block technique (now in use in PGI).
Using collimator – couch rotation technique.
Using planned gaps
Using other methods:
Using partial transmission blocks
Widen the penumbra so
Using penumbra generators
that abutting fields can be
Using wedges used without dose
Using beam spoilers inhomogeneity
Using vibrating jaws
Spinal field divergence:
Gap is given calculated as per formula. (Von Dyke Method)
Abutting fields treated with the “Double – Junction” technique
(aka spinal shift technique)
43. 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.
44. Determining collimator rotation
Collimator rotation allows SSD
Coll θ = arc tan (L1 /2 x SSD)
cranial field to match
For Co60 SSD = 80
spinal field divergence
L1
Zone of overlap of spinal field if collimator rotation is
not applied in cranial field
45. Determining couch rotation
SAD
L2 ( Length of cranial
field)
Cranial field
Zone of
overlap
Couch rotation
during
Spinal field
treatment of
cranial field
Couch θ = arc tan (L2/2 x SAD)
For Co60 SAD = 80
θ
46. Uncertainties due to rotations
The lesser separation at the neck can increase the dose to
the spinal cord.
Use of LINAC with flattening filters can result in overdose at
the lateral edges due to the overflattening at the field edges.
Due to the couch rotation the cranial portions of the skull can
move away and get treated a greater SSD (resulting in
underdosage)
Conversely in case of the spinal cord the lower SSD will
result in an increased dose.
Areas of the opposite lower temporal lobe can get lower
dose if customized blocks are used – lower border of the
cranial fields need to be more generous.
47. Other Issues
Where to place the cranio-spinal field junction?
High Junction : C1 or C2 usually
Low Junction : Lowest point of neck where shoulders can be
excluded (C5 - C7)
High Junction Low Junction
48. Placement of CSI Junction
High Junction:
Reduces the spinal cord dose (50% reduction in overdose as
compared to low junction)
Low Junction:
Reduces the dose to the mandible, thyroid, larynx and pharynx
(varying from 30% to the thyroid to 279% to larynx)
Exact impact of the increased dose is uncertain as the absolute dose
in the high junction technique to larynx is 28 Gy when 36 Gy target
dose is delivered with 6 MV photons.
Also allows the spinal field to be increased cranially in when
“feathered gap” technique is used.
49. Cranial Field Divergence
As the lateral cranial fields
diverge a dose to contralateral
eye is expected.
Pinkel et al give a method to
prevent this from happening
( described for Acute
leukemias initially)
They recommend that the
center of the cranial fields are
to be kept behind the eye to
minimize divergence to the
opposite eye
Caution: Reduced separation
Isocenter
(less dose at mid brain)
behind globe
Lesser Dose here !!
50. Aligning Spinal Fields
The two spinal fields can be aligned by various method:
Abutting fields: Will result in increased dose to the spinal
cord.
Techniques are available to overcome this problem:
Using the “Double Junction” technique
Using penumbra generators
Using partial transmission blocks
Using wedges
Using beam spoilers
Field gap technique: Will result in a cold spot above and a hot
spot in the deeper tissues.
“Feathering” of the gap can smoothen out the dose gradients
N.B.: Half beam block technique can't be used (as used in cranial field)
51. Double Junction technique
Lower Spine
Upper Spine
Day of Planning
Upper Spine Lower Spine
Day 1: The upper spinal
field is shortened
Upper Spine Lower Spine
Day 2: The lower spinal field is
shortened
Junction on D 1 Junction on D 2
52. Double Junction Technique
Method to ensure dose
homogeneity without the need for
gaps.
Described: Johnson and Kepka
(Radiology, 1982)
Principle : An overlapping
segment is treated with two
different fields on alternate days
The junction is therefore
automatically feathered on
alternate days
Receives homogeneous dose 50%
of the time
Receives junctional dose in the
remaining 50% time.
No cold spots are generated
54. Calculation of Field Gap
SSD 1 SSD 2
S = ½ (L1 x D / SSD1) + ½ (L2 x D / SSD2)
S
L2
L1
D
55. Gap Feathering
“Feathering” refers to
movement of the junction of
the two fields across the
treatment length.
Purpose:
Reduce overdose (due to
overlap)
Reduce underdose (due to
gap)
Allows a longer segment of
the cord to be exposed to
more homogeneous dose
Feathering also reduces
As the treatment progresses the under-
the impact of setup errors.
/over -dose gets spread over a greater
area of the spinal cord allowing more
homogeneous dose distribution
56. Gap Feathering..
2 mm overlap
No gap
2 mm gap
No Feathering Feathering
57. Clinical Marking
Cranial field
Position :
Supine
Ask patient to stare up straight to the ceiling
Draw a line along the pupillary line on the forehead : Line 1
Draw a line joining the lobule of the ear and the lateral canthus of the
eye and extend it to the former line: Line 2
With patient prone draw on the neck a line 6 cm transversely along
the C2 / C3 vertebrae: Line 3
Extend line 2 to the back to join line 3
Give gap of 1 – 0.5 cm with the spinal field and draw the spinal fields.
Posterior fossa
Anterior border: 2 cm Anterior to the tragus
Superior border 2.5 – 3 above the superior border of the zygoma
Inferior border below ear lobule
Posterior border: Keep open
59. Departmental planning process
Step 1: Positioned prone with
special prone face rest.
Step 2: Immobilization with
customized 4 or 5 clamp
thermoplastic cast.
Step 3: Table raised and moved
so that the tip of the C2 or C3
vertebrae is bought to the
treatment isocenter – using
lasers / gantry rotation tech.
60. Departmental planning process
Step 4: Gantry rotated to 270°
and a large 30 x 20 cm field is
opened (for younger children
smaller field sizes).
Step 5: X-ray film taken after
noting the SFD and markings
done on the cast – SSD is also
noted. Opposite side also
marked.
Step 6: Gantry rotated back to
0°
Step 7: Width of the upper
Spinal field is now changed to
6 cm(8 cm in older children)-
length remains same
61. Departmental planning process
Step 8: Markings made on the cast
to note the lowermost field extent
and the lateral field edges (as per
definition of target volume).
Step 9: Lower spinal field is now
simulated after moving the table
“in” (towards gantry)
Step 10: Again a field of requisite
length and width opened (usually
18 x 6 cm).
62. Departmental planning process
Step 12: Gap of 1 - 1.2 cm
is given.
Step 14: The table is
lowered to bring SSD to
100.
Step 13: Checked
fluroscopy to ascetain that
the lower border is at the
level of S2 vertebrae.
Step 14: Markings made on
the skin to note the borders.
63. Departmental planning process
Step 14: In the TPS X-rays
are scanned and half beam
block are placed:
Cranial field: The caudal
portion of the field (spinal
portion) is blocked upto
isocenter.
Spinal field: The cranial
portion of field blocked
upto isocenter.
Step 15: Treatment executed
after aligning patient with
lasers in the machine with
the 3 isocenter marks placed
in simulator.
64. Specimen of filled card
Note the alignment
of the prone face rest
Instruction for
biweekly hemogram
Instruction for
posterior fossa boost
65. Disadvantage of the half beam technique
Requires asymmetrical jaws.
10% - 25% dose inhomogenity at the match line
Width of inhomogeneous strip is 2 -4 mm.
In event of misaligned jaws or improper movement unintended dose
inhomogeneities
Increase divergence to opposite eye under the block.
Spinal field size reduced – two fields needed in most children.
Dose with fields
abutting
0.6 cm wide
66. Hockey Stick Technique
Designed by Tokars et al 1966
Used extended SSD of 170 cm with field size
of 70 cm
After 1000 rad post fossa boost was given
Delivered 100 rad per day
Total dose 4000 rad over 40 #
Pair of customized blocks designed for two
days
Tokars et al , Cancer 1979
D1 D2
67. Monitoring during CSI
CSI results in predictable, if quantitatively variable, acute changes
in the peripheral blood counts.
Neutropenia or thrombocytopenia are most often noted during or
after the third week of CSI.
Traditionally, CSI is interrupted if:
The TLC falls below 3000 per cumm
The neutrophil count falls below 1,000 cells per milliliter
Platelet count falls below 80,000 per cumm
Any neutropenia with fever or thrombocytopenia with bleeding
manifestations
If blood counts necessitate interrupting CSI for more than 2
consecutive days, initiation of posterior fossa irradiation can be
done
In PGI a biweekly hemogram is done – one on Monday and the
next on Thursday.
68. Posterior fossa Irradiation
Rationale: Majority of the the
failures occur at this site only.
The borders for the post fossa
boost are:
Anterior: Anterior to posterior
aspect of clivus
Posterior border: In air (defined on
the basis of internal occipital
protuberence)
Inferior border: C2 lower border
Superior border: Impact of the orientation of the line
joining the foramen magnum to the
rd
2/3 distance from foramen skull on the definition of the posterior
magnum to the skull (POG # fossa boundary. Drayer et al IJROBP
9032) 1998.
½ to 2/3rd the distance from
foramen magnum to the skull
(Halperin)
69. Posterior fossa irradiation
Drayer et al have proposed a method
to mark the superior border.
AB – Line joining the posterior clinoid
to the internal occipital protuberence
DE – Bisects AB and is perpendicular
to it extending from the base of skull to
the inner table of superior skull.
Midpoint of line DE corresponds to the
apex of the tentorium.
Another convinient landmark in adults
– calcified pineal gland
70. Dose, Time and Fractionation
Craniospinal irradiation:
36 Gy in 20 # over 4 weeks to the cranium
Dose per fraction: 1.8 Gy
30 Gy in 20 # over 4 weeks to the spine
Dose per fraction: 1.5 Gy
Posterior fossa boost
18 Gy in 10 # over 2 weeks to the posterior fossa.
Dose per fraction: 1.8 Gy
71. Results: RT alone
Reference Year Patients 5 yr survival 10 yr survival
Hirsch et al 1964-76 57 54% NA
Mazza et al 1970-81 45 27% NA
Merchant et al 1979-94 100 50% 25%
Khafaga et al 1976-91 149 53% 38%
Punita et al 1991-99 36 54% NA
Selected results of Childhood Medulloblastomas
Reference Year Patients 5 yr survival 10 yr survival
Kopelson et al 1962-69 17 46% 46%
Hughes et al 1960-81 15 63% 38%
Bloom et al 1952-81 47 54% 40%
Frost et al 1955-88 48 62% 41%
Prados et al 1975-91 47 60% NA
Selected results of adult Medulloblastomas
72. Patterns of failure
Median time of recurrence ~ 20 months
Collin's rule: Period of risk – “age at diagnosis + 9 months”
Previous studies show – PF common site of failure
Recent studies – PF and Leptomeningeal failure common
together
Also with use of CCT and better RT more recurrences noted
systemically.
Fukunaga-Johnson et al 1998 , IJROBP
73. Sequele of Rx
2-4 point decline in IQ every year
Enoocrine Dysfunctions: GH
Growth disturbances
Induction of 2nd malignancy – 2 –
3%
Future fertility
74. CSI Controversies
Can we omit supratentorial irradiation?
M4 French Cooperative Study Group (Bouffet et al, 1992)
55 Gy to the PF and 36 Gy to the spine @ 1.8 Gy fractions +
preirradiation 8 drug – 1 day CCT x 2 + High dose Mtx x 2
Delayed RT till 5 -7 weeks
Good risk patients
High relapse rate in supratentorium – 69%
18% alive after 6 yrs!!
Premature study closure - “supratentorial radiotherapy may not be
avoided.”
M7 French Cooperative Study Group (Jentet et al 1995)
Added low dose supratentorial radiation 27 Gy
28% of patients who had relapsed has supratentorial disease
26% patients received > 30 Gy (Protocol violation)
In poor risk patients – 7 yr DFS 69% in patient with protocol
violation (vs 52% in others)
ANSWER: NO!!
75. CSI Controversies..
Can Lower CSI dose be given?
MED84 trial – SIOP (Neidhart et al 1987)
25 Gy / 20# vs 35 Gy / 25# in good risk patients
In low dose group more frequent relapses after 1st year
1st CCSG study: Evans et al (J Neurosurgery 1990)
Significant association between low dose and poor EFS
CCSG & POG study (Deutch et al 1991)
36 Gy / 23# vs 23.4 Gy / 13# in good risk patients
Lower dose increased risk of recurrence
Hughes et al (Cancer 1998)
Small reduction in survival with spinal cord doses < 27 Gy (60%
vs 69%)
However local spinal control not different
76. CSI Controversies..
Goldwein et al (Cancer 1991)
Used 18 Gy in 10# with 50 – 55 Gy PF boost + Vincristine during
RT + Vincristine & CCNU after RT – good risk patients
All patients younger than 5 yrs.
3/10 patients relapsed – study closed
All had relapsed at the spine
CCG-923/POG #8631 (JCO 2000)
Comparison of 23.4 Gy CSI vs 36 Gy
EFS at 8 yrs 52% (vs 69%) in the low dose group (p = 0.08)
Significantly increased risk of neuraxis failure
ANSWER: Lower dose of CSI alone results in poorer control and
survival especially when doses < 27 Gy are delivered. The defecit is
not made up by addition of CCT when dose is below 20 Gy. CSI
alone in doses below conventional ones are not recommended for
any group of patients.
77. CSI Controversies..
Is posterior fossa boost necessary?
Silverman et al (IJROBP 1982)
71% of failures occurred in the posterior fossa.
Hughes et al (Cancer 1988)
78% failures occurred in the posterior fossa
CCSG trial (Deutch et al - 1991)
Posterior fossa was 1º site of failure in 54% after doses were
standardized to 50 – 55 Gy.
Fukugana et al (IJROBP 1998)
Posterior fossa as one of the sites of the failures in almost 91% patients
who relapsed after treatment.
ANSWER: Posterior fossa boost remains a very important
component of craniospinal irradiation
78. CSI Controversies..
Dose to the posterior fossa?
Berry et al (Neurosurgery, 1981): Local control at the PF
79% for greater than 53.5 Gy (N = 14),
82% for 52-53.5 Gy (N = 34),
75% for 50-51 Gy (N = 38)
42% for less than 50 Gy (N = 33)
Silverman et al: (IJROBP 1982)
Dose > 50 Gy :
80% local control at 5 yrs
85% survival at 5 yrs
Dose < 50 Gy :
38% local control at 5 yrs
38% survival at 5 yrs.
Hughes et al (Cancer 1988): Local control at 5 yrs at the PF
Dose > 50 Gy : 78%
Dose < 50 Gy : 33%
ANSWER: Doses ≥ 50 Gy are essential for better local control
79. CSI Controversies..
How much high dose to posterior fossa?
Wara et al (IJROBP, 1999):
Hyperfractionated RT with total dose of 79Gy to the posterior
fossa (Phase II)
Adjuvant CCT given to high risk (CCNU, cisplatin, and vincristine)
43.7% had failures outside the primary site.
Three-year PFSs
63% - good risk
56% - poor risk
ANSWER: Thus doses more than 54 Gy may not be effective in
preventing local recurrences further.
80. Role of Adjuvant Chemotherapy
Biological rationale:
Vascular tumors
High growth fraction
Experience extrapolated from other childhood tumors
(including PNETs)
Settings for adjuvant CCT:
Post-operative : In infants and children < 3 yrs to delay / avoid
RT
Post RT:
In high risk patients: To improve cure rates
In average risk patients: To allow reduced RT dose
82. Adjuvant CCT in High Risk
Many trials – few randomized comparisons with standard RT alone
arms.
Randomized trials in both CCG and SIOP) between 1978 and
1981 documented the impact of adjuvant chemotherapy
(lomustine and vincristine, with prednisone added in the CCG
study)
Significant improvement in disease control and survival among
patients with locally advanced, incompletely resected, and
metastatic disease.
Particularly the study conducted by Evans et al (CCG) showed a
significant difference in the 5 yr EFS of 46% vs 0% in the patients
who had not received CCT. (Evans , 1990)
Packer et al (1994) administered adjuvant VCR + Cisplatin +
CCNU after CSI (with concomitant VCR) – 85% EFS in 63 patients
with high risk medulloblastomas.
83. Adjuvant CCT in High risk
In contrast two randomized trials conducted by Tait et al (1990)
and Kirscher (1991) showed no significant benefit of CCT with
VCR+CCNU or MOPP respectively.
Adjuvant CCT may improve the disease control rates but long term
follow up studies will be required to assess the impact on the OS.
May be suitable in patients with disseminated disease at
presentation.
The considerable additive cost and toxicity are deterrents to
routine implementation in 3rd world countries.
84. Adjuvant CCT in average risk
Packer et al reported on the largest series of patients treated with
adjuvant CCT following low dose CSI
421 patients with non disseminated medulloblastoma
Age > 3yrs
Randomly assigned to treatment with 23.4 Gy of CSRT, 55.8 Gy of
posterior fossa RT, plus
Cisplatin + CCNU + VCR x 8 cycles
Cisplatin + Cyclophosphamide + VCR x 8 cycles
5 year EFS and OS were 81% and 86% respectively
Considerable Rx toxicity: (Grade III/IV)
Hematologic: 98%
Hepatic: 12%
Renal 12%
Nervous System 50%
Hearing 28%
Infections 30%
Also no comparison with standard RT alone arm !!
85. Adjuvant CCT to delay RT
Pediatric Oncology group: (Duffner et al, NEJM, 1993) n = 198
Planned 12 – 24 months adjuvant CCT to defer RT till the age of 3 yrs
Two cycle of Vincristine + Endoxan → One cycle of Cisplatin + Etoposide
CSI delivered after CCT (after 3 yrs age)
2 yr PFS 34%
CCG:(Geyer et al, JCO, 1994)
8 drugs in 1 day regimen after surgery
43% response rates
3 yr PFS 22%
CCG 9921(Geyer et al JCO, 2005) n = 299
CCT delivered as follows:
Induction CCT with Cisplatin/Carboplatin, Vincristine, Cyclophosphamide
and Etoposide
Maintainence CCT with VCR, Etoposide, Carboplatin & Endoxan
5 yr EFS was 32%
72% response rates
RT could be avoided in 50% patients.
86. Adjuvant CCT to delay RT: Issues
Approach may be used in a trial setting in children < 3yrs age.
RT is always given in the event of disease progression (eventually
RT given in 50% patients)
Patients with Gross total excision and those with M1 or M0
disease fare the best.
Compliance with future RT poor (delivered in 40% patients actually
intended)
Considerable chemotoxicity:
Universal nausea and vomiting
Grade III and IV hematological toxicity : 90% - 100%
2% - 4% children die due to treatment related causes
15% - 20% children suffer serious infections
1% risk of 2nd malignancies (AML)
Considerable ototoxicity (Cisplatin)
87. Pre irradiation CCT
Rationale: Post RT microvascular changes may impair drug
delivery
CCG study (Zelter et al) -1995:
Only Poor risk patients
CSI → Adjuvant CCT (CCNU+Vincristine)
8 Drug 1 day CCT x2 → CSI → 8 Drug 1 day CCT x 8
Patients receiving preirradiation CCT had poorer outcome. (55% vs
62%)
SIOP study (Bailey et al) – 1995:
Immediate CSI vs Pre RT CCT with MVP for 6 weeks
Statistically significant poorer outcome in study arm if RT dose less.
GCG (Kuhl et al) – 1998:
Poor risk patients
CSI → Adjuvant Cisplatin + Vincristine
Preirradiation CCT with 7 drugs → CSI
Poorer OS in preirradiation CCT arm (55% vs 86%)
Preirradiation CCT can thus reduce OS , increase relapse and impair
delivery of radiation in the poor risk patient
89. Importance of RT quality
SFOP study (IJROBP 45, 1999) – Carrie et al
3 yr relapse rates:
No protocol deviation: 23%
Protocol deviation: 36.9% (p = NS)
Impact of number of deviations on relapse rates:
1 Major deviation: 17%
2 Major deviations: 67%
3 Major deviations: 78% (p = 0.04)
Impact of eye block positioning:
With deviation: Relapse in 5/28
Without deviation: No relapse
Conclusion: Improvement in the local control rates in the
past 2 decades attained by improved RT technique(?)
90. PGI results
Retrospective review of 55 children (2000-04)
75% patients were males
Median symptom duration – 3 months
71% classical medulloblastoma and 75% were located in midline
Only 38% had complete surgery done
81% could complete CSI
56% received CCT ( MC Cisplatin + Etoposide)
Leucopenia was the most severe toxicity – 54%
Acturial 2 yr DFS – 52%
Completeness of Sx most important factor influencing survival
23% patients failed at the PFS
91. Conclusions
Medulloblastomas are radiosensitive and curable also in a
significant number of patients
Adequate surgery and good quality radiotherapy forms the
corner stone of management
Late term neurological sequlae are considerable specially in
children < 3 yrs
Adjuvant chemotherapy may allow CSI dose reduction and
improve results
93. Target Volume Cranium: Method 1
A = Inferior border of the
orbit
C= posterior margin of the
mandibular angle
E= Tip of the mastoid
B= Point of intersection of
the perpendicular from point
C on a straight line joining A
and E.
D= Anterolateral margin of
the orbit.
94. Penumbra Generators
Use specially shaped metal
blocks at the beam periphery
so as to generate an widened
penumbra.
Two such abutted fields will
result in almost homogeneous
dose
Homogeneous dose
profile at the beam
abutment region
Penumbra field 1
Penumbra field 2
3 cm
