Medulloblastomas

Moderator:?Department of RadiotherapyPGIMER, Chandigarh

Management of Medulloblastomas

IntroductionIntroduction

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 presentationHigh intrinsic radiosensitivityPropensity for intracranial spread via the CSF pathwaysPotential for metastatic spread

HistoryHistory

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

In 1925, changed name to medulloblastoma – from “medulloblast” - a hypothetical multipotent cell

Percival Bailey

Harvey Cushing

IncidenceIncidence

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

1½ – 2 times more common in males.

Peak incidence at the age of 5 – 6 yrs.

Medul-loblastoma

Cerebral low gradeAstrocy-

Cerebellar Astrocy-toma

Ependymoma

High grade Astrocy-toma

Brain Stem Glioma

Others

Relevant NeuroanatomyRelevant Neuroanatomy

2. Foramen of Magendie3. Foramen of Luschka

CSF pathwaysCSF pathways

Raised ICT Symptoms and signsRaised 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

Other Signs and SymptomsOther Signs and Symptoms

Ataxia, long-tract signs, or cranial neuropathies

Initial cerebellar dysfunction may be insidious:

Clumsiness, worsening handwritingDifficulty with hopping or runningSlow or halting speech

Midline cerebellar masses lead to truncal unsteadiness or increased ICP.

Duration of symptoms : Lesser duration poorer prognosis (Halperin et al)

Adult vs Pediatric MedulloblastomasAdult vs Pediatric Medulloblastomas

Usual age ~ 4 – 8 yrs

Shorter clinical History (~ 3 months)

Classical type predominates

Median cerebellar syndrome predominates

72% pediatric cases are median in origin

Biologically more aggressive – more labeling index and less apoptotic index

Poorer resectability – median location

Higher surgical morbidity and mortality

Poorer RT tolerance

Poorer long term survival

Median age ~ 24 – 30 yrs

Longer history ( ~ 5 months)

Desmoplastic type relatively commoner

Lateral cerebellar syndrome seen

45% are median in origin and 43% lateral

Biologically less aggressive – less labeling index and more apoptotic index

Greater resectability - lateral location

Lower surgical morbidity and mortality – impact of location and age

Better RT tolerance

Better long term survival

Medulloblastoma in < 3 yrsMedulloblastoma in < 3 yrs

Comprehensive review by Saran et al (IJROBP , 1998)

Accounted for 25% of all pediatric medulloblastomasAverage 5 yr RFS ~ 40% - 45%

Higher frequency of disseminated disease at presentationLater presentation due to lack of closure of cranial suturesLower 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 RTPoorer RT toleranceUnusual HP subtype : ATRT ( Atypical Teratoid/ Rhabdoid tumor) – associated with very poor prognosis – recently recognized.

Natural HistoryNatural 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

Extra neural spreadExtra 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

Pathology: Gross AppearancePathology: 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.

Microscopic AppearanceMicroscopic Appearance

Highly cellular tumor

High N:C ratio

“Carrot shaped” nucleus

Cells arranged in typical Homer – Wright rosettes

Multiple histological subtypes

Other VariantsOther Variants

Large Cell Medulloblastoma

Desmoplastic Medulloblastoma Neuroblastic Medulloblastoma

Medullomyoblastoma

OriginOrigin

Classical :Fetal remnant cells in the external granular layers of the cerebellum

WHO: Classifies Medulloblastomas under the category of embryonal neoplasms:

MedulloblastomaEpendymoblastomaPNETs

PNET

Medulloblastoma

Ependymoblastoma

Pineloblastoma

Cerebral Neuroblastoma

Esthesioneurblastoma

Medulloepithelioma

NeuroimagingNeuroimaging

CT appearance

Hyperattenuated, well-defined vermian cerebellar massSurrounding vasogenic edemaEvidence of hydrocephalusHomogeneous contrast enhancementCyst formation (59% of cases) Calcification - uncommon

NeuroimagingNeuroimaging

MRI features:

Iso- to- hypointense relative to white matter (T1 images)Hyperintense in T2 weighted imagesEnhance following contrastHeterogeneous enhancement.Vasogenic edema +

Adult Medulloblastomas:

Poorly defined masses located in the cerebellar hemisphereCyst like regions are more commonly seenAbnormal leptomeningeal enhancement (cf. Meningioma) – desmoplatic variant

Metastatic diseaseMetastatic disease

Leptomeningeal disease:

Spinal cord is the most common siteMost metastases are found along the posterior margin of the spinal cord – CSF flow from cisterna magna to posterior margin of spinal cordSupratentorial involvement frequently involves the frontal and subfrontal regionsSulcal and cisternal effacementEpendymal-subependymal enhancementWidened tentorial enhancementCommunicating hydrocephalus

Staging SystemsStaging 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 SystemHalperin System

Chang's Staging SystemChang'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)

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

StagingStaging

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.

Laurent's Classification: MAPSLaurent's Classification: MAPS

M= Metastasis

A= Age

P= PathologyS: Surgery

Risk GroupingRisk Grouping

Factors Average Risk Intermediate risk Poor risk

Age 7 yrs or greater NA 3 yrs or youngerHistology Undifferentiated Differentiated Rhabdoid elements

Biologic

Extent of Disease

Posterior Fossa, Not invading the brain stem

Tumor cells or clumps in CSF; ? Brain stem

involvement

Disseminated with intracranial or spinal

diseaseExtent of resection

Total ; Near total; <1.5 cm2 residual

? Subtotal; > 1.5 cm2 residual

Biopsy or minimal resection

? Diploid; High apoptotic index

? Aneuploid, ? Isochromosome 17q, low

apoptotic index

? C- myc amplification, low apoptotic index

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.

Management SummaryManagement Summary

Medulloblastoma

Age < 3 yrs

Gross excision ± Ventriculostomy

Chemotherapy Craniospinal Radiation + PF boost

Chemotherapy

High RiskRT/ Re-excision

Patient stablePatient extremely

somnolentHigh dose steroids + MRI

Pre-surgical ManagementPre-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.

Operative ConsiderationsOperative Considerations

Operative Approach: Posterior fossa craniotomy

Position: Prone (earlier sitting position – venous embolism) – “Concorde position”

Tumor mass is often soft, fleshy, and vascular – characteristically “suckable”

Definitions of resection:

> 90% : 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.

ComplicationsComplications

Operative mortality ~ 1%

Morbidity: 25%

Complications:

Hematoma,Aseptic meningitis, Cervical instability, Pseudomeningocele, Tension pneumocephalus,Postoperative mutism. - Typically seen with dissections of the vermis (10%)

Post operative mutism:

Typically one to several days after removal of a large midline cerebellar mass.Accompanied by cerebellar signsSlow recovery of spontaneous speech within 1 to 3 months,Damage to the dentatothalamocortical pathways is the underlying pathophysiologic mechanism

Interesting correlatesInteresting 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!!

Radiosensitivity of Medulloblastoma Radiosensitivity of Medulloblastoma

With the possible exception of germ cell tumors, medulloblastomas are the most radiosensitive tumors.

As the table shows the D0 for most cell lines will vary between 135 – 180 Gy and this indicates the intrinsic radiosensitivity of tumor.

SF2 Gy = 28% (Fertil et al)

Implications:

Radiosensitive and hence high degree of local control with post op RT

Errors in treatment delivery will be magnified as dose just at the threshold is being delivered.

Cell Line N D0 DqTX – 7 1.48 135 ~ 100

TX – 14 1.62 130 ~ 120Case#3 1.5 153DAOY ~180 ~ 110 0.44

SF2 Gy

Small reduction in dose

Lar

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educ

tion

in S

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Craniospinal Irradiation: HistoryCraniospinal 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.

Rationale for CSIRationale 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

Target VolumeTarget 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 CSFSpinal cord and the leptomeninges with CSFLower border of the thecal sacPosterior fossa - boost

Bony Skull AnatomyBony Skull Anatomy

Target Volume: CraniumTarget 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

Target Volume Cranium: Method 2Target 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

Target Volume Spinal FieldTarget 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.

Target Volume Spinal FieldTarget 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

Planning OverviewPlanning Overview

Localization

Positioning

Classical: Prone

New: Supine

Immobilization :

Use of binding tapes: Simple, cost effective and easy

Use customized thermoplastic devices

Field Selection:

Cranial fields: Two parallel opposing lateral fields

Spinal fields:Conventional SSD: Two fieldsExtended SSD: One field may suffice

Verification and Execution

Problems in planningProblems 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 matchingTreat at extended SSD:

Allows single field techniqueHowever simultaneous increase in the PDD occurs – increased organ dose under spinal field ( PDD ∞ SSD)

Posterior fossa boost : Definition of the upper border

PositioningPositioning

Prone:

Better immobilizationBetter 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.

Overcoming matching problemsOvercoming matching problems

Cranial and Spinal field divergence:

Using half beam block technique (now in use in PGI).Using collimator – couch rotation technique.Using planned gapsUsing other methods:

Using partial transmission blocksUsing penumbra generatorsUsing wedgesUsing beam spoilersUsing 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)

Widen the penumbra so that abutting fields can be used without dose inhomogeneity

Collimator – couch rotationCollimator – 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.

Determining collimator rotationDetermining collimator rotation

Zone of overlap of spinal field if collimator rotation is not applied in cranial field

SSD

L1

Collimator rotation allows cranial field to match spinal field divergence

Coll θ = arc tan (L1 /2 x SSD)For Co60 SSD = 80

Determining couch rotationDetermining couch rotation

Spinal field

Cranial fieldZone of overlap

Couch rotation during treatment of cranial field

Couch θ = arc tan (L2/2 x SAD)For Co60 SAD = 80

θ

L2 ( Length of cranial field)

SAD

Uncertainties due to rotationsUncertainties 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.

Other IssuesOther 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

Placement of CSI JunctionPlacement 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.

Cranial Field DivergenceCranial 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 (less dose at mid brain)

Isocenter behind globe

Lesser Dose here !!

Aligning Spinal FieldsAligning 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)

Double Junction techniqueDouble 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

Double Junction TechniqueDouble 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

Field Gap TechniqueField Gap Technique

SSD 1SSD 2

L2 L1S

Hot SpotCold Spot

Calculation of Field GapCalculation of Field Gap

SSD 1 SSD 2

L1 L2

S

D

S = ½ (L1 x D / SSD1) + ½ (L2 x D / SSD2)

Gap FeatheringGap 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 doseFeathering also reduces the impact of setup errors.

As the treatment progresses the under-/over -dose gets spread over a greater area of the spinal cord allowing more homogeneous dose distribution

Gap Feathering..Gap Feathering..

2 mm overlap

No gap

2 mm gapNo Feathering Feathering

Clinical MarkingClinical Marking

Cranial field

Position :

SupineAsk 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

Half Beam Blocking Half Beam Blocking

Spinal fieldActual Field Length

Actual F

ield Length

Departmental planning processDepartmental 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.


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


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).


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.


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.

Specimen of filled cardSpecimen of filled card

Note the alignment of the prone face rest

Instruction for biweekly hemogram

Instruction for posterior fossa boost

Disadvantage of the half beam techniqueDisadvantage 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

Hockey Stick TechniqueHockey 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

D1 D2

Tokars et al , Cancer 1979

Monitoring during CSIMonitoring 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.

Posterior fossa IrradiationPosterior 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 clivusPosterior border: In air (defined on the basis of internal occipital protuberence)Inferior border: C2 lower borderSuperior border:

2/3rd distance from foramen magnum to the skull (POG # 9032)½ to 2/3rd the distance from foramen magnum to the skull (Halperin)

Impact of the orientation of the line joining the foramen magnum to the skull on the definition of the posterior fossa boundary. Drayer et al IJROBP 1998.

Posterior fossa irradiationPosterior fossa irradiation

Drayer et al have proposed a method to mark the superior border.

AB – Line joining the posterior clinoid to the internal occipital protuberenceDE – 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

Dose, Time and FractionationDose, Time and Fractionation

Craniospinal irradiation:

36 Gy in 20 # over 4 weeks to the craniumDose per fraction: 1.8 Gy

30 Gy in 20 # over 4 weeks to the spineDose 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

Results: RT alone Results: RT alone

Reference Year Patients 5 yr survival 10 yr survivalKopelson 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

Reference Year Patients 5 yr survival 10 yr survivalHirsch et al 1964-76 57 54% NAMazza et al 1970-81 45 27% NAMerchant 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

Patterns of failurePatterns 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

Sequele of RxSequele of Rx

2-4 point decline in IQ every year

Enoocrine Dysfunctions: GH

Growth disturbances

Induction of 2nd malignancy – 2 – 3%

Future fertility

CSI ControversiesCSI 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 2Delayed RT till 5 -7 weeksGood risk patientsHigh 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 Gy28% of patients who had relapsed has supratentorial disease26% 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!!

CSI Controversies..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 patientsIn 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 patientsLower 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


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 patientsAll patients younger than 5 yrs.3/10 patients relapsed – study closedAll had relapsed at the spine

CCG-923/POG #8631 (JCO 2000)Comparison of 23.4 Gy CSI vs 36 GyEFS 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.


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


Dose to the posterior fossa?

Berry et al (Neurosurgery, 1981): Local control at the PF79% 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 PFDose > 50 Gy : 78%Dose < 50 Gy : 33%

ANSWER: Doses ≥ 50 Gy are essential for better local control


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.

Role of Adjuvant ChemotherapyRole of Adjuvant Chemotherapy

Biological rationale:

Vascular tumorsHigh growth fractionExperience extrapolated from other childhood tumors (including PNETs)

Settings for adjuvant CCT:

Post-operative : In infants and children < 3 yrs to delay / avoid RTPost RT:

In high risk patients: To improve cure ratesIn average risk patients: To allow reduced RT dose

Chemotherapy schedulesChemotherapy schedules

Single agent CCNU:

Lomustine 100 -130 mg/m2 6 weekly

PCV

Procarbazine 60 – 75 mg/m2 PO D18 – 21

CCNU 110-130 mg/m2 PO D1

Vincristine 1.4 mg/m2 IV D8 and D29

Cisplatin-Etoposide:

Cisplatin 30 mg/m2 IV D1 – D3

Etoposide 100 mg/m2 IV D1 – D3

CCV

CCNU 75 mg/m2

Cisplatin 75 mg/m2

Vincristine 1.5 mg/m2

8-in-1 regimen

Methyl PDN 300 mg/m2


CCNU 75 mg/m2

Procarbazine 75 mg/m2

Hydroxyurea 1500 mg/m2

Cisplatin 60 mg/m2

Cytarabine 300 mg/m2

Endoxan 300 mg/m2

CVP

CCNU 75 mg/m2


Prednisone 40 mg/m2

Adjuvant CCT in High RiskAdjuvant 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.

Adjuvant CCT in High riskAdjuvant 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.

Adjuvant CCT in average riskAdjuvant 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 cyclesCisplatin + 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 !!

Adjuvant CCT to delay RTAdjuvant 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 EtoposideMaintainence CCT with VCR, Etoposide, Carboplatin & Endoxan

5 yr EFS was 32%

72% response rates

RT could be avoided in 50% patients.

Adjuvant CCT to delay RT: IssuesAdjuvant 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)

Pre irradiation CCTPre irradiation CCT

Rationale: Post RT microvascular changes may impair drug delivery

CCG study (Zelter et al) -1995:Only Poor risk patientsCSI → Adjuvant CCT (CCNU+Vincristine)8 Drug 1 day CCT x2 → CSI → 8 Drug 1 day CCT x 8Patients 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 weeksStatistically significant poorer outcome in study arm if RT dose less.

GCG (Kuhl et al) – 1998:Poor risk patientsCSI → Adjuvant Cisplatin + VincristinePreirradiation CCT with 7 drugs → CSIPoorer 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

Recurrent MedulloblastomasRecurrent Medulloblastomas

Importance of RT qualityImportance 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 5/28Without deviation: No relapse

Conclusion: Improvement in the local control rates in the past 2 decades attained by improved RT technique(?)

PGI resultsPGI 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

ConclusionsConclusions

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

Moderator:?Department of RadiotherapyPGIMER, Chandigarh

Thank You

Target Volume Cranium: Method 1Target 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.

Penumbra GeneratorsPenumbra 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 23 cm

Medulloblastomas

Health & Medicine

Transcript of Medulloblastomas