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  1. 1. Management of Medulloblastomas Moderator: ? Department of Radiotherapy PGIMER, Chandigarh
  2. 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. 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. 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.
  5. 5. Relevant Neuroanatomy 2. Foramen of Magendie 3. Foramen of Luschka
  6. 6. CSF pathways
  7. 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. 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. 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. 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. 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. 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. 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. 14. Microscopic Appearance Highly cellular tumor High N:C ratio “Carrot shaped” nucleus Cells arranged in typical Homer – Wright rosettes Multiple histological subtypes
  15. 15. Other Variants Neuroblastic Medulloblastoma Desmoplastic Medulloblastoma Medullomyoblastoma Large Cell Medulloblastoma
  16. 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. 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. 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. 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. 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. 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. 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.
  23. 23. Laurent's Classification: MAPS M= Metastasis A= Age S: Surgery P= Pathology
  24. 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
  25. 25. Management Summary Medulloblastoma Patient stable Patient extremely somnolent High dose steroids + MRI Gross excision ± Ventriculostomy Age < 3 yrs Craniospinal Radiation Chemotherapy + PF boost RT/ Re-excision High Risk Chemotherapy
  26. 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. 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. 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. 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. 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. 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. 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. 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
  34. 34. Bony Skull Anatomy
  35. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
  53. 53. Field Gap Technique SSD 1 SSD 2 S L1 L2 Hot Spot Cold Spot
  54. 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. 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. 56. Gap Feathering.. 2 mm overlap No gap 2 mm gap No Feathering Feathering
  57. 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
  58. 58. Half Beam Blocking Actual Field Length Actual Field Length Spinal field
  59. 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. 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. 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. 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. 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. 64. Specimen of filled card Note the alignment of the prone face rest Instruction for biweekly hemogram Instruction for posterior fossa boost
  65. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
  81. 81. Chemotherapy schedules Single agent CCNU: 8-in-1 regimen Methyl PDN 300 mg/m2 Lomustine 100 -130 mg/m2 6 weekly Vincristine 1.5 mg/m2 PCV CCNU 75 mg/m2 Procarbazine 60 – 75 mg/m2 PO D18 Procarbazine 75 mg/m2 – 21 Hydroxyurea 1500 mg/m2 CCNU 110-130 mg/m2 PO D1 Cisplatin 60 mg/m2 Vincristine 1.4 mg/m2 IV D8 and D29 Cytarabine 300 mg/m2 Cisplatin-Etoposide: Endoxan 300 mg/m2 Cisplatin 30 mg/m2 IV D1 – D3 CVP Etoposide 100 mg/m2 IV D1 – D3 CCNU 75 mg/m2 CCV Vincristine 1.5 mg/m2 CCNU 75 mg/m2 Prednisone 40 mg/m2 Cisplatin 75 mg/m2 Vincristine 1.5 mg/m2
  82. 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. 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. 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. 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. 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. 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
  88. 88. Recurrent Medulloblastomas
  89. 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. 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. 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
  92. 92. Thank You Moderator: ? Department of Radiotherapy PGIMER, Chandigarh
  93. 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. 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