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A very detailed information regarding Medulloblastoma from various books like Perez, Devita, Gunderson, Evidence based, Khan's Physics

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  1. 1. MEDULLOBLASTOMA By Dr. Ayush Garg “© Mayo Foundation for Medical Education and Research. All Rights Reserved. Used with permission.”
  2. 2. • Learning Objectives for JRs • New molecular classification system • CSF Pathway • Risk groups • Learning Objectives for SRs • Line of management in recurrence
  3. 3. • Introduction • Epidemiology • Anatomy- CSF Pathway • Clinical Features • Classification • Diagnostic Work Up • Treatment
  4. 4. Introduction • Most common childhood malignant tumors. • Accounts for 15% to 20% of all CNS tumors in children. • Median age of presentation is 6 years. • The tumor arises in the cerebellar vermis and projects into the fourth ventricle. • It is a malignant invasive embryonal tumor of the cerebellum with predominantly neuronal differentiation and an inherent tendency to metastasize via CSF pathways. • Rare tumor in adults with an incidence of 0.5 per 100,000. • In adults the 20 to 40 years age group
  5. 5. • Leptomeningeal seeding at diagnosis is 30% to 35% • Systemic spread is seen in 5% of patients, mostly to bone and bone marrow. • Overall 5-year OS & DFS is approx 70% to 85%.
  6. 6. Epidemiology • There is a 1.5:1 male-to-female ratio, and 70% of medulloblastomas are diagnosed by age 20 years. • Rarely cases found in those older than 50 years. • Gorlin and Turcot syndromes have increased rates of medulloblastoma but account for only 1% to 2% of cases • Location – Cerebellum – • Vermis (>75%) • Hemispheric – more in adults
  7. 7. • Turcot syndrome is a condition characterized by multiple adenomatous colon polyps • Gorlin Syndrome A genetic condition that causes unusual facial features and disorders of the skin, bones, nervous system, eyes, and endocrine glands.
  8. 8. Clinical Features
  9. 9. Classification
  10. 10. EMBRYONAL TUMORS OF CNS • WHO classification (2007) – Grade IV Medulloblastomas (MB) CNS primitive neuroectodermal tumors (CNS PNET) Supratentorial PNET Medulloepithelioma Ependymoblastoma Atypical teratoid / rhabdoid tumors (AT/RT) • Earlier - all tumors under the generic term PNET • Recent data support separation - Each tumor distinctive profile (morphology, immunohisto-chemical, molecular genetic & clinical)
  11. 11. Classification of Medulloblastoma (WHO 2007) Medulloblastomas (histologically defined)  Classic  4 histological variants  Desmoplastic/nodular  MB with extensive nodularity (MBEN)  Large cell MB  Anaplastic MB
  12. 12. Medulloblastoma is a densely cellular tumor with small, darkly staining ovoid cells with hyperchromatic nuclei and frequent mitoses. Homer Wright rosettes (clustered cells surrounding a central eosinophilic core) are characteristic. • Indicative of Neuronal diff. – Nuclei around a round solid central eosinophilic fibrillary zone containing cellular processes (neurofibrils) – No lumen – IHC positive for synaptophysin & neurofilament Medulloblastoma: small blue round cell tumor
  13. 13. Medulloblastoma (genetically defined) 1. Medulloblastoma WNT activated 2. Medulloblastoma, SHH activated and TP53 mutant  Medulloblastoma, SHH activated and TP53 mutant  Medulloblastoma, SHH activated and TP53 wild type 3. Medulloblastoma, group 3 4. Medulloblastoma, group 4 Medulloblastoma, non-WNT/non-SHH
  14. 14. Molecular Pathology
  15. 15. WNT (Wingless) • Least common in Medulloblastoma, found in approximately 10% of cases • WNT tumors most frequently occur in late childhood and adolescence but can arise in all ages • M:F ratio is 1:1. • Rarely metastatic • Most favorable prognosis • 5year survival>95%
  16. 16. • Tumors arise from the developing lower rhombic lip and embryonic dorsal brain stem • Prognosis- worse in adults, relative to pediatric patients • Most WNT tumors display classic medulloblastoma histology and nuclear localization of beta-catenin nucleopositivity, CTNNB1 gene mutations, and monosomy-6. • Associated with Turcot Syndrome
  17. 17. SHH (Sonic Hedgehog) • They are named after the sonic hedgehog signaling pathway, which is considered to drive tumor initiation in the majority of cases. • Incidence bimodal- infants aged <3 years and adults • M:F ratio is 1:1 • Intermediate prognosis between Group 3 and WNT • 5-year survival of approximately 70% • Associated with Gorlin Syndrome
  18. 18. • Tumors arise from neuron precursors found in the external granule layer of the developing cerebellum • The SHH MB subgroups include TP53 mutant and TP53 wild-type subgroups. • All nodular desmoplastic medulloblastomas can be characterized as SHH subgroup.
  19. 19. Group 3 • Group 3 tumors affect mostly infants and children, are rare in adults • Characterized by amplification of the MYC proto- oncogene, and almost all cases exhibit aberrant MYC expression. • M> F • Prognosis- worst (50% overall survival rate), often metastatic at the time of presentation • The majority of MBs in group 3 are classical MB and include the majority of large cell/anaplastic tumors.
  20. 20. Group 4 • Affect patients of all ages, seen in 30-40% of cases • Most common subgroup, found in 40% of all patients and associated with intermediate prognosis • They include classical and large cell/anaplastic histologies • M:F ratio is 3:1. • Association is seen with Isochromosome 17q in few cases.
  21. 21. Age distribution shown for males (solid lines) and females (dotted lines) Characteri stic WNT SHH Group 3 Group 4 Frequency ~10% ~30% ~25% ~35% Age (Yrs ) Distributed across ages median (9-10 yrs) – never in infancy Primarily in infants <3 & adults >16. Uncommon in 3-16 yrs group. Children – Peak 3 – 10 yrs. Rare in adults Distributed across ages – median: 9-10 yrs. More in adolescents
  22. 22. Diagnostic Work up • H&P • MRI of the brain (preop and postop within 24–48 h after surgery) • MRI of the spine to rule out leptomeningeal spread • CSF cytology • Baseline audiometry, IQ, TSH, CBC, and growth measurements • Eighty percent of systemic metastases are osseous. A bone scan, chest x-ray, and bilateral marrow biopsies should be routinely performed for M2 and M3 stages.
  23. 23. Radiographic Features • MRI is the gold standard. • Medulloblastomas are typically iso- to hypointense on T1- weighted images and of variable signal intensity on T2-weighted images and enhance heterogeneously. • MRI provides improved evaluation of • Foraminal extent beyond the fourth ventricle, • Invasion of the brain stem, and subarachnoid metastases. • On CT, medulloblastomas are classically discrete vermian masses that are hyperattenuated compared with the adjacent brain and enhance avidly.
  24. 24. Postoperative axial T2-weighted magnetic resonance imaging for a patient receiving craniospinal irradiation (CSI) for medulloblastoma showing extension of cerebrospinal fluid along the optic nerves to the lamina cribrosa (A) and into the internal auditory canals (B).
  25. 25. T1 (A) and T1 contrast (B) MRI in an 11-year-old boy. The typical midline location of the tumor that is causing ventricular outlet obstruction with dilatation of the third and lateral ventricles.
  26. 26. Extension of cerebrospinal fluid along the optic nerves to the lamina cribrosa (A) and into the internal auditory canals (B)
  27. 27. Cerebrospinal Fluid Cytology • Sampling of the CSF in the immediate postoperative period may lead to false-positive results • Best done before surgery or more than 3 weeks after surgery, as long as intracranial pressure is not elevated. • CSF findings: • CSF pressure above 150 mm H2O at the lumbar level in a laterally positioned patient, • elevated protein level (>40 mg/dL in the lumbar cistern), • a reduced glucose level (below 50 mg/mL), tumor cells by cytologic examination. • Tumor markers in the CSF may help in making the diagnosis.
  28. 28. • On MRI CSF dissemination is seen as diffuse enhancement of the thecal sac, nodular enhancement of the spinal cord or nerve roots, or nerve root clumping, predominantly seen along the posterior aspect of the spinal cord based on CSF circulatory patterns. • Spine MRI- Ideal time prior to surgery; otherwise, 10 to 14 days post surgery to avoid a potential false-positive interpretation from surgical cellular debris and blood products.
  29. 29. Pediatric MB Chang Criteria  primary staging system since their inception 1969  2-tier stratification system Staging Packer RJ, Goldwein J, Nicholson HS, Vezina LG, Allen JC, Ris MD, et al. Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: a Children’s Cancer Group Study. J Clin Oncol.1999;17:2127–36. A modified version of the Chang staging system is currently used.
  30. 30. M Staging  M0 represents no tumor dissemination,  M1 represents tumor cells in the CSF  M2 represents presence of gross tumor nodules in the intracranial, subarachnoid, or ventricular space  M3 represents gross tumor nodules in the spinal subarachnoid space  M4 represents systemic metastasis.
  31. 31. Current clinical risk-stratification for medulloblastoma Average-risk High-risk Age ≥3 yrs <3 yrs Residual Tumor ≤1.5 x 1.5 cm2 >1.5 cm2 Metastases No metastases (M0) Metastases (M1 – M4) Pathology Desmoplastic Anaplastic Brain Stem invasion None Present Mitotic index Low High Tumor DNA Content Diploid Aneuploid Apoptotic Index High Low DFS 60–90% 20–40%, increased to 50–85% with adjuvant chemo
  32. 32. Risk Groups • The presence of metastatic disease is prognostically significant, with 5-year PFS rates according to CCG-921: • 70% for M0 disease • 57% for M1 • 40% for M2 or higher • The disease-free survival of high-risk patients treated with CSI with or without chemotherapy is 25% to 30%
  33. 33. Management of Medulloblastoma • Previously standard of care for patients>3 years with standard-risk disease-> PORT to the craniospinal axis to a dose of 35 to 36 Gy followed by a boost to the whole posterior fossa to a total dose of 54 to 55.8 Gy • Long term results were EFS in 60% to 65% of patients • Sequelae of treatment include hormonal deficits, decreased bone growth, and neurocognitive deficits that correlate with the age of the child and the radiation dose.
  34. 34. Management of Standard-Risk Medulloblastoma • Currently, the standard of care for children with standard-risk MB is with CSRT 23.4 Gy with a boost to the tumor bed to a total dose of 54.0 Gy, followed by eight cycles of chemotherapy with vincristine, CCNU, and cisplatin.
  35. 35. Management of High-Risk Medulloblastoma According to COG study hyperfractionated accelerated radiotherapy (HART) regimen given in combination with pre- and postradiotherapy chemotherapy is being tried for high risk cases
  36. 36. Is there a role for modified fractionation? HFRT & HART Strong radio-biologic rationale SFOP pilot study- tested HFRT to a CSI dose of 36 Gy without chemotherapy, early toxicity was reduced and progression-free survival at 3 years was 81%.
  37. 37. HFRT in Medullblastoma: TMH Study • Median age: 8 years (range 5-14 years) • Risk-stratification: Average-risk disease (all patients) • CSI dose: 36 Gy/36 fx, 1 Gy BID, 6 hrs apart over 3.5 wks • Tumor bed boost: 32 Gy/32 fx, 1 Gy BID, 6 hrs apart over 3 wks • Total tumor bed dose: 68 Gy /68 fx, 1 Gy BID, 6 hrs apart over 6.5 wks • Adjuvant chemotherapy: Given only at progression • Median follow-up: 27 months (range 13-54 months) HFRT without upfront chemotherapy has an acceptable acute toxicity profile, without an unduly increased risk of relapse, with preserved cognitive functioning in children with average-risk medulloblastoma. Gupta T,IJROBP 2012
  38. 38. Is Hyperfractionated RT better than Standard fractionation in Avg risk Medulloblastoma..... SIOP PNET 4 Randomised trial Lannering, JCO 2012 • 322 Children with avg risk medulloblastoma across 122 european centres. • Standard fraction:23.4 Gy to the CS axis and 54 Gy to whole posterior fossa • HFRT: 36Gy CS and 60 Gy to Posterior fossa in 68Fractions,1Gy/# twice daily • Chemotherapy regimen consisting of eight cycles of cisplatin, lomustine, and vincristine • EFS and OS for HFRT was not superior to STRT
  39. 39. Medical Therapy Medical decompressive therapy is recommended in the pre-operative Period • The steroid of choice is dexamethasone administered in a loading dose of 0.5-1 mg/kg intravenously (with the maximum dose being 10 mg). • Subsequently, dexamethasone (0.25-0.5 mg/kg/day) iv or PO in divided doses 6-8 hourly, + antacids for GI protection. • Severe hydrocephalus may require Mannitol or frusemide • Elevation of the head-end of the bed (by 30 degrees) can help children with symptomatic hydrocephalus
  40. 40. Surgery • Complete surgical resection is ideal, but this may not always be safe or feasible. • In such cases, it is recommended to attempt maximal safe resection to avoid aggressive surgical resection that can cause significant morbidity
  41. 41. • Generally a radiosensitive & chemosensitive tumour • Historical controls: No long-term survivors without RT • High recurrence rates with focal posterior fossa (PF) RT • High recurrence rates for reduced dose craniospinal irradiation (CSI) without chemotherapy (CT) Landberg, 1953 RADIATION ALONE PF- 5% PF+SC- 25% PF+CSI- 53% Rationale of radiotherapy in medulloblastoma Radiotherapy
  42. 42. Radiotherapy • PORT should begin within 28 to 31 days following surgical resection whenever possible. • Radiotherapy is delivered to the entire craniospinal axis followed by a boost to the tumor bed for average-risk patients and to the posterior fossa and gross metastatic disease for high-risk patients. • Adults treated for medulloblastoma with a mean dose to the whole brain of 35 Gy
  43. 43. • Young adults with average-risk disease- reduced-dose CSI (23.4 Gy) • High-risk disease- Full-dose CSI (36 Gy) • This is then followed by a boost to the posterior fossa. • Intracranial and spinal metastases should be boosted as well to total doses on the order of 45 to 50 Gy for spinal metastases and 50 to 54 Gy for intracranial metastases. Treatment is usually delivered at 1.8 Gy/day
  44. 44. ALTERNATIVE DELIVERY METHODS • Protons may be employed to reduce exit dose and toxicity, particularly the risk for secondary malignancy • The use of proton therapy has been associated with a meaningful reduction in hematologic and GI toxicity • Tomotherapy may avoid the need to match fields, but greater whole body dose exposure • VMAT may be used to increase conformality and reduce toxicity
  45. 45. Chemotherapy • CNS tumors in which combination regimens are standard of care include CCNU, cisplatin, and vincristine or cisplatin, cyclophosphamide and vincristine • The role of adjuvant chemotherapy in children with medulloblastoma is well established but remains unclear in adults.
  46. 46. Chemotherapy Recommendations: • Adjuvant chemotherapy following RT • Adjuvant chemotherapy following surgery in infant medulloblastoma (<3-years) • Pre-irradiation chemotherapy in infant medulloblastoma to defer RT (till 3-years) • High-dose chemotherapy with autologous stem-cell rescue • Concurrent chemotherapy with RT • Salvage therapy in relapsed/recurrent medulloblastoma.
  47. 47. • A series of 32 adults with medulloblastoma from Germany has shown a nonsignificant trend to prolonged survival with adjuvant chemotherapy. • NOA-07 trial of chemoradiotherapy for adult medulloblastoma demonstrated favorable EFS-67%.
  48. 48. Concurrent chemotherapy with RT • Concurrent weekly vincristine (1.5mg/m2) given as iv bolus throughout the course of RT is recommended for children with standard risk disease being treated with reduced dose CSI. • Daily concurrent carboplatin (35mg/m2) as a short intravenous infusion throughout the course of RT For children with high risk medulloblastoma is recommended
  49. 49. Age > 3 years Age < 3 years
  50. 50. For standard-risk patients • A phase II trial of lomustine, vincristine, and cisplatin for eight cycles following the reduced CSI prescription of 23.4 Gy demonstrated PFS rates of 86% and 79% at 3 and 5 years, respectively. • Hence CSI to 23.4 Gy with chemotherapy is the standard of care
  51. 51. • High-risk Medulloblastoma- chemotherapy dose intensification. • Vincristine, lomustine, and prednisone resulted in a 63% 5-year PFS rate, which was better than an eight- in-one chemotherapy regimen. • Eight drugs (vincristine, hydroxyurea, procarbazine, CCNU, cisplatin, cytosine arabinoside, high-dose methylprednisolone, and either cyclophosphamide or dacarbazine) were administered within 12 hours in an attempt to minimize myelosuppression
  52. 52. Chemotherapy for medulloblastoma (>3-years of age) Recommendations for adjuvant chemotherapy (>3-years): • It should start at least 3 weeks after completion of RT to allow for myelo-recovery • Neuraxial imaging should be done for re-assessment of the disease status prior to initiation of adjuvant chemotherapy • RFT, LFT, S. Electrolytes- Normal • Baseline hearing assessment with pure-tone audiometry prior to starting adjuvant chemotherapy and repeat after every two cycles of platinum-containing regimen • A total of 6-8 cycles of adjuvant chemotherapy should be administered generally cycled at 3-6 weekly interval
  53. 53. Chemotherapy for Infant Medulloblastoma (<3-years of age) • Multi-agent chemotherapy including carboplatin/ cisplatin, etoposide, cyclophosphamide, vincristine with or without the use of systemic high dose methotrexate and/or intrathecal methotrexate.
  54. 54. RT Planning in CSI
  55. 55. Craniospinal Axis Irradiation • Craniospinal axis irradiation is required in most medulloblastomas and occasionally in other brain tumors, such as • Advanced or metastatic germ cell tumors • Primitive neuroectodermal tumors • Pinealoblastoma • Ependymomas • Neuroblastoma with leptomeningeal spread • Leukemia/lymphoma (with CNS axis mets)
  56. 56. • CSI is a very complex technique • Goal is to achieve uniform dosage Throughout the subarachnoid space, Encompassing the entire intracranial vault and spinal canal • Fundamental is The use of opposed lateral fields including the cranium and upper cervical spinal canal, Matching a posterior spinal field including the full spinal subarachnoid space with cranial field In larger children, the upper posterior spinal field matching with a separate lower posterior spinal field
  57. 57. Radiotherapy Techniques • EBRT using Conventional RT, 3D-CRT or IMRT (WBRT or Partial Brain Irradiation) • Stereotactic radiosurgery (SRS) • Fractionated Stereotactic RT (FSRT) • Craniospinal Irradiation (CSI) • Interstitial brachytherapy may have a role in selected patients.
  58. 58. Target Volume: • Entire brain and its meningeal coverings with the CSF • Spinal cord and the leptomeninges with CSF • Posterior fossa – boost
  59. 59. Target Volume Definition • CT simulation is necessary to ensure adequate coverage of the CTV in the subfrontal region at the cribriform plate. • Traditionally, blocks have been used in the lateral fields to shield not only the facial structures but also the lenses.
  60. 60. • The lower border of the spinal CTV (using MRI) should include the lower border of the thecal sac, which can be at L5 or S3. • The use of CT simulation with contouring of the cord and overlying meninges that extend laterally to the lateral aspect of the spinal ganglia results in a field width that is narrower than one based on bony anatomy. • The addition of shielding further reduces the volume of normal tissues included in the treated volume.
  61. 61. GTV- Tumor bed on MRI CTV = GTV + 15 mm. PTV = CTV + 3-5 mm, modified only at sella. Immobilization accuracy +/- 3-5 mm. 95% of isodose covers 100% of CTV & 95% of PTV. Constraints: < 70% Supratentorial brain to receive > 50% boost dose. < 80% Left & right cochlea to receive > 80% of boost dose. < 50% Pituitary to receive > 30% of boost dose. < 10% Left & right optic nerve & chiasma to receive >50.4 Gy each.
  62. 62. • Energy • 4-6 MV linac or Co60 • Portals • Whole Brain: Two parallel opposed lateral field. • Spine: Direct Posterior field • Scheduling of radiotherapy: • Starting time : within 28 - 40 days following surgery • Duration of treatment : 45 to 47 days
  63. 63. WBRT • Superior: Skin fall off • Anterior: Skin fall off • Posterior: Skin fall off • Inferior: Skull base
  64. 64. Radiation Dose and Dose Fractionation Regimens • The total dose is generally 54 to 55.8 Gy @ 1.8Gy/#. • Lower doses for children <3 years to reduce the risk of neurocognitive deficits • When the target contains only a small volume of normal brain tissue, dose escalation may be possible using HFRT.
  65. 65. Dose (Conventional) • CSI (Phase I) • 30- 36 Gy in 18 - 21 # over 4 weeks to the cranium @ 1.5- 1.8 Gy per # • 30-36 Gy in 18-21 # over 4 weeks to the spine @ 1.5-1.8 Gy per # • Posterior fossa boost (Phase II) • 18-20 Gy in 10-11# over 2 weeks to the posterior fossa
  66. 66. Doses & volumes as per risk-stratification CSI for average-risk disease Standard dose CSI: 35-36 Gy/21-20#/4 weeks @ 1.67-1.8 Gy/# Reduced dose CSI: 23.4 Gy/13#/2.5 weeks @1.8 Gy/# (+ adj CT) Boost If Standard dose CSI : PF or TB boost: 19.8 Gy/11#/2 weeks If reduced dose CSI: Tumour bed boost: 32.4 Gy/18#/3.5 weeks CSI for high-risk disease Standard dose CSI: 35-36 Gy/21-20#/4 weeks @ 1.67-1.8 Gy/# Higher dose spinal RT: 39.6 Gy/22#/4.5 weeks @1.8 Gy/# Boost Whole posterior fossa boost: 19.8 Gy/11#/2 weeks Boost for gross focal spinal deposit: 5.4-9 Gy/3-5#/1 week Total tumor bed dose: 54-56 Gy/30-33#/ 6.5 weeks (conventional #)
  67. 67. Treatment Planning and Delivery • Newer treatment planning and delivery methods such as IMRT together with daily image verification allow for improved dosimetry • Clinically relevant dose reductions to structures anterior to the target volume such as the heart, gastrointestinal (GI) tract, and gonads.
  68. 68. PLANNING STEPS • Positioning • Immobilization • Simulation • Field arrangement • Matching of CSI • Aligning of spinal field • Implementation of plan
  69. 69. • Prone (preferred) • Supine: • More patient comfort. • In-anaesthetic patient for airway • Head position • Slightly extended and the shoulders pulled down to avoid beam divergence into the mandible & dentition. • Facilitates the use of a moving junction between the cephalad border of post. Spine field and the lower borders of cranial fields. • Lumbar and Thoracic spine parellel to couch • Immobilization is essential and involves the use of a head shell or full-body immobilization. Patient Positioning and Immobilization
  70. 70. Different RT techniques for CSI • Initially entire CNS is irradiated at one stretch with a single field. Pt. is prone below a shielded screen on top of RT table. It is known as Patterson FARR technique. Co60 source exposes the entire craniospinal axis at a focus distance of 125 c.m. • Moving Field technique: Table and pt. moves longitudinally in relation to a perpendicular Co60 beam which is stationary at 50 cm focal skin distance. • Hockey Stick technique: Pt. prone with head turned to one side. • Field at base of brain is defined by cribriform plate and is above both orbital cavities. • Include middle cranial fossa and to exclude orbit and lens. • Each side of head is treated on alternate days.
  71. 71. German Helmet Technique German Helmet Technique: • Field set so that beam flashes over entire head in ant , post, & sup directions and only the caudal margin is defined by collimator by RT machine . • Caudal margin is set up so that it follows a line drawn from Lateral canthus through the ext. auditory canal to the post aspect of the skull At C2-C3 jt. • Here we shield extra-Cranial structure in the subfrontal region,facial structures, teeth and lens.
  72. 72. Field Arrangements • Whole brain o In the simulator, opposing lateral fields are applied to the whole brain with a collimator rotation of 7-11o to match the divergence of the direct posterior spinal field. • SFOP guidelines- The recommended placement of block is: o 0.5 cm below the orbital roof . o 1 cm below and 1 cm in front of the lower most portion of the temporal fossa . o 1 cm away from the extreme edges of the calvaria. In Medulloblastoma nearly 15-20% of recurrences occur at cribriform plate site which is attributed to overzealous shielding ,because of its proximity to ocular structure it often get shielded.
  73. 73. Spinal Field  Laterally - 1 cm margin beyond the pedicles, to cover the spinal cord and meninges along the nerve roots upto the spinal ganglia  Caudal- 1cm below the termination of the thecal sac i.e. L5 –S3.  2 spinal fields are used if the length is > 36 cm.  In Dorsal Region, block lat. Field to cover heart and lungs.  In Lumber Region, reduce field to spare BM and Gonads. SSD technique Gantry Angle = 0 degree IMP point is length and depth of spinal fields. Field of approx.4–6 cm wide box over the spinal cord/vertebral bodies extends from C2 –S2
  74. 74. Post fossa boost • Volume includes entire Infratentorial compartment. • Field arrangement :  Two lat opposing fields . SFOP Guidelines :  Ant -0.5 cm in front of clivus  Upper -1 cm above midpoint b/w line joining foramen magnum and the skull.  Post- ll to ant margin in air .  Lower – 1 cm below occipital foramen.
  75. 75. TECHNIQUES OF MATCHING CS FIELDS Collimator/Couch rotation Half beam block Asymetric jaws Moving Junction technique
  76. 76. 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).
  77. 77. Collimator rotation allows cranial field to match spinal field divergence Coll θ = arc tan (L1 /2 x SSD) For Co60 SSD = 80 Zone of overlap of spinal field if collimator rotation is not applied in cranial field SSD L1 Collimator rotation : While treating cranial field rotate Collimator of lateral field so that its inferior border is parallel to divergence of sup. Aspect of spinal field . θ
  78. 78. In order to avoid the overlap resulting from inf. Divergence of cranial field, rotate the couch towards the collimator so that fields margins of two fields become parallel. Degree of couch rotation depends upon the length of lateral cranial fields and SAD Θ couch = arc tan (1/2 x L2 /SAD) L2 = Cranial field length COUCH ROTATION Fig: Rotation of the couch toward the gantry is necessary to match the caudal margin of the lateral cranial fields with the cephalad margin of the posterior spinal field.
  79. 79. Couch θ = arc tan (L2/2 x SAD) For Co60 SAD = 80 L2 ( Length of cranial field) Cranial field SAD Zone of overlap Spinal field Couch rotation during treatment of cranial field θ COUCH ROTATION
  80. 80. Half Beam Blocking Actual Field Length Spinal field
  81. 81. Moving junction in CSI • Feathering after every 5-7 fraction smoothes out any over or underdose over a longer segment of cord . • Usually shifted by 1-2cm at each shift . • Either in cranial or caudal direction. • Lower border of sup. Spinal field & sup. Border of inf. Spinal field are also shifted superiorly , maintaining the calculated gap b/w them. “Feathering” refers to movement of the junction of the two fields across the treatment length.
  82. 82. S 2 Junction shift in CSI
  83. 83. Junction shift in CSI S 2
  84. 84. S 2 Junction shift in CSI
  85. 85. Aligning Spinal field  Abutting fields : will result in heterogenous dose to the spinal cord .  To overcome this various techniques are available o Gap technique o Double junction technique o Moving junction technique
  86. 86. Fixed or calculated gap spinal fields Gap calculation formula S= [½ x L1(d/SSD1)] + [½ x L2(d/SSD2)] Cold Spot Hot Spot SSD 2 SSD 1 L2 S L1
  87. 87. Double junction techniques  The post field divided into two halves.  An overlapping segment is treated with two diff. fields on alternate days.  The junction is therefore automatically feathered on alternate days Upper Spine Lower 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
  88. 88. Metastatic Medulloblastoma? M2-M3 Medulloblastoma SIOP-PNET3 study 1 in 2 children likely to survive for 5 years even with metastatic disease SIOP PNET 3 STUDY
  89. 89. TECHNICAL CONSIDERATIONS FOR CRANIOSPINAL IRRADIATION Target volume definition may be difficult using conventional simulation Use CT simulation with CT-MRI co- registration Prone position- Uncomfortable, Difficult to monitor airway Supine position preferred Field matching over cervical spine/risk of over- or Underdosage Angle brain fields Use half-beam block for brain fields Use couch rotation or match line wedge Choice of extended SSD or second field for treatment of spinal axis Two fields preferred Inhomogeneity along spinal axis Use compensator, MLC Irradiation of normal tissues- Mandible/teeth, Thyroid, Heart, GI tract, Gonads Neck extension, Care with level of junction, Use lower junction, Care with width of spine field, Use protons, IMRT, electrons, Use protons, IMRT, electrons, Care with lower limit and width of spine field
  90. 90. RADIATION TOXICITY ACUTE TOXICITY • Nausea, vomiting • Neutropenia, thrombocytopenia • Fatigue, headache, drowsiness • Alopecia, mild dermitis • Serous otitis media • Mucositis, oesophagitis (exit dose from spinal cord) Spinal cord Chronic progressive myelitis Brain Radiation necrosis, Intellectual deficit Lens of eye Cataract formation Retina Radiation retinopathy Optic nerve Optic neuritis Inner ear Sensorineural hearing loss Hypothalamic -pituitary axis Endocrinopathies ( hypothyroidism and decreased growth hormone secretion) Gonads Reduced Fertility Secondary Malignancy LATE TOXICITY
  91. 91. Radiotherapy Toxicity: Dose-Volume Related Mulhern et al: Lancet Oncol 2004
  92. 92. Strategies that have been used to avoid or minimize the long-term effects of treatment for pediatric brain tumors include the following: • Use of new radiation modalities- Proton • Reduced target volumes: e.g., tumor bed rather than whole posterior fossa for the boost in standard-risk • Reduction of radiotherapy dose (e.g., in young patients with standard-risk dose for CSI has been reduced progressively from 35 to 36 Gy to 23.4 Gy and to 18 Gy for children younger than 8 • Use of HFRT in standard-risk medulloblastoma
  93. 93. Follow-Up During and After Radiotherapy • Nausea and vomiting can be prevented by using 5HT-3 antagonists. • Headache is not an expected side effect and should be investigated by physical examination for signs of raised ICP and imaging. • Steroids, usually are tapered by the second or third week of treatment. • Fatigue is a rather common symptom and is cumulative. • Children usually recover relatively quickly and often can get back to their usual routine quite soon after completion of treatment.
  94. 94. • Hormonal deficits, especially primary hypothyroidism and growth hormone deficit secondary to inclusion of the hypothalamic– pituitary axis. • Patients should be monitored closely in follow-up • Regular follow-up in ophthalmology and audiology. • Extra pedagogic support may be necessary. • Patients should have ready access to a neuropsychologist for evaluation of any special needs and in the longer term to vocational assessment and counseling.
  95. 95. Recurrence • There are no curative treatments, and most patients succumb from the disease in less than 2 years • Nonsurgical treatment options for this group consist of second-line chemotherapy • Stem cell harvest with high-dose chemotherapy • Reirradiation
  96. 96. Recurrence • Recurrent medulloblastoma is responsive to a variety of neoplastic agents, including vincristine, nitrosoureas, procarbazine, cyclophosphamide,etoposide, and cisplatin • A CCG trial to evaluate carboplatin, thiotepa, and etoposide with peripheral stem cell rescue showed 3-year EFS and OS rates of 34% and 46%, respectively.
  97. 97. Follow up • MRI should be repeated every 3 months the first year; every 4-6 months the second year; and yearly thereafter. • Lower cranial nerve or cerebellar signs also may signal recurrence.
  98. 98. Clinical Evidences • Huang et al. n=15, treated with conventional craniospinal radiotherapy followed by a boost to the posterior fossa using IMRT. • IMRT delivered lower doses of radiation to the auditory apparatus while maintaining full doses to the desired target volume. • Conclusion- Despite receiving higher doses of cisplatin and despite receiving radiotherapy before cisplatin therapy, IMRT can significantly decrease the rate of hearing loss in children treated for medulloblastoma.
  99. 99. • Eaton et al, n=88, chemotherapy + RT (either photon or proton) for standard-risk found no significant difference in disease control, survival, or patterns of failure between proton and photon radiation, suggesting equivalent efficacy.
  100. 100. • Barney et al., n=50 treated with proton CSI, documented extremely low median radiation doses to the thyroid of 0.003 Gy (RBE); the lung 1.1 Gy (RBE), heart 0.002 Gy (RBE), kidney 0.04 Gy (RBE), bowel 0.02 Gy (RBE), testicles 0.003 Gy (RBE), and ovaries 0.003 Gy (RBE). • Treatment-related morbidity included grade 3 leukopenia in 9%, thrombocytopenia in 2%, and median weight loss of 1.1 kg or 1.6% loss from baseline. • PFS at 2 and 5 years were 82% and 68%, with 80% of treatment failures involving a local recurrence. These data suggest that craniospinal irradiation with proton therapy is effective but potentially much less toxic acutely and much less likely to result in late effects.
  101. 101. Summary • Common & radiosensitive childhood brain tumor • Molecular classification has identified four distinct subtypes: WNT, SHH, group 3 and group 4. • Maximal surgical resection should be performed, where feasible. • Standard treatment consists of postoperative radiotherapy to the craniospinal axis followed by a boost to the tumor bed for average-risk disease and to the posterior fossa and any intracranial/spinal metastases for high-risk disease. • The use of chemotherapy generally follows the pediatric indications and guidelines.
  102. 102. • Patients typically present with symptoms and signs of raised intracranial pressure (i.e., headache and morning vomiting). • On MRI, medulloblastomas appear as solid masses that enhance usually fairly homogeneously with contrast material. • Investigation at diagnosis must include a gadolinium- enhanced MRI of the spinal axis and CSF cytology. The former should be obtained whenever possible preoperatively or else at least 2 weeks postoperatively • Radiotherapy: An integral component of multi-modality management
  103. 103. TMH Protocol for Medulloblastomas /PNET https://tmc.gov.in/SBF/Nouro/flowcharts_final.pdf