Radiation Therapy for Pediatric Brain Tumors
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1 Radiation Therapy for Pediatric Brain Tumors David B. Mansur, M.D. Associate Professor of Radiation Oncology and Pediatrics Vice Chair and Director Proton Therapy Center Case Western Reserve University School of Medicine Cleveland, OH, USA
2 Disclosures No conflict of interests
3 Overview Surgery Post operative staging and work up Management of Specific Tumors Low Grade Glioma High Grade Glioma Ependymoma Embryonal Tumors / Medulloblastoma Radiation Therapy Techniques Neurocognitive Late Effects
4 Surgery
5 Surgery Extent No Surgery Gross Total Resection
6 Surgery Extent No Surgery Gross Total Resection Optic pathway glioma Diffuse intrinsic pontine glioma (DIPG)
7 Surgery Extent No Surgery Gross Total Resection Optic pathway glioma Diffuse intrinsic pontine glioma (DIPG) Lymphoma Germinoma
8 Surgery Extent No Surgery Gross Total Resection Optic pathway glioma Diffuse intrinsic pontine glioma (DIPG) Lymphoma Germinoma Gliomas Ependymoma Embryonal Tumors (medulloblastom a, PNET) Everything else
9 Surgery Extent No Surgery Gross Total Resection Optic pathway glioma Diffuse intrinsic pontine glioma (DIPG) Lymphoma Germinoma Not fully resectable due to tumor location Gliomas Ependymoma Embryonal Tumors (medulloblastom a, PNET) Everything else
10 Post-operative Imaging Verify extent of resection Determine if spinal dissemination is present
11 Extent of Resection
12 Extent of Resection 24 hours post-op
13 Extent of Resection 24 hours post-op 3 weeks post-op
14 Spinal Dissemination Tumor % with spinal dissemination at diagnosis Glioma < 5 Ependymoma Germ cell tumor 30 Embryonal tumor (medulloblastoma, PNET, etc) 30
15 R/O Dissemination Wait >10 Days post-op: Because debris and blood products can mimic drop metastases. Then: MRI spine Lumbar puncture for cytology
16 Radiation Therapy Considerations Surgery Extent To Irradiate or not? Radiation Volume Radiation Dose Chemotherapy?
17 The decision to use radiation therapy is a balancing act
18 Tumor progression Treatment Toxicity Maximize survival AND quality of life
19 Predisposing Syndromes Tuberous Sclerosis, von Hippel Lindau, Gorlin Neurofibromatosis NF A group of syndromes with neuro-cutaneous manifestations Autosomal Dominant Multiple Café au Lait spots Neurofibromas Brain Tumors
20 Neurofibromatosis Type 1 (von Recklinghausen) 1:3000 Optic pathway gliomas Lisch Nodules Axillary/inguinal freckles Mental delay Sphenoid dysplasia Pheochromocytoma Renal artery stenosis Type 2 1:50,000 Bilateral acoustic neuroma Meningioma Spinal cord ependymoma Childhood cataracts
21 For NF-1 patientsb Tumors tend to be low grade and slowly growing RT complication risk is higher 3x risk of vasculopathy and occlusion of the Circle of Willis: moyamoya syndrome 3x increase risk of radiation-induced second malignancies
22 Low Grade Glioma
23 Surgery: CCG 9891 POG 9130 Prospective study of surgery for all low grade gliomas in children n=660 Progression-Free Based on Surgery extent: Shaw Neuro-Oncol 5:153, 2003
24 Chemotherapy COG A9952 Initial Chemotherapy CV vstpcv All low grade gliomas Patients < 10 years old n=274 No NF patients Median f/u 5 yrs Overall PFS 45-50% CV TPCV p=ns TPCV CV Ater JCO 30:2641, 2012
25 Radiation Therapy 35 children with unresectable pilocytic astrocytoma (Grade 1) RT alone Median dose 54 Gy Median f/u 5 years No NF patients 5 yrpfs 68% 8/9 patients who progressed did within the irradiated volume Mansur et al, Int. J. Radiation Oncol Biol Phys, 79:829, 2011
26 Radiation Therapy German (HIT-LGG 1996) 117 children 10 had NF Median age 9 yrs Pilocytic astrocytoma RT as first or 2 nd line treatment Median dose 54Gy Median f/u 8 yrs 5 yrpfs 77% Muller et al, Strahlenther Onkol 189:647, 2013
27 Radiation Therapy Dose Muller et al, Strahlenther Onkol 189:647, 2013
28 Chemotherapy And Radiation? Children s Cancer Group 945 Trial for High Grade Glioma, but 70 patients with LGG: Originally diagnosed as high grade Fouladi Cancer 98:1243, 2003
29 Chemo/RT: CCG 945 Pilocytics % Progression-free p=0.04 Fibrillary Fouladi Cancer 98:1243, 2003
30 Low Grade Astrocytoma Extent of surgery is prognostic and GTR is usually curative PFS with chemotherapy is 45-50% PFS with RT is 70% Appears to be no benefit for the addition of chemotherapy compared to RT Conformal RT and dose of 50.4 Gy Approach to each patient must be individualized:
31 NFNo Surgery Low Grade Brain Tumor Symptomatic NF Yes Asymptomatic < GTR Surgery Observe GTR Observe GTR < GTR Observe Progression? < 10 y.o. Progression? >10 y.o. Observe Observe Progression? Chemotherapy Progression? Radiation therapy Chemotherapy Progression? Chemotherapy Radiation therapy Progression? Chemotherapy Progression? Radiation therapy
32 High Grade Astrocytoma
33 Glioblastoma An adult tumor, median age 60 yrs Only 6% of Childhood brain tumors are high grade gliomas(anaplastic Astrocytoma and Glioblastoma) GB Incidence by Age Percent Total < >80 Age From Ohgaki and Kleihues J Neuropath Exp Neurol 64:479, 2005
34 Childrens Cancer Group 943 First systematic use of chemotherapy for children with high grade astrocytomas Randomized comparison: 54 Gy regional vs 54 Gy regional + Prednisone CCNU (Lomustine) Vincristine Sposto R J Neuro-Onc 7:165, 1989
35 CCG 943 Sposto R J Neuro-Onc 7:165, 1989
36 Single Institution Glioblastoma 24 children since 1970 Median age 11 yrs 58% had chemotherapy Median follow up 12.5 months Perkins et alint J Radiat Oncol Biol Phys 80:1117, 2011
37 EORTC RT alone vs RT + Temozolomide 75mg/m2 daily mg/m2 x5d x6mo 96% GB 573 pts Median age 57 Stupp NEJM 352:987, 2005, Lancet Oncol 10:459, 2009.
38 Children s Oncology Group ACNS 0126 Temodar 90mg/m2 daily + 54/59.4 Gy Maintenance Temodar 200mg/m2 x5d monthly x 10 cycles Phase II 107 patients COG Progress Report Fall 2007
39 Children s Oncology Group ACNS 0822
40 High Grade Astrocytoma Poor outcome RT: Total dose 59.4 Gy All patients treated with chemotherapy in addition to RT Results with Temozolomideless encouraging than in adults Optimal chemotherapy still to be determined
41 Ependymoma
42 Ependymoma Classification 2007 Subependymoma Myxopapillary ependyoma Ependymoma Cellular Papillary Clear Cell Tanycytic Anaplastic Ependymoma Grade I Grade II Grade III
43 Ependymoma Classification 2007 Subependymoma Myxopapillary ependyoma Ependymoma Cellular Papillary Clear Cell Tanycytic Anaplastic Ependymoma Grade I Grade II Grade III
44 Surgery Alone For Ependymoma? Author n F/U yrs % Progression free Awaad (1996) Venkatramani (2012) Palma (2000) Hukin (1998)
45 Chemotherapy? CCG -942 Children s Cancer Group 942 Medulloblastoma trial Included infratentorial ependymoma 80% Grade II, median age 5, CSI VS CSI + VCR, CCNU, Pred Evans et almed Ped Onc 27:8, 1996
46 CCG year f/u Overall survival 39% No difference between treatment arms
47 Chemotherapy to Delay RT? Mansur DB, CNS Oncology 2(3):247, 2013
48 Role of Post Operative Radiation Therapy Author F/U yrs n -RT / +RT %PFS -RT / +RT %OS -RT / +RT Perilongo (1997) 3 16 / / / 58 Rogers (2005) GTR only Metellus (2010) STR only /13 50 / / /35 36 / / 95 Pollack / / / 88 Rousseau (1994) / 65 0 / / 63 Koshy (2011) All < 3 yrs old / 81 Post Operative RT established as standard of care in the US
49 Disseminated Disease at Diagnosis Author Institution n Grade % + Robertson CCG II/III 9.4 all grade II Horn Multi-Insti 72 II/III 15 Timmerman German 55 III 9 Pollack Pittsburgh 31 II/III 21 (8% supra, 28% infra) Perilongo Italian 29 II/III 7 Rousseau IGR 69 II/III 6 Disseminated disease requires craniospinal RT, localized disease does not!
50 Ependymoma Pattern of Relapse % of patients with isolatedout-of-field recurrence Pollack (U. Pittsburgh) 5 Carrie (Lyon) 3 Merchant (MSK) 0 Rousseau (IGR) 12.5 Merchant (St. Jude) 3 Mansur (Wash. U) 0
51 Dose Response in Ependymoma Author (Institution) Dose Response Dose Level (Gy) Goldwein (CHOP) Yes > 45 Carrie (Lyon) No +/- 50 Kim (U. Michigan) Yes > 45 Merchant (MSK) Yes Continuous Variable to 59.4 Rousseau (IGR) No +/- 50 Stuben (Germany) Yes > 45 Mansur (Wash U) Yes > 54 Current recommendations: Gy
52 Radiosurgery for Ependymoma Mansur DB, CNS Oncology 2(3):247, 2013
53 Ependymoma Post op RT is standard of care in USA Local conformal volume if no dissemination Craniospinal RT if disseminated disease is present Many questions remain (role of chemotherapy?, role of surgery alone?, best incorporated into clinical trialsb.
54 Ependymoma --COG 0831 Supratentorial Grade II GTR STR Everybody Else chemo CR 2 nd Look Surgery GTR Conformal RT to 59.4 Gy 0.5 cmctv, 3-5 mm PTV Observation Randomized Maintenance chemo
55 Embryonal Tumors
56 Embryonal Tumor Classification Medulloblastoma Primitive Neuroectodermal Tumors CNS neuroblastoma, ependymoblastoma, medulloepithelioma Atypical Teratoid Rhabdoid Tumor Pineoblastoma
57 Embryonal Tumors High grade tumors (all Grade 4 in W.H.O) High rate of cerebrospinal fluid dissemination Careful work up of spine CraniospinalRT required with boost to primary site and possibly metastatic deposits Poor prognosis, except for medulloblastoma
58 Medulloblastoma Average Risk Age >3 years AND <1.5 cm 2 residual AND No Dissemination High Risk Age < 3 years or >1.5 cm 2 residual or Disseminated tumor or Anaplastic Histology PFS: 80% vs 30-60%*
59 Medulloblastoma Average Risk Age >3 years AND <1.5 cm 2 residual AND No Dissemination High Risk Age < 3 years or >1.5 cm 2 residual or Disseminated tumor or Anaplastic Histology Reduced intensity RT Lower CSI dose Smaller boost volume Standard dose and volume of RT Intensified chemotherapy Treated with other embryonal tumors
60 Average Risk Medulloblastoma COG Gy 23.4 Gy (Cisplat, VCR, CCNU, Cytoxan)
61 High Risk Medullo and Other Embryonal Tumors: COG 0332 RT: CSI 36 Gy Boost to 55.8 Gy (Cisplat, VCR, Cytoxan)
62 Radiation Therapy Techniques
63 Simulation
64 Image Fusion For Contouring CT Simulation Diagnostic MRI
65 Image Fusion For Contouring Diagnostic MRI CT simulation image
66 Summary of Volume, Dose, and Chemotherapy for Pediatric Brain Tumors Tumor Volume (CTV in cm) Chemotherapy and Dose (Gy) Local Field Whole Ventricle +Boost Craniospinal + Boost To defer RT Concomitant Adjuvant Low Grade Glioma 1 cm Ependymoma Localized 1 cm /- --- ON STUDY Ependymoma Disseminated Gy Boost to / High Grade Glioma 2-3 cm Average Risk Medulloblastoma +/ Gy Boost to 54 Gy +/ All other Embryonal tumors Gy Boost to Gy +/ Craniopharyngioma cm Gy Pure Germinoma (Localized) Gy Boost to Neoadjuvant on study Pure Germinoma (Disseminated) Gy Boost to Mixed Germ Cell tumor (Localized) Gy Boost to Neoadjuvant standard Mixed Germ Cell Tumor (Disseminated) Gy Boost to 54 Neoadjuvant standard
67 Ependymoma GTV CTV: 1 cm PTV: 0.5 cm
68 High Grade Astrocytoma Initial volume T2 signal cm Gy Boost volume T1 signal and/or tumor cavity cm Total Dose 59.4
69 EmbryonalTumors: CraniospinalTechnique
70 Technical Challenge Craniospinal RT
71 Cribriform Plate
72 Cribriform Plate
73 Cribriform Plate
74 Helical Tomotherapy
75 Tomotherapy Craniospinal Avoids matching of fields More conformal prescription isodoses More low dose spread to other tissues.
76 Posterior Fossa Boost
77 Posterior Fossa Boost Conventional Fields Draw a line from posterior clinoid (A) to the internal occipital protuberance (B) Draw a line bisecting and perpendicular to AB (DE) Tentorial apex (C) is ½ the distance between D- E. Drayer et al IJROBP 41:625, 1998
78 Posterior Fossa Boost Conventional Fields Draw a line from posterior clinoid (A) to the internal occipital protuberance (B) Draw a line bisecting and perpendicular to AB (DE) Tentorial apex is ½ the distance from E-D Draw lateral portal with 1-2 cm margin Not as accurate for children < 1 yr of age Drayer et al IJROBP 41:625, 1998
79 Posterior Fossa Boost Conventional Fields Conventional lateral view
80 Posterior Fossa Boost Conformal Technique
81 Posterior Fossa Boost Conformal Technique
82 IMRT Posterior Fossa Boost
83 Proton Beam For Pediatric Brain Tumors
84 Photons vs Protons Depth Dose Curve Proton
85 5 Field IMRT 1 Field Proton Courtesy Beth Pierburg, CMD
86 Pseudoprogression
87 Pseudoprogression
88 Neurocognitive Toxicity
89 Neurocognitive Toxicity --Surgery
90 CCG 9891 / POG 9130 Prospective protocol of Low Grade Glioma patients age 3-18 treated with surgery alone between Neuro-cognitive testing within a year of surgery.
91 Posterior Fossa Tumors n=103 Supratentorial Tumors n=93 Ris JCO 26:4765, 2008 Beebe JCO 23:5198, 2005
92 Neurocognitive Toxicities --RT
93 Radiation Induced Cognitive Decline RT Dose RT Volume Age at RT
94 IQ following RT for infant medulloblastoma 35 Gy Craniospinal Walter JCO 17:3720, 1999
95 CCG GyCraniospinal Change in Mean Full-Scale Intelligence Quotient n = 43 Ris et al JCO 19:3470, 2001
96 CCG GyCraniospinal Age < 7 yrs (n=30) Age >7 (n=13) Change in Mean Non-Verbal IQ by Patient Age Ris et al JCO 19:3470, 2001
97 Mean IQ Decline After RT Mean IQ Decline With Time After RT Mean IQ 60 Ris et al Walter et al Ris et al (age > 7) Initial Mean IQ Time Follow Up Mean IQ * Influence of DOSE and AGE Courtesy Gisele Pereira
98 Hoppe-Hirsch et al1995 Ependymoma Posterior Fossa only 50 Gy vsmedulloblastoma whole brain PF boost to 50 Gy IQ: no sig. Differences at 1 year. At 10 years, only 10 % of medullokids had IQ > 90 School Performance:
99 St. Jude Neurocognitive Testing after conformal RT Ependymoma patients >12 months old High dose Gy conformal RT Tumor/cavity + 1 cm Median f/u 60 months IQ stable, however modest decline in readingfunction observed * Influence of VOUME Conklin JCO 26:3965, 2008
100 Neurocognitive Decline Multi-factorial Damage from the tumor Surgery Chemotherapy esp. methotrexate RT RT effects result from 3 variables: Dose Volume Age of child
101 Obrigado
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