7/1/2015. Radiotherapy in Infant Brain Tumors. Goals and Objectives. Primary Brain and CNS Tumors (0-14 years) Brain Tumors (1 to 4 years)

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1 Radiotherapy in Infant Brain Tumors ARNOLD C. PAULINO, M.D. PROFESSOR OF RADIATION ONCOLOGY MD ANDERSON CANCER CENTER AND TEXAS CHILDREN S HOSPITAL Radiotherapy in Infant Brain Tumors 1. Try to Avoid Irradiation 2. If radiation needs to be given, try to use very conformal radiotherapy fields Goals and Objectives Primary Brain and CNS Tumors (0-14 years) To gain an understanding of problems associated with irradiation of the brain in the very young To gain an understanding of recent trends in management of infant brain tumors To gain familiarity with different radiotherapy technology available for treatment of pediatric brain tumors Central Brain Tumor Registry of the United States Ostrom QT et al Neurooncol 2015 (in press) Brain Tumors (0 to 1 Year) Brain Tumors (1 to 4 years) Ostrom QT et al Neurooncol 2015 (in press) Ostrom QT et al Neurooncol 2015 (in press) 1

2 Brain Tumor Type and Age Brain Tumor Survival Rates (0-1 Year) Histology N 2 Years 5 Years 10 Years Pilocytic Astrocytoma % 80.1% 80.1% Other Low Grade Glioma % 77.1% 70.7% High Grade Glioma % 54.1% 54.1% Ependymoma % 60.1% 51.4% Medulloblastoma % 41.6% 38.2% ATRT % 0% 0% All Brain Tumors % 55.3% 53.2% Ostrom QT et al Neurooncol 2015 (in press) Ostrom QT et al Neurooncol 2015 (in press) Brain Tumor Survival Rates (1-4 Years) Neural Growth Pattern Histology N 2 Years 5 Years 10 Years Pilocytic Astrocytoma % 97.5% 95.9% Other Low Grade Glioma % 88.9% 88.9% High Grade Glioma % 27.3% 24.4% Ependymoma % 71.4% 59.4% Medulloblastoma % 62.3% 58.0% ATRT % 33.5% 33.5% PNET % 54.4% 49.4% All Brain Tumors % 71.9% 68.6% Rapid postnatal growth which slows down in adolescence Examples include brain, kidney, heart and lung Ostrom QT et al Neurooncol 2015 (in press) Brain Brain Most sensitive during fetal period but postnatally during first few years of life Most neurons present at birth but brain is still in an unfinished state Increase in axonal growth, dendritic arborization and synaptogenesis Myelin formation well developed at the second year of life and continues in some tracts until years By age 6, most children have attained adult brain size 2

3 Neurogenesis Impact of Age in Low Grade Glioma Barani IJ et al. Int J Radiat Oncol Biol Phys 2007; 68: Merchant TE et al. J Clin Oncol 2009; 27: Neurocognitive Effects Moyamoya Syndrome N Older Average Risk Older High Risk Younger Average Risk Younger High Risk Intercept Slope Points/yr Intercept Slope Points/yr Intercept Slope Points/Yr Intercept Slope Points/Yr IQ Reading Spelling Math Mulhern RK et al. J Clin Oncol 2005; 23: Desai SS et al. Int J Radiat Oncol Biol Phys 65:1222-7, 2006 Orbital and Midfacial Growth Retardation Orbital and Midfacial Growth Retardation Retinoblastoma patients treated from at Utrecht University Measurement (mm) Irradiated Orbits Mean +/- SD Nonirradiated Orbits Mean +/- SD P-value Width / /- 1.9 < Height / /- 3.0 < 0.01 Edge-tragus / /- 3.8 < 0.01 Imhof SM et al. Ophthalmology 1996; 103:263-8 Imhof SM et al. Ophthalmology 1996; 103:

4 Orbital and Midfacial Growth Retardation Craniospinal Irradiation (Medulloblastoma) Age Group (months) No. of Orbits Width (mm) Mean +/- SD Height (mm) Mean +/- SD Edge-Tragus (mm) Mean +/- SD 0 to / / / to / / / to / / /- 6.1 > / / /- 4.1 Imhof SM et al. Ophthalmology 1996; 103:263-8 Radiotherapy Volume Radiobiology University of Lund University of Toronto Strong Memorial Hospital SURVIVAL ACCORDING TO RT VOLUME Posterior Fossa only Posterior fossa + spine Craniospinal 5% 25% 53% 0% 53% No RT: 0% Whole brain RT: 20% 50% Tumor Mean Inactivation Dose (Gy) SF2 Wilms tumor Burkitt s lymphoma Medulloblastoma Neuroblastoma Osteosarcoma Melanoma Glioblastoma Deschavanne PJ, Fertil B. Int J Radiat Oncol Biol Phys 1996; 34: Craniospinal Irradiation Psycho social Dental Visual Neuro cognitive Late Effects Auditory Endocrine Second Tumor I SWEAR by Apollo the physician and Aesculapius..I will follow that system of regimen which, according to my ability and judgment, I consider for the benefit of my patients, and abstain from whatever is deleterious and mischievous.. Musculo Gastro skeletal intestinal Cardio vascular Pulmo nary excerpt from the Hippocratic Oath 4

5 Delaying or omitting radiotherapy Baby POG Study Popular approach in the 80s and 90s particularly in children < 3 years with brain tumors Craniospinal radiotherapy is delayed until patient is 3 years or older in medulloblastoma Involved field radiotherapy delayed until patient in 3 years or older in ependymoma, malignant glioma Duffner PK et al. N Engl J Med, 1993; 328: children received 2 rounds of 2 cycles of VCR, CPM followed by 1 cycle of VP-16 and CDDP after resection Chemotherapy given from months until child turned 3 years 1- and 2-year PFS rates were 42% and 34% (medulloblastoma) and 58% and 42% (ependymoma) Baby POG Study 82 children < 18 months of age with CNS PNET or ependymoma had surgery followed by 8 cycles of 8 in 1 chemotherapy Radiotherapy was administered to only 9 children prior to progression (involved field after two cycles or CSI after 1 year) 3-year PFS was 22% for medulloblastoma and 26% for ependymoma CCG-921 Duffner PK et al. N Engl J Med, 1993; 328: Geyer JR et al. J Clin Oncol 1994; 12: HIT-SKK 92 for Medulloblastoma HIT-SKK 92 for Medulloblastoma After surgery, 43 children < 3 years received 3 cycles of intravenous chemotherapy and intraventricular methotrexate. Treatment was terminated if a complete remission was achieved. 5-year PFS: 82% in those with complete resection and M0 disease (17 patients) 19/23 evaluable pts had asymptomatic leukoencephalopathy Rutkowski S et al. N Engl J Med 2005; 352: Rutkowski S et al. N Engl J Med 2005; 352:

6 Medulloblastoma Molecular Subtypes Anatomically Distinct Types of Medulloblastoma Wingless-type Murine Mammary Tumor Virus Integration Site (WNT) Sonic Hedgehog (SHH) Type C Type D Prognosis Excellent Good Dismal Fair Frequency 10% 25% 30% 35% Typical Age Older childhood Infant and adult Childhood Childhood Male: Female Ratio 1:1.7 1:0.5 1:0.7 1:0.5 Typical histology Classic Desmoplastic or classic Classic or anaplastic Classic or anaplastic Metastatic disease 0% 7% 75% 31% Cytogenetic markers Monosomy 6 9q loss Isochromosome 17q Isochromosome 17q Molecular markers Beta-catenin SFRP1 or GAB1 MYC unknown Clinical strategy Reduction in therapy SHH pathway inhibitors, Omit radiotherapy in young children Intensified therapy, novel therapeutics Research focus needed Gibson P et al. Nature 2010; 468: HIT 2000 HIT-SKK 2000 for Medulloblastoma von Bueren AO et al. Neuro-oncol 2011; 13: HIT-SKK 2000 for Medulloblastoma SFOP Trial for Medulloblastoma Children < 5 years of age N = 79 Maximal safe resection of primary tumor 3 courses given in 7 cycles Course 1: carboplatin Course 2: etoposide and cisplatin Course 3: vincristine and cyclophosphamide For disease progression or relapse, salvage therapy including high-dose chemotherapy, stem cell rescue and radiotherapy (involved field for M0, involved or craniospinal field for M+) For M0 children with non-desmoplastic/non-nodular variants, For which predominantly local relapses lead to less favorable survival rates, local RT has been added after chemotherapy von Bueren AO et al. Neuro-oncol 2011; 13: Grill J et al. Lancet Oncol 2005; 6:

7 SFOP Trial for Medulloblastoma SFOP Trial for Medulloblastoma Mean IQ Chemo alone 91 HDCT + RT 72 For 64 pts without metastases at diagnosis, radiotherapy free-survival at 3 and 5 years was 23% and 22%. Craniospinal-radiotherapy-free at 3 and 5 years was 63% and 57% Grill J et al. Lancet Oncol 2005; 6: Grill J et al. Lancet Oncol 2005; 6: Head Start I and II for Medulloblastoma Head Start I and II for Medulloblastoma 21 children < 6 years with M0 medulloblastoma 4 treatment-related deaths Dhall G et al. Pediatr Blood Cancer 2008; 50: Dhall G et al. Pediatr Blood Cancer 2008; 50: International Meta-Analysis Medulloblastoma (HIT-REZ 1997 & 2005) Rutkowski S et al J Clin Oncol 2010; 28: Muller K et al. Int J Radiat Oncol Biol Phys 2014; 88:

8 Craniospinal RT Dose (1800 cgy) COG ACNS0031 Protocol A prospective study from CHOP used 1800 cgy CSRT and 5580 cgy to the posterior fossa with 8 cycles of VCR, CCNU and CDDP in 10 children mos 4-year survival was 69% No marked change in IQ scores among survivors Indiana University study of 7 children (age mos) treated with 4 mos of chemotherapy followed by 1800 cgy CSRT + 54 Gy PF boost 3 patients relapsed (all outside PF) 2 of 3 were salvaged 4/6 survivors have endocrine deficits All 6 required special assistance in school 18 Gy 23.4 Gy CTV = GTV cm Goldwein JW et al. Int J Radiat Oncol Biol Phys 1996; 34: Jakacki RI et al. Int J Radiat Oncol Biol Phys 2004; 60:531-6 Mulhern RK et al. Lancet Oncol 2004, 5: Infant Studies in Ependymoma SFOP Ependymoma Study Baby POG study: 1 and 2 year progression free survival rates were 58% and 42% 73 children < 5 years of age underwent surgery and postoperative chemotherapy 7 cycles of 3 courses alternating 2 drugs at each course: procarbazine and carboplatin, etoposide and cisplatin, vincristine and cyclophosphamide) for 1.5 years Salvage was reresection + local radiotherapy 4 year PFS was 22% 4 year OS was 59% 4 year freedom from XRT: 23% Grill J et al. J Clin Oncol 2001; 19: Ependymona: Head Start III Ependymoma 19 children < 10 years of age with ependymoma treated with surgery followed by 5 induction chemo cycles and 1 consolidation cycle of myeloablative chemotherapy followed by autologous stem cell rescue XRT given to children 6-10 years and < 6 years with residual disease prior to consolidation 3/3 supratentorial and 1/6 infratentorial had CR after induction chemotherapy Venkatramani R et al. J Neurooncol 2013; 113: St. Jude study of 88 children treated with 3D conformal RT Dose 50.4 Gy (n = 15, all < 18 months) to 59.4 Gy Median age at RT: 2.85 years Clinical target volume was tumor bed + residual tumor with a 10 mm margin. Planning target volume was CTV with a 3 to 5 mm margin Merchant TE et al. J Clin Oncol 2004; 22:

9 Ependymoma MGH Proton Ependymoma Study 70 children with localized ependymoma received postoperative involved field proton therapy Median age: 38 months (range, 3 months to 20 years) 73% had infratentorial tumors 47% were anaplastic 66% had gross total resection Median follow-up: 46 months Merchant TE et al. J Clin Oncol 2004; 22: MacDonald SM et al. Neuro-oncology 2013; 15: MGH Proton Ependymoma Study MGH Proton Ependymoma Study MacDonald SM et al. Neuro-oncology 2013; 15: MacDonald SM et al. Neuro-oncology 2013; 15: Different Types of Radiotherapy Technology Three Dimensional, Conformal Radiotherapy Intensity modulated radiation therapy Proton therapy Stereotactic radiosurgery Brachytherapy I CR U 9 9 Gross Tumor Volume (GTV) Clinical Target Volume (CTV) Internal Target Volume (ITV) Planning Target Volume (PTV) 9

10 Difference between 3D-CRT and IMRT INTENSITY MODULATED RADIATION THERAPY (IMRT) 3D-CRT IMRT Craniopharyngioma IMRT Intensity Modulated Radiation Therapy IMRT in Medulloblastoma Ototoxicity and IMRT in Medulloblastoma Median follow-up (months) Mean dose to cochlea Mean cisplatin Dose Pediatric Oncology Group Ototoxicity Grade (number of patients) N = 50 Conventional RT N=11 IMRT N=15 IMRT N=88* Gy ( ) Gy ( ) Gy (standard risk), 43 Gy (high risk) 220mg/ m 2 ( ) 290mg/ m 2 ( ) Grade 0 Grade 1 Grade 2 Grade 3 Grade % mg/ m 2 * Number of ears 13% 18% Paulino AC et al. Cancer 2011; 117: Huang E et al. IJROBP 2002; 52: , Paulino AC et al. IJROBP 2010; 78:

11 IMRT in Pediatric Brain Tumors Proton Therapy First Author Tumor Type N Local Control Overall Survival Paulino Medulloblastoma % (5yr) 72% (5yr) Polkinghorn Medulloblastoma % (median:63 mos) Vieira Medulloblastoma % (median:44 mos) 87-88% (median:63 mos) 90% (median:44 mos) Schroeder Ependymoma 22 68% (3yr) 87% (3yr) Paulino Low grade glioma % (8yr) 93.7% (8yr) Greenfield Craniopharyngioma % (solid, 10yr) 96.0% (10yr 60.7% (cystic, 10yr) Merchant Craniopharyngioma % (5yr) NA Spread Out Bragg Peak Proton CSI fomedulloblastoma r Medulloblastoma and Protons Organ Mean Dose (Gy) Maximum Dose (Gy) Thyroid 0 4 Testis 0 0 Pituitary Hypothalamus Esophagus 9 25 Thyroid Courtesy of Dr. Anita Mahajan Proton Therapy for Craniopharyngioma Posterior Fossa Ependymoma Photon Therapy for Craniopharyngioma PROTONS IMRT Courtesy of D. Grosshans MacDonald SM et al. Neuro-oncology 2013; 15:

12 Protons in Pediatric Brain Tumors First Author Tumor Type N Local Control Overall Survival Bishop Craniopharyngioma 21 81% (3yr cystic) 96% (3yr) MacDonald Ependymoma 70 83% (3yr) 95% (3yr) McGovern AT/RT 31 Median progression-free survival: 20.8 mos MacDonald Germ cell tumor % (median:28 mos) Hug Low grade glioma 27 21/27 pts (median:3.3 years) Median survival: 34.3 mos 100% (median:28 mos) 21/27 pts (median:3.3 years) Int J Radiat Oncol Biol Phys 87(2), 2013 Method of radiotherapy in which sealed radioactive sources are used to deliver radiation at a short distance by interstitial, intracavitary or surface application. With this mode of radiation therapy, a high dose can be delivered locally to the tumor with rapid dose falloff in the surrounding normal tissue BRACHYTHERAPY Commonly Used Brachytherapy Sources Radionuclide Half-life Gamma ray energy Physical configuration Cesium years 662 KeV Tubes, needles Iodine days KeV Seeds, liquid Iridium days MeV Wire, seeds Palladium days KeV seeds Radium years MeV Tubes, needles Brachytherapy Iodine-125 Seeds for Pediatric Low-Grade Glioma 147 pts < 20 yrs treated with I-125 stereotactic brachytherapy 30 day morbidity: 5.4% 5- and 10-year overall survival rates were 93% and 82% 21 (14.8%) relapsed Complete response in 24.6%, partial response in 31.0% and stable disease in 29.6% Tumor volume > 15 ml. associated with increased relapse Ruge MI et al. J Clin Oncol 2011; 29:

13 Stereotactic Radiosurgery Stereotactic Radiosurgery The intersection of multiple arcs of radiation results in a high target dose while sparing normal brain tissue. One treatment Radiobiologically more effective for more radioresistant tumors as high fraction size is delivered Highly conformal form of treatment Can be linear accelerator based or gamma knife Size limit Does not follow the 4Rs Principle of Radiobiology In children, screws to the developing skull may limit its use Need neurosurgeon to put frame Brain and Head and Neck although now there is SBRT Stereotatic radiosurgery using a single isocenter to treat 4 separate targets with HELIOS inverse planning system and 120-leaf Multi-leaf collimator Other Radiotherapy Modalities Heavy Particles other than Proton Intraoperative Radiotherapy RADIOTHERAPY IN INFANTS WITH BRAIN TUMORS PEDIATRIC NEUROONCOLOGY TUMOR BOARD: PUBLIC ENEMY # 1 RADIATION ONCOLOGIST CURE COGNITIVE DEFICIT ENDOCRINOPATHY GROWTH RETARDATION VASCULOPATHY SECONDARY MALIGNANCY 13

14 Conclusions Conclusions Rapid development of organs during infancy is a critical concern in radiation therapy of infant brain tumors There is accumulating evidence that a subset of infants with medulloblastoma and ependymoma will not need radiotherapy There is a growing body of literature that children 1 to 3 years of age may be treated with localized, conformal radiotherapy IMRT and proton therapy are currently being employed in the treatment of brain tumors. Current evidence indicate that local control rates are comparable to historical control with the possible reduction of late toxicity in the future 14