1. Neurocognitive Sequelae of Pediatric Brain Tumors A Presentation to the FDA Center for Drug Evaluation and Research Pediatric Oncology Subcommittee of the Oncologic Drug Advisory Committee Daniel Armstrong, Ph.D. Department of Pediatrics Mailman Center for Child Development University of Miami Miller School of Medicine and Holtz Children’s Hospital at the University of Miami/Miller School of Medicine

2. Mechanisms of CNS Injury Genetics –Direct –Genetic Modifiers Structural damage Vascular injury: Large vessel, Microvascular Neurotransmitter abnormalities (acute and chronic) Metabolic abnormalities Neuroendocrine abnormalities Disruptions in development of –Myelin formation –Neural connections Environmental and Learning Factors

3. Things Related to Neurocognitive Late Effects Tumor: Size & Location Surgery and consequences of surgery Radiation Therapy to the head Chemotherapy Age at time of treatment Gender Shunt, Seizures CNS Infection Other Considerations –Genetics and family history –Injury unrelated to cancer –Limited learning experiences

4. Cognitive and Adaptive Outcome in Low-Grade Pediatric Cerebellar Astrocytomas (CCG 9891/POG 9130) Population Base Rate Rate in Sample % Scores Below Normal *** * * IQ TestsVMIWRAT-RVineland Adaptive BehaviorAchenbach Proportion of sub-normal scores higher than base rate: *p<.05, **p<.01, ***p<.001 Beebe, Ris,Armstrong, Fontanesi, Mulhern, & Holmes, ( J. Clin. Oncol, 2005)

5. Culprits Radiation Therapy & Chemotherapy –Damage to small blood vessels, resulting in calcification and potentially affecting brain metabolism and chemistry –Interference with normal brain growth and development Myelin Connecting structures –Sensory impairment Hearing with Cysplatin & RT Peripheral neuropathy (VCR)

6. Long-term Cognitive Outcomes in Low Risk Medulloblastoma POG 8631: Standard vs. Reduced Dose Cranial Radiation Therapy Mulhern, Kepner, Thomas, Armstrong, Friedman, & Kun, J Clin Oncol, 1999

7. Long-term Cognitive Outcomes in Low Risk Medulloblastoma POG 8631: Standard vs. Reduced Dose Cranial Radiation Therapy Mulhern, Kepner, Thomas, Armstrong, Friedman, & Kun, J Clin Oncol, 1999.

8. Treatment Factors Associated with Outcomes Neurosurgery –Focal Deficit (include sensory, motor impairment –Bleed –Posterior Fossa Syndrome (primarily medulloblastoma) Mutism Motor weakness/impairment

9. Treatment Factors Associated with Outcomes Radiation Therapy –Method of delivery Whole Brain, Hyper-fractionated, Stereotactic Dose Portal –Possible Outcomes Significant global intellectual impairment Specific impairment of functions developmentally in the RT field

10. Treatment Factors Associated with Outcomes Chemotherapy –Vincristine- Acute motor speed and coordination –Anti-angiogenesis chemo (e.g., thalidomide) Possible effects on memory, attention, processing speed –Methotrexate (primarily used in ALL; now considered for CNS protocols) Breakdown in folate pathway Calcification White matter abnormality –Cisplatin/Carboplatin Hearing loss –Cyclophosphamide, Etoposide, other New Agents Unknown…little experience without RT

11. Neruodevelopmental Model of Neurocognitive Late Effects Treatment seems to have its greatest effect on the part of the brain that develops after treatment. The parts of the brain that have developed before treatment seem to be relatively safe.

12. Emerging Cognitive Deficits: Developmental Patterns 123456789 Gross Motor Skills Language Skills Attention Fine Motor Skills Visual-Spatial Motor Skills

13. Basic Tenets of a Neurodevelopmental Model of Neurocognitive Late Effects The evaluation of the functional ability is influenced by: –The timing of the treatment disruption in the normal developmental course –The complexity of the mechanism(s) involved (e.g., dose of radiation, types of chemotherapy). –The age of the child at the time of assessment (expected developmental abilities-time since treatment)

14. Emerging Cognitive Deficits: Developmental Patterns 123456789 Gross Motor Skills Language Skills Attention Fine Motor Skills Visual-Spatial Motor Skills

15. Common Late/Emerging Effects Slow Processing Speed Attention Difficulties –Not hyperactive Memory Difficulties –Visual –Sequential Fine Motor Coordination and Speed Planning, Organization, Executive Function Difficulties Visual-Spatial-Motor Integration Difficulties Mathematics Difficulties (calculation, not application) Reading Difficulties (comprehension) Social Difficulties –Processing Speed –Social Cue Detection

16. The Neurodevelopmental Model Treatment-Academic Linkages Cranial Radiation Chemotherapy (MTX, Steroids) Surgery Interrupted Myelination Calcification Failure of Connecting Structure Development Processing Speed Visual Memory Visual-Motor Integration Attention & Concentration Organization & Planning Structural Damage Reading (Comprehension ) Math (Calculations) Handwriting Shunt Seizure Genetics Sensory Impairment Other Impairment

17. Prevention and Treatment of Neurocognitive Late Effects Education Adjust Primary Therapy (e.g., Baby POG) Identify neuroprotective medications Cognitive Rehabilitation Stimulant Medications; Other medications?- Risks with children Compensatory Intervention/Assistive Technology & Accommodations Targeted Early Intervention