Neurocognitive Sequelae of Pediatric Brain Tumors

A Presentation to the FDA Center for Drug Evaluation and ResearchPediatric Oncology Subcommittee of the Oncologic Drug Advisory

Committee

Daniel Armstrong, Ph.D.Department of Pediatrics

Mailman Center for Child DevelopmentUniversity of Miami Miller School of Medicine

andHoltz Children’s Hospital at the University of Miami/Miller School of

Medicine

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

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

Cognitive and Adaptive Outcome in Low-Cognitive and Adaptive Outcome in Low-Grade Pediatric Cerebellar Astrocytomas Grade Pediatric Cerebellar Astrocytomas

(CCG 9891/POG 9130)(CCG 9891/POG 9130)

0

20

40

60V

IQ

PIQ

FS

IQ

VM

I

Rea

din

g

Ari

th.

Sp

ellin

g

Com

mu

n.

Dai

ly L

vg.

Soc

ial

Mot

or

AB

C

Inte

rnal

Ext

ern

al

Su

m

PopulationBase Rate

Rate in Sample

% S

core

s B

elow

Nor

mal

****

***

*

***

*** ***

IQ Tests VMI WRAT-R Vineland Adaptive Behavior Achenbach

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)

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)

Long-term Cognitive Outcomes in Low Risk Long-term Cognitive Outcomes in Low Risk MedulloblastomaMedulloblastoma

0

20

40

60

80

100

Younger,SRT

Younger,RRT

Older, SRT Older, RRT

VIQPIQFSIQAttention

POG 8631: Standard vs. Reduced Dose Cranial Radiation TherapyPOG 8631: Standard vs. Reduced Dose Cranial Radiation Therapy

Mulhern, Kepner, Thomas, Armstrong, Friedman, & Kun, Mulhern, Kepner, Thomas, Armstrong, Friedman, & Kun, J Clin OncolJ Clin Oncol, 1999, 1999

Long-term Cognitive Outcomes in Low Risk Long-term Cognitive Outcomes in Low Risk MedulloblastomaMedulloblastoma

0

20

40

60

80

100

120

Younger,SRT

Younger,RRT

Older SRT Older, RRT

ReadingMath

POG 8631: Standard vs. Reduced Dose Cranial Radiation TherapyPOG 8631: Standard vs. Reduced Dose Cranial Radiation Therapy

Mulhern, Kepner, Thomas, Armstrong, Friedman, & Kun, Mulhern, Kepner, Thomas, Armstrong, Friedman, & Kun, J Clin OncolJ Clin Oncol, 1999, 1999..

Treatment Factors Associated with Outcomes

• Neurosurgery– Focal Deficit (include sensory, motor

impairment– Bleed– Posterior Fossa Syndrome (primarily

medulloblastoma)• Mutism• Motor weakness/impairment

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

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

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.

Emerging Cognitive Deficits: Developmental Patterns

1 2 3 4 5 6 7 8 9

Gross Motor Skills

Language SkillsAttention

Fine Motor Skills

Visual-Spatial Motor Skills

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)

Emerging Cognitive Deficits: Emerging Cognitive Deficits: Developmental PatternsDevelopmental Patterns

1 2 3 4 5 6 7 8 9

Gross Motor SkillsGross Motor Skills

Language Language SkillsSkillsAttentionAttention

Fine Motor SkillsFine Motor Skills

Visual-Spatial Motor Visual-Spatial Motor SkillsSkills

Common Late/Emerging Common Late/Emerging EffectsEffects

• 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

The Neurodevelopmental ModelTreatment-Academic Linkages

Cranial Radiation

Chemotherapy(MTX,

Steroids)

Surgery

Interrupted Myelination

Calcification

Failure of Connecting Structure

Development

Processing Speed

Visual Memory

Visual-MotorIntegration

Attention &Concentration

Organization & Planning

Structural Damage

Reading

(Comprehension)

Math (Calculations)

Handwriting

ShuntSeizureGenetics

Sensory Impairment Other

Impairment

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