Research Description
Highlights of Major
Accomplishments
Major Results
1. Consequences of CNS Proplylaxic in Childhood ALL
2. Neurodevelopmental Bases of Learning Disabilities
1.
Consequences of CNS Prophylaxis in Childhood ALL
Over two decades, we have tracked late neurocognitive effects associated
with therapies for acute lymphoblastic leukemia in collaboration with
the Dana-Farber Cancer Institute Consortium Acute Lymphoblastic Leukemia
Consortium. These studies have documented a steady lessening of adverse
late effects as efficacy of therapies has improved.
1.1. Cranial Radiation Therapy for Children with High-Risk ALL
We evaluated late neuropsychological effects at seven years post-diagnosis
and long-term survival for a cohort of patients treated for high-risk
childhood acute lymphoblastic leukemia with cranial radiation therapy.
All patients received 18 Gy cranial radiation as a component of central
nervous system treatment. Five-year overall survival % + standard error
was 82% + 2, and 5-year event-free survival was 75% + 3. IQ and memory
were at expected mean for age, but performance on a complex figure drawing
task was reduced. Efficacious therapy that includes cranial radiation
does not necessarily incur heightened risk for significant cognitive impairment.
1.2. Steroid Therapy May Adversely Affect Neuropsychological Outcome.
In a preliminary study, we compared the cognitive sequelae of treatment
for childhood acute lymphoblastic leukemia (ALL) of a group of patients
who received dexamethasone during the intensification and maintenance
phases of therapy with those of a historical control group for whom anti-leukemia
therapy was similar, except that the corticosteroid component of therapy
was prednisone. Patients were evaluated by standard cognitive and achievement
tests. Children treated with dexamethasone performed less well on cognitive
testing. Subsample analysis indicated that cranial radiation therapy (XRT)
and methotrexate (MTX) dose did not account for differences in cognitive
outcomes. Dexamethasone therapy may increase risk for neurocognitive late
effects in children treated for ALL. DFCI Consortium Protocol 00-01 randomizes
patients to prednisone or dexamethasone; planned follow-up will provide
a more definitive test of the hypothesis.
1.3. Hyperfractionated Cranial Radiation Therapy for Childhood ALL.
We evaluated 8-year survival and late neuropsychological toxicity
in children with acute lymphoblastic leukemia treated in a randomized
clinical trial to test whether hyperfractionated (twice daily) cranial
radiation therapy (CRT) can reduce incidence and severity of late toxicities
associated with 18 Gy CRT. Three hundred sixty-nine children treated on
two consecutive Dana-Farber Cancer Institute Consortium protocols for
high-risk acute lymphoblastic leukemia were randomized to conventionally
fractionated (CFX) or hyperfractionated (HFX) CRT to a total dose of 18
Gy. Event-free survival was 80 + 3% for children randomized to CFX and
72 + 3% for HFX (p = 0.06). Overall survival was 85 + 3% for CFX and 78
+ 3% for HFX (p = 0.06). CNS relapses occurred in 2.8% of patients in
CFX and 2.7% in HFX (p = 0.99). Cognitive function for both groups was
solidly in the Average range, with no group differences in intelligence,
academic achievement, visuospatial reasoning or verbal learning. Children
on the HFX arm exhibited a modest advantage for visual memory (p < 0.05).
Hyperfractionated radiation provides no benefit in terms of cognitive
late effects and may compromise anti-leukemic efficacy.
2.
Neurodevelopmental Bases of Learning Disabilities
2.1 Neurobehavioral Factors Associated with Referral for Learning Problems.
We evaluated community general education, community special education,
and hospital referred children (ages 7;6-11;11) prospectively over a two
year period. During this period, 17 general education children were referred
for evaluation (community referred). Prior to referral, Community referred
performed more poorly than community non-referred children on cognitive
ability, academic achievement, attention problems, and information processing.
Community referred performance was equivalent to that of community special
education and hospital referred, but hospital referred had poorer academic
achievement. Referred children performed more poorly on all measures than
non-referred, whether or not they met formal diagnostic criteria for a
disorder. Learning disorders may be better conceptualized as a context-dependent
problem of functional adaptation than as a "disability" analogous to the
physical disabilities, raising questions about validity of using psychometric
test scores as the criterion for identification.
2.2. Information Processing Deficits in Children with Attention Deficit/Hyperactivity
Disorder, Inattentive Type and Children with Reading Disability.
We examined the information processing capabilities of children diagnosed
with the inattentive subtype of attention deficit/hyperactivity disorder
(AD), who have been characterized as having a "sluggish cognitive tempo."
Children referred for school-related problems and non-referred community
controls participated. Among the referred children, 24 met criteria for
AD, 52 met criteria for reading disability (RD), and nine were comorbid
for RD and AD. Children with AD differed from those without AD on a visual
search task but not on an auditory processing task; the reverse was true
for children with RD. Decomposition of the visual search task into component
operations demonstrated that children in the AD group had a slow processing
rate, which was not attributable to inattention. The children with AD
were not globally poor at information processing nor inattentive, but
demonstrated diminished speed of visual processing, raising questions
about characterization of AD inattentive subtype as an "attention disorder."
