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Research Description

Highlights of Major Accomplishments

  • Documented decreasing neurotoxicity in combination with improving efficacy over successive DFCI ALL protocols.

  • Documented that cranial radiation therapy (CRT, 1800 cGy) can be associated with excellent efficacy and minimal neurotoxicity in therapy for ALL, despite longstanding belief that CRT poses unacceptable risk for late neurotoxicity in these children.

  • Documented decreased efficiency of low-level information processing in children referred for learning problems, independent of their academic skill levels, suggesting that learning disability is better understood as a developmental disorder than a deficit in academic skill levels.

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."