the effects of chemotherapy on the pediatric brain christine kim md 1,2, michael iv md 2, kristen w....
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The Effects of Chemotherapy on the Pediatric Brain
Christine Kim MD1,2, Michael Iv MD2, Kristen W. Yeom MD1
1 Department of Radiology, Pediatric Neuroradiology Section, Lucile Packard
Children’s Hospital, Stanford University, Palo Alto, CA2 Department of Radiology, Stanford University and Stanford University
Medical Center, Stanford, CA
CONTROL # 1791 POSTER # EP-122
DISCLOSURES
No disclosures
BACKGROUND Neurotoxic effects after chemotherapy for malignancies,
such as breast cancer, lymphoma, and acute lymphoblastic leukemia, have been previously described1-14
Management and treatment of cancer may require aggressive chemotherapy regimens, which can produce adverse effects. For example, methotrexate is associated with neurocognitive
deficits and/or leukoencephalopathy.
BACKGROUND The radiologic signs of leukoencephalopathy have been
well established, including increased T2/FLAIR signal intensity in the supratentorial white matter. Diffusion restriction can be seen with acute toxicity.
Studies have shown that the incidence of leukoencephalopathy increases with methotrexate dose, and the risk of developing this adverse effect decreases upon treatment completion15-16.
Leukoencephalopathy After Methotrexate Chemotherapy
BACKGROUND Major depressive disorder and depressive symptoms are of
high prevalence in patients with malignancy.
Post traumatic stress disorder is found with variable prevalence in this population.
BACKGROUND Previous studies in patients with Hodgkin’s disease who
received Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) demonstrated17-18 Significant but transient hypometabolism in the prefrontal
cortex (Brodmann area 10)Early significant reduction of glucose metabolism in the
prefrontal cortex, orbitofrontal cortex (Brodmann area 11), and anterior cingulate cortex (Brodmann area 32)
PURPOSE The purpose of this study was to identify the effects of
chemotherapy on cerebral perfusion in pediatric oncology patients treated with chemotherapy.
Based on prior studies of adult lymphoma patients with altered brain metabolism on PET imaging, we hypothesized that children treated with chemotherapy have abnormal perfusion in the frontal and cingulate cortices.
MATERIALS AND METHODS: SUBJECTS
All pediatric patients presenting to Lucile Packard Children’s Hospital presenting for therapy of acute lymphoblastic leukemia (ALL) or Langerhans cell histiocytosis (LCH) were included in this retrospective study.Patients with ALL received chemotherapy regimens that
included methotrexate.Patients with LCH received chemotherapy regimens that
included prednisone, vinblastine, cytosine arabinoside, 2-chlorodeoxyadenosine, and/or 6 mercaptopurine
Inclusion criteria:Children aged 0-18 years old at the time of ALL or LCH
diagnosisHistory of current or prior chemotherapy treatmentPatients who underwent imaging [MRI with arterial spin
labeling (ASL) imaging at 3 Tesla] for neurologic symptoms or surveillance of underlying pathology
MATERIALS AND METHODS: SUBJECTS
Exclusion criteriaHistory of radiation therapy Patients presenting with other unrelated pathology, such
as infection, stroke, or seizures Normal controls: age-matched controls with no known
pathology were provided from our database
MATERIALS AND METHODS: SUBJECTS
MATERIALS AND METHODS: IMAGING TECHNIQUE
All patients were imaged at 3 Tesla MRI (Discovery 750; GE Medical Systems, Milwaukee, WI) using an eight-channel head coil.
Imaging included ASL imaging using following parameters19-20:Whole-brain images obtained with 3D background-suppressed
fast-spin-echo (FSE) stack-of-spirals methodTR/TE 4632/10.5, FOV 24cm x 24cm, 512 x 8 matrix, NEX of 3.Pseudocontinous labeling period of 1500 ms, followed by a 1500
ms post-label delay
MATERIALS AND METHODS: IMAGING ANALYSIS
Region of interest method was used to evaluate ASL cerebral blood flow (ml/100 g/min) and performed over the brain regions in the following areas17-
18:
Angular gyrus (Brodmann area 39)
Anterior prefrontal cortex (Brodmann area 10)
Orbitofrontal cortex (Brodmann area 11)
Dorsal anterior cingulate cortex (Brodmann area 32)
Hippocampi (included due to known cognitive deficits associated with chemotherapy)
Quantile (median) regressions were run for each ROI location.
REGIONS OF INTEREST ON ASL CEREBRAL BLOOD FLOW IMAGING
Anterior Prefrontal Cortex Bilateral Angular Gyri Bilateral Dorsal Anterior Cingulate Cortex
Bilateral Hippocampi Bilateral Orbitofrontal Cortex
REGIONS OF INTEREST ON ASL CEREBRAL BLOOD FLOW IMAGING
RESULTS The following number of patients met the inclusion criteria
and were included in the analysis:21 patients with ALL
12 patients had negative conventional MRI findings 9 patients had positive conventional MRI findings,
which included acute or evolving leukoencephalopathy19 patients with LCH33 age-matched control patients
CEREBRAL BLOOD FLOW IN PATIENTS WITH ALL AND LCH COMPARED TO AGE MATCHED CONTROLS
Region of the Brain
Overall CBF Difference in CBF of ALL patients
versus Age Matched Controls
Difference in CBF of LCH patients
versus Age Matched Controls
Difference in CBF of Regions on the
Left Versus the Right
Angular Gyrus 61.3 -5.7 (p=0.144) -9.8 (p=0.018) 1.1 (p=0.737)
Anterior Prefrontal Cortex
70.0 -7.0 (p=0.058) -8.6 (p=0.027) 8.9 (p=0.005)
Dorsal Anterior Cingulate Cortex
62.1 -6.8 (p=0.054) -8.1 (p=0.030) 7.2 (p=0.016)
Hippocampus 51.5 -1.3 (p=0.667) -1.7 (p=0.594) 0.0 (p=1.000)
Orbitofrontal Cortex 69.8 -6.4 (p=0.202) -5.2 (p=0.325) 5.2 (p=0.219)
CBF = cerebral blood flow (mL blood/100g tissue/minute)
COMPARISON OF CEREBRAL BLOOD FLOW FOR LCH, ALL, AND AGE MATCHED
CONTROLS PATIENTS
N = Age matched controls
Orb = Orbitofrontal cortex
Ant = Anterior prefrontal cortex
Dors = Dorsal anterior cingulate cortex
Hipp = Hippocampus
RESULTS SUMMARY
Significantly abnormal perfusion was seen in children treated for chemotherapy in LCH compared to age matched controls in the angular gyrus, anterior prefrontal cortex, and dorsal anterior cingulate cortex.
While no significant perfusion abnormality was detected in children treated for ALL in specific brain regions, wide variability in perfusion was observed in both patients with and without abnormality on conventional MRI compared to age matched controls.
CONCLUSION Our findings suggest altered cerebral perfusion in children
treated with chemotherapy. This might reflect altered underlying metabolism or
chemotherapy-associated impact on cerebral hemodynamics.
Future studies that combine cognitive assessment and perfusion changes may further provide insight into role of ASL perfusion in assessing neurotoxic effects in children treated by chemotherapy.
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