Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, Hematology, Pediatrics, 1103 Clinical Sciences, 1112 Oncology and Carcinogenesis, 1114 Paediatrics and Reproductive Medicine, Oncology & Carcinogenesis, 3211 Oncology and carcinogenesis, 3213 Paediatrics

Abstract:

Purpose of study: Central nervous system (CNS) directed chemotherapy (CT) and radiotherapy (CRT) for childhood acute lymphoblastic leukemia (ALL) has neurotoxic properties. The aim of this study is to find the underlying mechanisms of neurocognitive sequelae in adulthood, 25 years after treatment. Method: Twenty-four patients treated with standard dose CT+CRT (2500 Gy), 29 patients treated with standard dose CT only, 20 patients treated with high dose CT and 49 healthy controls were assessed with the Amsterdam Neuropsychological Tasks program (ANT) and MR Diffusion Tensor Imaging (DTI). Differences in Fractional Anisotropy (FA) - a DTI measure describing white matter (WM) integrity - were analysed using whole brain voxel-based statistical analysis. Correlations with cognition and age were investigated. Results: Survivors treated with CT+CRT demonstrated significantly decreased FA (pFWE corrected < 0.05) compared to controls in orbitofrontal WM tracts, the corpus callosum and cingulum (frontal and parietal) and the inferior longitudinal and fronto-occipital fasciculi. At a lower threshold (p<0.001 uncorrected for multiple comparisons), indications for lower WM integrity were seen for the group that received standard dose CT in frontal WM tracts, and for the group treated with high dose CT in the lemnisci. Decreases in FA correlated well with impaired performance on tasks measuring visuomotor control, working memory and sustained attention. Within the CT+CRT group, a steep decline of FA with age was found that was not seen in the CT groups or controls. Conclusion: For survivors treated with CT+CRT, both FA and cognition are significantly impaired 25 years after treatment for ALL. Effects of CT alone seem relatively mild. The steep decline of FA with age compared to controls, is a strong indication for accelerated aging after CRT. Long-term follow-up and screening for early onset dementia seem warranted. In future treatment regimens, CRT should only be used as a last resort.