Neurologic Changes Occur Long After Pediatric Lymphoid Malignancy

August 29, 2013

By Will Boggs, MD

NEW YORK (Reuters Health) Aug 29 - Decreased white matter integrity and associated neuropsychological dysfunction can occur decades after cranial radiotherapy (CRT) for childhood lymphoid malignancy, a new report says.

The findings lead the authors to recommend that CRT be used in these children only as a last resort.

Dr. Ilse Schuitema from Leiden University, The Netherlands and colleagues investigated white matter changes and associated neuropsychological dysfunction in 285 survivors of pediatric ALL or lymphoma 25 years after treatment.

They note that neurotoxic effects have been seen following chemotherapy and CRT, and younger age has been associated with more severe white matter lesions and worse neurocognitive outcomes.

In their new study, survivors who had been treated with CRT showed significantly worse visuomotor accuracy, visuomotor stability, work pace during sustained attention, and visuospatial sequential working memory than did survivors who had not been treated with CRT.

CRT-treated survivors also had significantly decreased fractional anisotropy (FA, a measure of white matter microstructure integrity) in several brain areas, whereas chemotherapy treatment was associated only with trends for lower FA in the frontal white matter tracts.

FA in the frontal, parietal, and temporal white matter tracts correlated significantly with measures of visuomotor control, visuospatial sequencing, and sustained attention work pace, the researchers reported August 19th in the Journal of Clinical Oncology online.

The FA decline with age in the CRT group indicated accelerated aging of white matter, the researchers note.

Declines in FA were related to cumulative CRT dose, but there were no correlations between dose and FA in the chemotherapy group.

"Accelerated aging of the brain and increased risk of early onset dementia are suspected after CRT, but not after chemotherapy," the investigators conclude.

"The growing support for the concept of accelerated aging after CRT implicates screening for early onset dementia," they explain. "Recommending lifestyle modifications that are implicated in slowing the progression of dementia, such as not smoking and getting regular physical exercise, could be considered."

"Although detrimental effects of chemotherapy on white matter and neuropsychological function are not completely absent," the authors say, "they are mild compared with CRT, although chemotherapy is equally effective in terms of survival and recurrence rates after ALL. This warrants a recommendation to use CRT only as a last resort."

In an editorial, Dr. F. Daniel Armstrong from University of Miami Miller School of Medicine in Miami, Florida writes, "Although the challenges of providing treatment and support to the adult survivors and their families who experience long-term problems associated with long-ago therapy are daunting, there is an opportunity to embark on studies that may bring about changes in treatment and long-term outcomes for the children we are treating today."

"The potential impact of this late effect in terms of both financial cost and burden to the patient and family is great; a similarly great response from the scientific and funding community is needed," Dr. Armstrong concludes.

Dr. Bernward Zeller from Oslo University Hospital in Norway, who has studied late effects of leukemia treatments in children, told Reuters Health, "It is not surprising that CNS-irradiation affects white matter integrity negatively; the opposite would have been surprising. For me it may be a little surprising that chemotherapy-only treated patients were affected so mildly."

"I think we should mention the possible neurocognitive deficits also not applying radiation therapy, but should stress that these defects usually do not preclude a meaningful life and a normal function in daily life, also in academic professions," Dr. Zeller said. "We should definitely not speak about premature dementia; these facts are not well proven at the moment, the eldest survivors from ALL just having reached an age of about 60 years."

Finally, Dr. Zeller recommends "avoiding irradiation whenever possible. Not overstating the significance of chemo-treatment on neurocognitive function, but every treatment has its price, so we should aim at further reducing treatment intensity where this is feasible (i.e., mainly in low-risk leukemias). Be aware of possible neurocognitive impairments (and chronic fatigue, which I am working with mainly) - and which is a common late effect, even when not radiated."

Dr. Schuitema did not respond to a request for comments on this report.


J Clin Oncol 2013.


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