The best data on the cognitive effects of chemotherapy alone have come from studies of children with leukemia who did not have CNS leukemia. Unlike children with brain tumors – for whom there are many confounding variables that could influence intellect adversely, such as hydrocephalus, surgery, epilepsy, anticonvulsant therapy, as well as the tumor itself – children with leukemia receive chemotherapy as a preventative measure (CNS prophylaxis) and, therefore, have no specific risk factors for cognitive dysfunction. Rowland et al
] reported in 1984 that children with acute lymphoblastic leukemia (ALL) who had been irradiated for CNS prophylaxis had significantly lower IQs and worse performance on Wide Range Achievement Tests than children treated with chemotherapy alone (methotrexate injected either intrathecally (into the cerebrospinal fluid) or intravenously and intrathecally). This study and many others confirmed the prevailing belief that chemotherapy, in the absence of radiation, did not affect intellect.
In addition, 'methotrexate leukoencephalopathy', first reported in 1978 and characterized on computed tomography (CT) scans as calcifications in the basal ganglia, cerebral atrophy and less dense areas in the white matter, was reported in children with ALL treated with cranial radiation and methotrexate [11
], whereas children treated with methotrexate but no radiation did not suffer this complication. The only exception to this was those children with CNS leukemia who were unable to clear the methotrexate from the cerebrospinal fluid [12
It was concluded from these early studies that administration of methotrexate was safe if children had no CNS disease and were not irradiated. This concept was widely accepted until 1997, when we identified a group of non-irradiated children with ALL without CNS leukemia who developed evidence of methotrexate leukoencephalopathy on CT and magnetic resonance imaging (MRI) scans associated with concomitant cognitive changes (unpublished data). A subsequent group-wide study of neuroimaging and IQ testing of children treated for leukemia confirmed these preliminary findings of methotrexate-induced leukoencephalopathy in patients that had been considered to be at low-risk [13
]. Moreover, 40% of the children in that study had IQs less than 85, a striking difference from the average. As the dose and frequency of administration of methotrexate had been gradually increased over the previous two decades, the earlier optimistic predictions that methotrexate could be given with impunity were no longer valid.
Further evidence of the development of methotrexate-induced leukoencephalopathy in the absence of cranial radiation was shown in a German study of infants with medulloblastoma treated with high-dose intravenous methotrexate (5 g/m2
) and also methotrexate injected into the brain cavities (intraventricular injection), together with other chemotherapy, but no radiation [14
]. Only 4 of 23 children failed to develop leukoencephalopathy. A correlation was found between the cumulative dose of intraventicular methotrexate and the grade of leukoencephalopathy, but not the number of doses of intravenous methotrexate. Although children in this study fared better cognitively than those who had been irradiated in a previous trial, the mean IQ was still significantly lower than controls. Despite these findings, as well as the accumulating data on methotrexate leukoencephalopathy in non-irradiated children with leukemia, one arm of a proposed international study for infants with medulloblastoma will include high dose intravenous methotrexate (unpublished data). Concerns over the German experience [14
], however, convinced investigators to withhold intraventricular methotrexate from the trial.
It is becoming increasingly clear that not only CNS irradiation but also chemotherapy alone can cause severe neurotoxicity leading to cognitive decline and leuko-encephalopathy (not to mention secondary malignancies and adverse effects on endocrine function and growth). The pediatric neuro-oncology community has recognized the adverse effects of CNS radiation and has modified treatment with the dual goals of lessening late effects while maintaining acceptable survivals. In order to accomplish this, however, chemotherapy in increasing doses has become routine. Very high dose chemotherapy, requiring bone marrow transplantation or peripheral stem cell support, is now standard therapy for children with certain brain tumors, especially for the very young. Because of the rapid myelinization that occurs in infants, the finding by Noble and colleagues [1
] of the adverse effects of chemotherapy on oligodendrocytes are especially troubling. Mulhern et al
] had previously found a correlation between cognitive deficits in very young children treated with CNS radiation with or without chemotherapy and white matter loss, as identified on quantitative MRI scans. They attributed the reduction in normal-appearing white matter to radiation-induced damage to oligodendrocytes and endothelial cells [15
]. It would be important to determine whether infants treated with chemotherapy alone develop a similar reduction in normal-appearing white matter, as might be anticipated based on the finding by Noble and colleagues of loss of cell division of O-2A/OPCs following chemotherapy exposure, which would presumably lead to an inability to repair damaged myelin.
There are no easy answers. We must balance the need for survival with quality of life. In the mean time, until effective targeted therapy sparing normal tissue is developed or neuroprotective therapies are available, we will need to continue using various combinations of chemotherapy and cranial radiation. The excellent correlation of the in vitro
and in vivo
results of Noble and colleagues' study [1
] raises the hope that the technique used might allow investigators to evaluate both the effects of established agents (such as methotrexate) and newer agents on CNS neural progenitor cells and adjust treatment accordingly. As chemotherapy is almost never given as a single agent, testing these agents in combination would also be crucial. It is clear from Noble and colleagues' study [1
] that chemotherapy is potentially as neurotoxic as radiation, and much closer attention needs to be paid to the long term follow-up of both children and adults who receive this form of therapy.