Long-term sequelae of cancer treatment on the central nervous system in childhood

Increasing numbers of children with cancer, including those with acute lymphocytic leukemia and medulloblastoma, are experiencing long-term disease control. As survival increases, so does the recognition that the treatment used to prolong survival may have significant detrimental effects on the central nervous system (CNS). Because of the slow replication rate of most constituents of the CNS, these effects tend to be delayed. Radiotherapy, and to a lesser extent, chemotherapy (primarily methotrexate) have been implicated in the causation of such sequelae. The pathogenesis of CNS damage is only partially understood and evidence suggests that direct effects on intracranial endothelial cells and brain white matter and immunologic mechanism play a role. A spectrum of clinical syndromes may occur, including radionecrosis, necrotizing leukoencephalopathy, mineralizing microangiopathy with dystrophic calcification, cerebellar sclerosis and spinal cord dysfunction. The two most common forms of sequelae are neuropsychological and neuroendocrinologic damage. The frequency, degree of and etiology of neurocognitive dysfunction is less than completely elucidated. Radiotherapy has been implicated as the major cause of damage, but the relationship between radiotherapy and the type of damage caused and the volume and dose of radiotherapy and degree of cognitive damage is unclear. Cognitive deficits are progressive in nature. Younger children are more likely to suffer the severest damage; but no patient of any age is free of risk of damage. Growth hormone impairment is the most common form of neuroendocrinologic dysfunction. There is increasing evidence that children with cancer who are long-term survivors are at increased risk for the development of secondary CNS tumors; possibly due, in part, to previous treatment. Much work needs to be done to characterize the sequelae which may occur, develop means of earlier detection, investigate ways to ameliorate sequelae and devise less toxic treatment.