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

Abstract

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.

Irradiation-induced progenitor cell death in the developing brain is resistant to erythropoietin treatment and caspase inhibition

“…8 Up to half of the children who received cranial RT developed significant intellectual or behavioral retardation, and these symptoms were more severe in children less than 3 years of age at the time of RT. [8][9][10][11] In addition to these neuropsychological complications, short stature resulting from growth hormone secretory or regulatory dysfunction has also been reported in the majority of brain tumor patients who received RT. 4,[12][13][14] If the severe aftereffects of the anticancer therapy can be reduced, the overall quality of life would be greatly improved for the increasing number of children who survive their cancer.…”

Phase I study of temozolomide in combination with thiotepa and carboplatin with autologous hematopoietic cell rescue in patients with malignant brain tumors with minimal residual disease

“…4,5,18 It has also been employed in very young children 19,20,22,23 in an attempt to avoid the deleterious long-term consequences of radiotherapy. 24 Previously successful myeloablative regimes often involved combinations of thiotepa, etoposide, carboplatin, carmustine and topotecan. 4,5,15,20,23,25 Thiotepa is an important component of high-dose chemotherapy owing to its steep dose-response and evidence that thiotepa is non-cross resistant with other alkylating agents such as cyclophosphamide and melphelan.…”

Neuropsychiatric aspects of paediatric brain tumours: an update

“…(56) Similarly extent of resection in neurosurgery has also been associated with deficits in intellectual functioning with higher decline associated with more extensive resection. (57) Posterior fossa syndrome (mutism, ataxia and behavioural changes), developing after surgery has a higher risk for neuropsychiatric squeal. (58,59) Further studies demonstrated that the surgical resection of brain tumours without adjuvant therapy was itself associated with deficits in neuropsychological testing in attention, memory, processing speed, and visuospatial processing, and a variety of behavioral problems.…”