Table 2. CNS-Directed Treatment Regimens for Newly Diagnosed Childhood ALL continued...
Toxicity of CNS-directed Therapy
Toxic effects of CNS-directed therapy for childhood ALL can be divided into the following two broad groups:
- Acute/subacute toxicities (e.g., seizures, stroke, somnolence syndrome, and ascending paralysis).
- Late-developing toxicities (e.g., meningiomas and other second neoplasms; leukoencephalopathy; and a range of neurocognitive, behavioral, and neuroendocrine disturbances).[25,26,27]
The most common acute side effect associated with intrathecal chemotherapy alone is seizures. Up to 5% of nonirradiated patients with ALL treated with frequent doses of intrathecal chemotherapy will have at least one seizure during therapy. Higher rates of seizure were observed with consolidation regimens that included multiple doses of high-dose methotrexate in addition to intrathecal chemotherapy.
Patients with ALL who develop seizures during the course of treatment and who receive anticonvulsant therapy should not receive phenobarbital or phenytoin as anticonvulsant treatment, as these drugs may increase the clearance of some chemotherapeutic drugs and adversely affect treatment outcome. Gabapentin or valproic acid are alternative anticonvulsants with less enzyme-inducing capabilities.
In general, patients who receive intrathecal chemotherapy without cranial radiation appear to have less severe neurocognitive sequelae than irradiated patients, and the deficits that do develop represent relatively modest declines in a limited number of domains of neuropsychological functioning.[30,31,32,33] This modest decline is primarily seen in young children and girls.
A comparison of neurocognitive outcomes of patients treated with methotrexate versus triple intrathecal chemotherapy showed no clinically meaningful difference.[Level of evidence: 3iiiC]
Controversy exists about whether patients who receive dexamethasone have a higher risk of neurocognitive disturbances. Long-term neurocognitive testing in 92 children with a history of standard-risk ALL who had received either dexamethasone or prednisone during treatment did not demonstrate any meaningful differences in cognitive functioning based on corticosteroid randomization.
Long-term deleterious effects of cranial radiation, particularly at doses higher than 18 Gy, have been recognized for years. Children receiving these higher doses of cranial radiation are at significant risk of neurocognitive and neuroendocrine sequelae.[37,38,39,40,41] At doses of 18 Gy, it does not appear that irradiated patients have more severe neurocognitive impairments than ALL survivors who were treated without radiation. On current clinical trials, many patients who receive prophylactic or presymptomatic cranial radiation are treated with an even lower dose. Longer follow-up is needed to determine whether 12 Gy will be associated with a lower incidence of late effects.