Remission Induction for Newly Diagnosed ALL
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 include seizures, stroke, somnolence syndrome, and ascending paralysis.
- Late developing toxicities include meningiomas and other second neoplasms, leukoencephalopathy and a range of neurocognitive, behavioral, and neuroendocrine disturbances.[51,52,53]
The most common acute side effect associated with IT chemotherapy alone is seizures. Up to 5% of nonirradiated patients with ALL treated with frequent doses of IT 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 IT 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.
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.[56,57,58,59,60] Young children (i.e., younger than 4 years) are at increased risk of neurocognitive decline and other sequelae following cranial radiation.[61,62,63] Girls may be at a higher risk of radiation-induced neuropsychologic and neuroendocrine sequelae than boys.[62,63,64] Long-term survivors treated with 18 Gy radiation appear to have less severe neurocognitive sequelae than those who had received higher doses of radiation (24 Gy-28 Gy) on clinical trials conducted in the 1970s and 1980s. In a randomized trial, hyperfractionated radiation (at a dose of 18 Gy) did not decrease neurologic late effects when compared with conventionally fractionated radiation; in fact, cognitive function for both groups was not significantly impaired.; [Level of evidence: 1iiC] On current clinical trials, many patients who receive prophylactic or presymptomatic cranial radiation are treated with an even lower dose (12 Gy). Longer follow-up is needed to determine whether 12 Gy will be associated with a lower incidence of neurologic sequelae.
In general, patients who receive IT 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.[67,68,69,70] This modest decline is primarily seen in young children and girls. A comparison of neurocognitive outcomes of patients treated with methotrexate versus triple IT therapy showed no clinically meaningful difference.[Level of evidence: 3iiiC] Controversy exists about whether patients who receive dexamethasone are at higher risk for neurocognitive disturbances, although 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.