Cranial irradiation and permeability of blood-brain barrier to cytosine arabinoside in children with acute leukemia

Cranial irradiation (CI) is an effective way to prevent central nervous system (CNS) leukemia in children with acute leukemia (AL). However, it is still unclear whether the antileukemic effect of CI is mediated by alteration of blood-brain barrier (BBB) permeability and consequent increased levels of systemically administered drugs or whether it simply results from a direct cytolytic effect on leukemic cells in the meninges at diagnosis. We evaluated the influence of CI on BBB permeability to 1-beta-D-arabinofuranosylcytosine (ara-C) in 23 children with AL undergoing CI for CNS leukemia prophylaxis. CI was administered at 18 Gy (16 patients) and 24 Gy (7 patients). ara-C levels were measured in cerebrospinal fluid (CSF) and plasma before, during, and after CI. Two doses were evaluated: 75 mg/m2/day (12 patients) and 480 mg/m2/day (11 patients). CSF and plasma ara-C levels were measured when steady state was achieved. CSF:plasma ratios, obtained before, during, and after CI, were compared by an ANOVA model for repeated measures and by Tukey's test. At the 75-mg/m2/day dose, the mean values of ara-C CSF:plasma ratios before, during, and after CI were 0.20, 0.27, and 0.27, respectively. At the 480-mg/m2/day dose, the mean CSF:plasma ratios before, during, and after CI were 0.09, 0.12, and 0.13, respectively. No significant differences were observed when CSF:plasma ratios were compared before and during, during and after, and before and after CI. Our results indicate that CI at the doses used for CNS prophylaxis in AL does not significantly alter the BBB as far as ara-C is concerned