Comparison of Intermediate-Dose Methotrexate with Cranial Irradiation for the Post-Induction Treatment of Acute Lymphocytic Leukemia in Children

Abstract

We compared two regimens with respect to their ability to prolong disease-free survival in 506 children and adolescents with acute lymphocytic leukemia. All responders to induction therapy were randomized to treatment with 2400 rad of cranial irradiation plus intrathecal methotrexate or to treatment with intermediate-dose methotrexate plus intrathecal methotrexate, as prophylaxis for involvement of the central nervous system and other "sanctuary" areas. Patients were then treated with a standard maintenance regimen. Complete responders were stratified into either standard-risk or increased-risk groups on the basis of age and white-cell count at presentation. Among patients with standard risk, hematologic relapses occurred in 9 of 117 given methotrexate and 24 of 120 given irradiation (P less than 0.01). The rate of central-nervous-system relapse was higher in the methotrexate group (23 of 117) than in the irradiation group (8 of 120) (P = 0.01). Among patients with increased risk, radiation offered greater protection to the central nervous system than methotrexate (P = 0.03); there was no difference in the rate of hematologic relapse. In both risk strata the frequency of testicular relapse was significantly lower in the methotrexate group (1 patient) than the radiation group (10 patients) (P = 0.01). Methotrexate offered better protection against systemic relapse in standard-risk patients and better protection against testicular relapse overall, but it offered less protection against relapses in the central nervous system than cranial irradiation.

Long-Term Effects of Treatment for Acute Lymphoblastic Leukemia with and without Cranial Irradiation on Growth and Puberty: A Comparative Study

“…MDMTX. In NHR-ALL, this system of CNS prophylaxis has been shown to be more effective than 25-Gy cranial irradiation in achieving continuous remission (7,8), but its long-term effect on growth is unknown.…”

Evidence for CSF accumulation of 5-methyltetrahydrofolate during repeated courses of methotrexate plus folinic acid rescue

“…CNS involvement in non-I Hodgkin's lymphoma and acute lymphocytic leukaemia may be prevented or treated by repeated medium or high dose MTX combined with FA rescue (Freeman et al, 1983;Balis et al, 1985). Data were missing on the possibility of an adverse accumulation of FA in CSF in such protocols; in addition, as dihydrofolate reductase is present in the brain (Pollock & Kaufman, 1978), information is required on the appropriate systemic FA dose for neutralisation of excessive MTX exposure in CSF (Cohen et al, 1986).…”

“…Chemotherapy using methotrexate (MTX), associated (Freeman et al, 1983) or not (Balis et al, 1985) with intrathecal injections, may be effective in eradicating or preventing meningeal diseases. High dose MTX is increasingly used in place of radiotherapy (Brouwers et al, 1987), particularly for preventive purposes.…”

Single-Arm Standard-Dosage Combination Chemotherapy for Childhood Acute Lymphocytic Leukemia (All-KFSH-84 Protocol)

“…5 8,12 The use of chemotherapy alone to prevent central nervous system leukemia has been studied by Freeman, et al, utilizing simultaneous intravenous intermediate dose methotrexate (500 mg/m2 with 1/3 as a push dose and the remaining 2/3 as a 24-hour infusion) given three times at three-week intervals following the remission of induction. 13 Others have attempted to control central nervous system disease with periodic intrathecal therapy alone with comparable results and with less toxicity to the central nervous system. [14][15][16] The randomized study by the Children's Cancer Study Group indicated clearly the inferior results obtained in a group of patients (Group IV) receiving intrathecal therapy as the sole form of prevention of central nervous system leukemia.…”