High-dose methotrexate in childhood ALL

An event-free survival is currently achieved in 70-80% of children diagnose d with acute lymphotic leukemia (ALL). A decline in the long-term sequalae from therapy is a challenge at present. Due to the high incidence of centra l nervous system (CNS) relapse in ALL patients, cranial irradiation was int roduced as a prophylactic measure in the beginning of the 1970s. Cranial ir radiation, however, may cause secondary malignancies in the CNS. In recent years neurotoxicities have been demonstrated to follow cranial irradiation in a large proportion of ALL patients. Because of these deleterious effects , most ALL protocols are limited to the combination intrathecal and intrave nous methotrexate as the standard for CNS prophylaxis. In the 1970s, an int ermediate dose was administered, while from the 1980s a high dose of methot rexate was combined with intrathecal methotrexate. The regular methotrexate dose of later years has been in the range of 5-8 g/m(2). The intravenous m ethotrexate dose has actually varied from 2 to 33.6 g/m(2). The highest dos e, 33.6 g/m(2), has been without intrathecal instillation. In a study from Norway, high-dose methotrexate (6-8 g/m(2)) was used, and only two (2.2%) o f 89 ALL cases showed CNS relapse, both of reversible kind. In the United K ingdom, a randomized controlled by standard risk and white blood cell count below 50 x 10(9); a 4% reduction in CNS relapse was found for high-dose me thotrexate in comparison to those treated only with long-term intrathecal m ethotrexate. The use of methotrexate unalterably warrants some precautions. Rescue therapy with folinic acid is usually started 36 h after initiating the methotrexate infusion. Steps are also taken to secure adequate intake o f fluids and alkalinization of the urine. Provided irradiation is avoided, neurotoxicities rarely occur. For regular high-dose methotrexate adverse ef fects mostly involve mucositis and myelosuppresion.