title: High-dose methotrexate in acute lymphoblastic leukemia: where is the evidence for its continued use?
abstract: High-dose intravenous methotrexate is an important component of many effective chemotherapeutic regimens for childhood acute lymphoblastic leukemia (ALL). Its use has a strong pharmacologic rationale: to overcome mechanisms of resistance of the malignant cells and to achieve cytotoxic concentrations in sanctuary sites for lymphoblasts. Although therapeutic progress in ALL during the past 4 decades has been closely associated with more widespread use of intravenous methotrexate and in progressively larger doses, little data exist to clearly support the use of high-dose intravenous methotrexate over a regimen of prolonged administration of low-dose methotrexate. The implied superiority of intravenous methotrexate mainly stems from studies that used identical leucovorin rescue with low-dose methotrexate or from studies of upfront window therapy in untreated children with ALL in which single standard doses of oral methotrexate were compared with high-dose intravenous methotrexate with leucovorin rescue. The evidence favoring administration of intravenous methotrexate for children with ALL is critically reviewed. Despite its extensive use, high-dose intravenous methotrexate has not been proved conclusively to be more effective than less toxic, less labor intensive, and less costly methods of methotrexate administration.
authors.affiliation: Department of Pediatric Hematology-Oncology, University Hospital of Heraklion, Crete, Greece.
authors.forename: Elpis
authors.initials: E
authors.lastname: Mantadakis
authors.forename: Peter D
authors.initials: PD
authors.lastname: Cole
authors.forename: Barton A
authors.initials: BA
authors.lastname: Kamen
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D002648:Child; D002986:Clinical Trials as Topic; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005493:Folic Acid Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000627:therapeutic use; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*
chemical_list: D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D002955:Leucovorin; D008727:Methotrexate