High‐Dose Methotrexate in Acute Lymphoblastic Leukemia: Where Is the Evidence for Its Continued Use?

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.