High‐dose Methotrexate Therapy—An Area of Uncertainty *

Summary: A brief review of our present knowledge of the pharmacology and the pharmacokinetics of high‐dose methotrexate (MTX) therapy is presented. Although this drug has been in use for 30 years, there are many areas of uncertainty regarding the mode of action of its selective cytotoxicity, the degree of plasma protein binding, the renal toxicity, pharmacokinetics and extent of metabolism after a high dose. During the last decade, high‐dose methotrexate followed by citrovorum factor (CF) rescue has become a popular mode of cancer treatment, especially for osteogenic sarcoma, even though there is a lack of definitive evidence in man supporting the superiority of the high dose over more conventional doses. The rationale for the administration of these high doses and the necessity of citrovorum factor rescue to prevent toxicity are discussed. Even with citrovorum factor rescue and the recommended routine hydration and alkalinisation of the patient, a 6% mortality rate is still encountered with this therapy. It is to be hoped that the relative safety of these high‐dose regimens will be increased in the future with the greater availability of a rapid, precise assay for monitoring methotrexate during and after infusion as an indication of impending toxicity and the discovery of more efficient rescue agents (such as thymidine?). More research is required to determine the optimal methotrexate regimens with regard to the many variables which are associated with this therapy. Bearing in mind the high cost of high‐dose MTX therapy and the increased risk of severe toxicity, further comparative trials against the conventional‐dose regimens are essential to establish whether high‐doses do offer additional clinical advantages.