After 75 Years of Methotrexate, Can Treatment Results Be Improved With Appropriate Folinic Acid Rescue?

After 75 years of clinical use of folic acid antagonists such as methotrexate, relevant pharmacological data currently important for the effective and safe use of methotrexate were reviewed to see if it is possible to improve outcomes. Specifically, to improve how high-dose methotrexate (HD-MTX) can be given safely, what doses of MTX (methotrexate) are adequate to achieve therapeutic levels, and what is the appropriate folinic acid (FA) dose for effective rescue. This review is based on 50 years of personal experience with the use of HD-MTX in published literature. Many pharmacologic studies were performed over 50 years ago, but are still relevant and stand up to scrutiny today. What should be considered HD-MTX and how it can be given safely and effectively without late toxicity are presented. The variables responsible for effective folinic acid rescue, especially the doses of MTX and folinic acid and the time to start of rescue, are discussed. Understanding these highlighted aspects of therapy could help to prevent acute toxicity, improve treatment results, and prevent late effects.