Challenging the clinical relevance of folinic acid over rescue after high dose methotrexate (HDMTX)

Ian J. Cohen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The hypothesis: The use of adequate folinic acid rescue (in clinically relevant doses) after high dose methotrexate will prevent neurotoxicity without reducing treatment results. Methods: A literature search was performed to test the hypothesis that no evidence for the existence of folinic acid over-rescue of high-dose methotrexate (MTX) in clinically relevant situations exists (evidence that too much folinic acid reduced cure rate). Empirical data: Examples of folinic acid over-rescue after lower doses of MTX were found and has been cited as evidence of over rescue of high dose MTX. Mega doses of folinic acid, used when toxic levels of MTX occurred, also could neutralize the MTX effect. Data were found to support the contention that higher levels of MTX require disproportionally higher folinic acid doses for rescue. Careful examination of the available studies after HDMTX yielded more convincing alternative explanations for reduction in cure rate than over rescue. Little convincing evidence for the existence of over rescue after HDMTX was found. Discussion: The rescue of high-dose MTX with an appropriate dose of folinic acid that can prevent toxicity, especially neurotoxicity, was not shown to reduce the therapeutic effect. No evidence was found that higher doses of folinic acid after high dose MTX reduces the therapeutic effect. Consequences of the hypothesis: Acceptance of the hypothesis can prevent harm being caused (especially brain damage) by reversing the trend of dose reduction in FA rescue. The recognition that the use of higher folinic acid doses is safe, can prevent neurotoxicity, and does not reduce prognosis has important implications for the development of effective non toxic treatment protocols.

Original languageEnglish
Pages (from-to)942-947
Number of pages6
JournalMedical Hypotheses
Issue number5
StatePublished - Nov 2013


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