Comment on: Leukoencephalopathy, a Frequent Complication After High‐Dose Methotrexate in Treatment of Osteosarcoma. Why Does This Occur in 2025?

To the Editor: The elegant article by Raimbault et al. [1] showed that considerable neurotoxicity occurred when 165 mg/m2 folinic acid (FA) was given as rescue after 12 g/m2 methotrexate (MTX). This supports our study that inadequate FA causes neurotoxicity [2, 3]. They cited our article [3], which showed that giving less than 300 mg/m2 FA after high-dose MTX results in significant neurotoxicity but were unable to suggest any alternative cause of this complication. I would suggest that they re-read these articles. The critical question that must be asked is why this disaster occurred and how it can be prevented in the future. Treatment with MTX has been in use for 75 years [4], but many of the critical studies defining the use of high doses of MTX and FA have been forgotten or ignored. Sirotnak [5] was able to find a dose of MTX (with the appropriate dose of FA) that virtually eliminated toxicity without diminution of the tumor effect [5]. There is thus no basis for the claim that toxicity is inevitable when FA rescue is used. This is the basis of the myth that the lowest dose of FA possible should be used to prevent a reduction in chemotherapy effect. This has resulted in avoidable, unnecessary damage to patients without any evidence-based data existing. Reviewing the literature over the last 50 years, no unchallenged study has shown any reduction in prognosis when larger FA rescue doses were administered, nor has any study showed an improvement in outcomes when the folic acid dose was reduced. A study that gave 760 mg/m2 FA started 30 hours after the start of 12 g/m2 MTX achieved results as good as the best that other groups have reported, but without any neurological or neurophysiological damage [3, 6]. Siratnik also showed that there is no linear ratio between the dose of MTX and the dose of FA required for successful rescue (no deaths and no toxicity) [5]. Doubling the dose of MTX required an increase in the dose of FA, three or four times larger than the baseline dose. This explains why FA over-rescue is a problem with low-dose MTX but not with high-dose MTX use. The use of problematic citations to support the myth of over-rescue after high-dose MTX has been exposed [7]. None of the many problematic citations put forward to attempt to support this myth have survived scrutiny. Raimbault et al. [1] state that “increasing leucovorin in osteosarcoma protocols requires controlled trials to assess safety and efficiency.” This, however, will only occur if cooperative groups realize that it is their responsibility to face up to this challenge. The author declares no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.