Reply to Prof Ian J. Cohen

Abstract

Regarding pharmacokinetics, Csordas et al. [3] recently confirmed that CSF MTX concentration was correlated with the 24-h MTX serum level, but they also demonstrated that CSF penetration rate of MTX was independent of the MTX dose on a total of 583 HD-MTX courses analyzed.May all of these aspects justify a routinely invasive procedure and the relative deep sedation for these "early" infants?Regarding the second point raised by Cohen, the folinic acid rescue dose of 15 mg/m 2 is a standard quantity provided for different protocols of HD-MTX. Borsi et al. [4] treating with HD-MTX up to 8 g/m 2 had previously evaluated the event-free survival of children receiving less or more than 15 mg/m 2 (75 mg/m 2 ) rescue in patients with acute lymphoblastic leukemia. Although no significant difference was found, a tendency was observed for a lower risk of cancer relapse in patients receiving less folinic acid. No major MTX-related toxicity was observed in the group of patients receiving the lower dose of rescue. Authors concluded that a reduction in a folinic acid rescue dose below the generally accepted 12-15 mg/m 2 dose may increase the efficacy of HD-MTX while still remaining safe in preventing treatmentrelated toxicity.Intriguingly, we agree with the comment regarding the folinic acid dose escalation in case of altered MTX elimination: it is an essential prescription for the safety of these little patients. References 1. Lucchesi M, Guidi M, Fonte C, Farina S, Fiorini P, Favre C, de Martino M, Sardi I (2016) Pharmacokinetics of high-dose methotrexate in infants aged less than 12 months treated for aggressive brain tumors. Cancer Chemother Pharmacol 77:857-864 Dear editor,We thank Professor Cohen for his interest and insightful comments regarding our recent report on high-dose methotrexate in infants aged less than 12 months treated for CNS tumors [1]. He raised two mainly points: the evaluation and the clinical value of cerebrospinal fluid (CSF) methotrexate (MTX) level, and the rescue dose of folinic acid. As Cohen notes, we agree the evaluation of CSF MTX levels for research findings. However, in clinical practice a routinely evaluation after 24 h from MTX beginning is not so easy in infant aged <12 months and with a median weight of 5.63 kg.Most of clinical trials on CSF MTX level were conducted on hematological malignancies. In particular, Morse et al.[2] evaluated MTX pharmacology in childhood leukemia. In leukemia, the positivity of CSF for malignant cells has an important prognostic role and therapeutic implications. In central nervous system (CNS) solid malignancies, there are some different features to be considered: the antineoplastic agent must act primarily on tumor lesion through an adequate drug concentration in the brain parenchyma. Indeed, chemotherapy programs for CNS malignancies provide high dose of different drugs given intravenously, without intrathecal injection. Moreover, the role (prognostic and predictive of distance metastases) of malignant cells spreading in CSF is not well known in some histo...