Does mifamurtide affect the elimination of high-dose methotrexate in children with osteosarcoma?
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BACKGROUND: The standard treatment protocol for osteosarcoma in children and adolescents includes neoadjuvant (pre-surgical) MAP chemotherapy (high-dose methotrexate [HD-MTX], high-dose doxorubicin, and cisplatin), full resection of the tumor, and then adjuvant post-surgical chemotherapy. In Europe, the immunostimulant mifamurtide is often added to the post-surgical MAP courses in patients with non-metastatic disease, based on evidence that it increases 6-year overall survival. It is unknown whether mifamurtide affects the elimination of HD-MTX. METHODS: In a retrospective single-center study, we reviewed clinical and laboratory parameters of children and adolescents with osteosarcoma who received the MAP protocol between 2012 and 2020. Patients were classified into two cohorts based on post-operative treatment exposure: an “HD-MTX + mifamurtide cohort” (patients with localized disease received pre-operatively HD-MTX and postoperatively HD-MTX with mifamurtide) and an “HD-MTX only” cohort (patients with metastatic disease received only HD-MTX pre- and post-operatively). For each HD-MTX dose, we calculated the area under the concentration curve (AUC24−72) from MTX plasma concentrations collected 24, 48, and 72 h after the beginning of the HD-MTX infusion. We compared AUC24−72 for HD-MTX doses before and after surgery in both cohorts. RESULTS: Among 21 patients (mean age 16; 38% female), 11 were in the “HD-MTX + mifamurtide cohort”, and 10 in the “HD-MTX only” cohort. Among patients in the “HD-MTX + mifamurtide cohort”, the median MTX AUC24−72 in cycles before surgery (67.6 µmol*h/L; interquartile range, 51.2-131.4 µmol*h/L) was not significantly different from that in cycles after surgery with concomitant mifamurtide (84.5 µmol*h/L; IQR, 50.2-155.8 µmol*h/L; P = 0.61). Similarly, in patients in the “HD-MTX only” cohort, median AUC24−72 before and after surgery were comparable (P = 0.70).ConclusionsConcomitant mifamurtide therapy does not have a significant effect on methotrexate elimination after HD-MTX in children with osteosarcoma