Abstract
BACKGROUND: In high-dose methotrexate (MTX) (HD-MTX) therapy, a dosage regimen utilizing the pharmacokinetic (PK) parameters of individual patients (PK method) has been developed to successfully reduce the intra- and inter-individual variability of serum MTX concentration. In this study, we evaluated the relationship between the therapeutic effect and serum MTX concentration in HD-MTX therapy performed under conditions in which the serum MTX concentration was precisely controlled using the PK method. METHODS: HD-MTX therapy consisted of 1 h of rapid dosing and 5 h of maintenance dosing, with a target serum concentration of 700–1000 µmol/L 1–6 h after the start of administration. The initial MTX dose was determined based on the body surface area, and subsequent courses were determined using PK parameters calculated from changes in MTX concentration at 1, 2, 4, 6, 7, 9, 12, 24, 48, and 72 h after the start of MTX administration. The relationship between the maximum serum MTX concentration (C(max)) and mean concentration from 1 to 6 h after MTX administration [C(mean(1−6))] and efficacy was evaluated. The cut-off values for C(max) and C(mean(1−6)) were the values with the best sensitivity and specificity in terms of 5-year survival in the receiver operating characteristic curve. RESULTS: We included 33 patients with osteosarcoma without distant metastasis who underwent HD-MTX therapy. Those with a C(mean(1−6)) > 768 µmol/L had significantly longer overall survival (OS) (p = 0.010) and tended to have longer event-free survival (EFS) (p = 0.061), with a 5-year survival rate as high as 92.9% (p = 0.077). In contrast, prolonged OS, EFS, and 5-year survival rates were observed in patients with C(max) >936 µmol/L, but none of these differences were significant (p = 0.088, 0.200, and 0.103, respectively). Moreover, OS and EFS improved for C(mean(1−6)) > 768 µmol/L regardless of C(max). In a subgroup analysis of 24 patients aged < 20 years, OS and EFS were significantly prolonged in patients with a C(mean(1−6)) > 768 µmol/L (p = 0.010 and 0.025, respectively). CONCLUSIONS: The usefulness of the serum MTX concentration was demonstrated by designing dosing using the PK method. Furthermore, C(mean(1−6)) contributed more to prolonging OS and EFS than C(max). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-025-15437-6.