PURPOSE: High-dose methotrexate (HD-MTX) with leucovorin rescue is widely used to treat osteosarcoma. Our objectives were to assess correlations between pharmacokinetic parameters and the outcome of osteosarcoma and to analyze the relation between HD-MTX exposure and toxicity. METHODS: Pharmacokinetic data of 105 patients with osteosarcoma treated with 989 HD-MTX courses were evaluated. Pharmacokinetic parameters (clearance, half-life and AUC) were calculated based on methotrexate (MTX) serum levels measured at 6, 24, 36, 48 h after the initiation of the infusion. Clinical data were collected by retrospective chart review. Hepato-, nephro- and bone marrow toxicity parameters were categorized according to Common Toxicity Criteria v.3.0, and MTX dose intensity was calculated. Event-free survival (EFS) and overall survival (OS) were estimated according to the Kaplan-Meier method. RESULTS: Patients with serious hepatotoxicity had higher mean peak MTX concentrations (p < 0.0001), 24-h (p = 0.001) and 48-h MTX serum levels (p = 0.008) and AUC(0-48) (p < 0.0001), and lower MTX clearance (p = 0.0002). No significant association was found between toxicity and age, gender, presence of metastases or histological tumor response. Patients with higher 48-h MTX serum levels had significantly better OS and EFS. Higher dose intensity was associated with better EFS (p = 0.0504). There was no association between presence of toxicity and survival. CONCLUSION: There was correlation between MTX exposure and the incidence of toxicity. Higher serum concentrations at 48 h were associated with a better 5-year OS and EFS. These results suggest that higher MTX exposure may lead to serious side effects, but it also improves treatment outcome.
PURPOSE: High-dose methotrexate (HD-MTX) with leucovorin rescue is widely used to treat osteosarcoma. Our objectives were to assess correlations between pharmacokinetic parameters and the outcome of osteosarcoma and to analyze the relation between HD-MTX exposure and toxicity. METHODS: Pharmacokinetic data of 105 patients with osteosarcoma treated with 989 HD-MTX courses were evaluated. Pharmacokinetic parameters (clearance, half-life and AUC) were calculated based on methotrexate (MTX) serum levels measured at 6, 24, 36, 48 h after the initiation of the infusion. Clinical data were collected by retrospective chart review. Hepato-, nephro- and bone marrow toxicity parameters were categorized according to Common Toxicity Criteria v.3.0, and MTX dose intensity was calculated. Event-free survival (EFS) and overall survival (OS) were estimated according to the Kaplan-Meier method. RESULTS:Patients with serious hepatotoxicity had higher mean peak MTX concentrations (p < 0.0001), 24-h (p = 0.001) and 48-h MTX serum levels (p = 0.008) and AUC(0-48) (p < 0.0001), and lower MTX clearance (p = 0.0002). No significant association was found between toxicity and age, gender, presence of metastases or histological tumor response. Patients with higher 48-h MTX serum levels had significantly better OS and EFS. Higher dose intensity was associated with better EFS (p = 0.0504). There was no association between presence of toxicity and survival. CONCLUSION: There was correlation between MTX exposure and the incidence of toxicity. Higher serum concentrations at 48 h were associated with a better 5-year OS and EFS. These results suggest that higher MTX exposure may lead to serious side effects, but it also improves treatment outcome.
Authors: G Bacci; S Ferrari; N Delepine; F Bertoni; P Picci; M Mercuri; P Bacchini; A Brach del Prever; A Tienghi; A Comandone; M Campanacci Journal: J Clin Oncol Date: 1998-02 Impact factor: 44.544
Authors: Laila Holmboe; Anders M Andersen; Lars Mørkrid; Lars Slørdal; Kirsten Sundby Hall Journal: Br J Clin Pharmacol Date: 2012-01 Impact factor: 4.335
Authors: Stefan Bielack; Herbert Jürgens; Gernot Jundt; Matthias Kevric; Thomas Kühne; Peter Reichardt; Andreas Zoubek; Mathias Werner; Winfried Winkelmann; Rainer Kotz Journal: Cancer Treat Res Date: 2009
Authors: S Smeland; C Müller; T A Alvegard; T Wiklund; T Wiebe; O Björk; A E Stenwig; H Willén; T Holmström; G Follerås; O Brosjö; A Kivioja; K Jonsson; O Monge; G Saeter Journal: Eur J Cancer Date: 2003-03 Impact factor: 9.162
Authors: P Bieling; S Bielack; G Delling; H Jürgens; R Kotz; C Dose; H Astheimer; G Exner; H Gadner; N Graf Journal: Klin Padiatr Date: 1991 Jul-Aug Impact factor: 1.349
Authors: Patrick J Messerschmitt; Ryan M Garcia; Fadi W Abdul-Karim; Edward M Greenfield; Patrick J Getty Journal: J Am Acad Orthop Surg Date: 2009-08 Impact factor: 3.020
Authors: Marc Ghannoum; Darren M Roberts; David S Goldfarb; Jesper Heldrup; Kurt Anseeuw; Tais F Galvao; Thomas D Nolin; Robert S Hoffman; Valery Lavergne; Paul Meyers; Sophie Gosselin; Tudor Botnaru; Karine Mardini; David M Wood Journal: Clin J Am Soc Nephrol Date: 2022-03-02 Impact factor: 10.614
Authors: Brittany Wippel; Kenneth R Gundle; Theresa Dang; Jillian Paxton; Joseph Bubalo; Linda Stork; Rongwei Fu; Christopher W Ryan; Lara E Davis Journal: Cancer Med Date: 2018-12-22 Impact factor: 4.452