Clinical relations of methotrexate pharmacokinetics in the treatment for pediatric osteosarcoma.
OBJECTIVE
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.


CONCLUSIONS
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.
2nd Department of Pediatrics, Semmelweis University, Tüzoltó Street 7-9, 1094 Budapest, Hungary. marta.hegyi@gmail.com
Marta
M
Hegyi
Agnes
A
Gulácsi
Edit
E
Cságoly
Katalin
K
Csordás
Olivér T
OT
Eipel
Dániel J
DJ
Erdélyi
Judit
J
Müller
Karolina
K
Nemes
Orsolya
O
Lautner-Csorba
Gábor T
GT
Kovács
D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D001853:Bone Marrow / Q000187:drug effects; D001859:Bone Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D012516:Osteosarcoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D012189:Retrospective Studies; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate