Methotrexate levels and outcome in osteosarcoma.
BACKGROUND
Peak serum concentrations of methotrexate (MTX) have been reported to correlate with outcome in osteosarcoma (OS). Modification of the MTX dose to achieve peak levels between 700 and 1,000 micromol/L has been recommended. The goal of the study was to assess whether there is a correlation between histologic necrosis of the tumor and/or prognosis with peak MTX serum concentration.


METHODS
Treatment included multi-agent adjuvant chemotherapy, including high-dose MTX (12 g/m2). Peak MTX levels were drawn following a 4-hr infusion. Histologic evaluation for percent necrosis was done at the time of definitive resection.


RESULTS
The median peak MTX level (n = 52 patients) was 1,060 micromol/L (range: 410-4,700 micromol/L), with significant intra-patient and inter-patient variability. Fifty-eight percent of the levels were 1,000 micromol/L or higher. Response to pre-operative chemotherapy was: 18% Grade I necrosis, 35% Grade II, 31% Grade III, and 16% Grade IV. No significant association was found between the mean peak MTX levels and necrosis (P = 0.44). Event-free survival (EFS) for the 48 patients with non-metastatic disease at diagnosis was 76% at 4 years of follow-up, with no association between the mean peak MTX level and EFS (P = 0.24).


CONCLUSIONS
The absence of a demonstrable correlation between peak MTX levels and histologic necrosis or EFS may suggest that most patients achieve therapeutic levels when MTX is given at a dose of 12 g/m(2). The significant degree of intra-patient variability in peak levels poses a dilemma for pharmacokinetic adjustment. Continued use of HD-MTX in all patients, rather than dose adapted therapy, may be justified.
Zelcer
Shayna
S
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Kellick
Michael
M
Wexler
Leonard H
LH
Shi
Weiji
W
Sankaran
Marie
M
Lo
Sarah
S
Healey
John
J
Huvos
Andrew G
AG
Meyers
Paul A
PA
Gorlick
Richard
R
D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D009336:Necrosis; D012516:Osteosarcoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D011446:Prospective Studies; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate