Methotrexate levels and outcome in osteosarcoma

Shayna Zelcer, Michael Kellick, Leonard H. Wexler, Weiji Shi, Marie Sankaran, Sarah Lo, John Healey, Andrew G. Huvos, Paul A. Meyers, Richard Gorlick

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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 μmol/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. Procedure. 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 μmol/L (range: 410-4,700 μmo,/L), with significant intra-patient and inter-patient variability. Fifty-eight percent of the levels were 1,000 μmol/L or higher. Response to pre-operative chemotherapy was: 18% Crade 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/m2. 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.

Original languageEnglish (US)
Pages (from-to)638-642
Number of pages5
JournalPediatric Blood and Cancer
Volume44
Issue number7
DOIs
StatePublished - Jun 15 2005

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Osteosarcoma
Methotrexate
Necrosis
Disease-Free Survival
Adjuvant Chemotherapy
Serum
Therapeutics
Pharmacokinetics
Drug Therapy

Keywords

  • Methotrexate
  • Necrosis
  • Osteosarcoma
  • Survival

ASJC Scopus subject areas

  • Cancer Research
  • Pediatrics, Perinatology, and Child Health
  • Hematology

Cite this

Zelcer, S., Kellick, M., Wexler, L. H., Shi, W., Sankaran, M., Lo, S., ... Gorlick, R. (2005). Methotrexate levels and outcome in osteosarcoma. Pediatric Blood and Cancer, 44(7), 638-642. https://doi.org/10.1002/pbc.20314

Methotrexate levels and outcome in osteosarcoma. / Zelcer, Shayna; Kellick, Michael; Wexler, Leonard H.; Shi, Weiji; Sankaran, Marie; Lo, Sarah; Healey, John; Huvos, Andrew G.; Meyers, Paul A.; Gorlick, Richard.

In: Pediatric Blood and Cancer, Vol. 44, No. 7, 15.06.2005, p. 638-642.

Research output: Contribution to journalArticle

Zelcer, S, Kellick, M, Wexler, LH, Shi, W, Sankaran, M, Lo, S, Healey, J, Huvos, AG, Meyers, PA & Gorlick, R 2005, 'Methotrexate levels and outcome in osteosarcoma', Pediatric Blood and Cancer, vol. 44, no. 7, pp. 638-642. https://doi.org/10.1002/pbc.20314
Zelcer S, Kellick M, Wexler LH, Shi W, Sankaran M, Lo S et al. Methotrexate levels and outcome in osteosarcoma. Pediatric Blood and Cancer. 2005 Jun 15;44(7):638-642. https://doi.org/10.1002/pbc.20314
Zelcer, Shayna ; Kellick, Michael ; Wexler, Leonard H. ; Shi, Weiji ; Sankaran, Marie ; Lo, Sarah ; Healey, John ; Huvos, Andrew G. ; Meyers, Paul A. ; Gorlick, Richard. / Methotrexate levels and outcome in osteosarcoma. In: Pediatric Blood and Cancer. 2005 ; Vol. 44, No. 7. pp. 638-642.
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abstract = "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 μmol/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. Procedure. 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 μmol/L (range: 410-4,700 μmo,/L), with significant intra-patient and inter-patient variability. Fifty-eight percent of the levels were 1,000 μmol/L or higher. Response to pre-operative chemotherapy was: 18{\%} Crade 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/m2. 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.",
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AU - Shi, Weiji

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AU - Lo, Sarah

AU - Healey, John

AU - Huvos, Andrew G.

AU - Meyers, Paul A.

AU - Gorlick, Richard

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N2 - 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 μmol/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. Procedure. 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 μmol/L (range: 410-4,700 μmo,/L), with significant intra-patient and inter-patient variability. Fifty-eight percent of the levels were 1,000 μmol/L or higher. Response to pre-operative chemotherapy was: 18% Crade 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/m2. 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.

AB - 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 μmol/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. Procedure. 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 μmol/L (range: 410-4,700 μmo,/L), with significant intra-patient and inter-patient variability. Fifty-eight percent of the levels were 1,000 μmol/L or higher. Response to pre-operative chemotherapy was: 18% Crade 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/m2. 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.

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