Journal of Clinical Oncology, Vol 12, 1443-1451, Copyright © 1994 by American Society of Clinical Oncology

ARTICLES

Methotrexate pharmacokinetics and prognosis in osteosarcoma

N Graf, K Winkler, M Betlemovic, N Fuchs and U Bode
Universitatsklinik fur Kinder- und Jugendmedizin, Homburg/Saar, Germany.

PURPOSE: The influence of methotrexate (MTX) pharmacokinetic parameters on the efficacy of high-dose MTX (HDMTX) in osteosarcoma was analyzed. PATIENTS AND METHODS: MTX serum peak values from 198 patients in 1,703 treatment courses and more detailed pharmacokinetic data from 185 patients in 1,045 treatment courses from the Cooperative Osteosarcoma Study Group (COSS) studies COSS-80, COSS-82, and COSS-86 were investigated. RESULTS: A mean threshold peak level of > or = 1,000 mumol/L for the repeated MTX courses of individual patients was found to correlate significantly to prognosis in study COSS-80 (18% v 64% actuarial 10-year disease-free survival [DFS], P = .0001). Six courses of HDMTX per patient who achieved peak values > or = 1,000 mumol/L were found to be sufficient for a full effect to be seen in DFS in COSS-80. The MTX peak level was found to correlate closely to the area under the curve (AUC). However, AUC was a less powerful determinator of prognosis than the mean threshold MTX peak value. In patients who received cisplatin (DDP) as one of the additional drugs to MTX, the peak values and AUC were significantly increased (1,396 v 1,276 mumol/L, P = .011; 6,684 v 5,820 h.mumol/L, P < or = .002) and only a few patients (6%) did not achieve mean threshold MTX peak values. In addition, following restriction of hydration fluid after the MTX infusion from 4.5 to 3.0 L/m2 per 24 hours, the early MTX half-life (t1/2) and the AUC, but not the MTX peak value, were significantly increased (3.4 v 3.05 hours, and 6,760 v 5,998 h.mumol/L, respectively, P < or = .002). CONCLUSION: MTX pharmacokinetics significantly influence the efficacy of MTX in osteosarcoma. Individual adaptation of the MTX dose to ensure a threshold peak serum level > or = 1,000 mumol/L does not seem necessary at a fixed dose of 12 g MTX/m2, restriction of hydration fluid to 3 L/m2 per 24 hours, and concomitant use of DDP within the drug regimen.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				N. Jaffe and R. Gorlick High-Dose Methotrexate in Osteosarcoma: Let the Questions Surcease--Time for Final Acceptance J. Clin. Oncol., September 20, 2008; 26(27): 4365 - 4366. [Full Text] [PDF]

				L. Alnaim Therapeutic drug monitoring of cancer chemotherapy Journal of Oncology Pharmacy Practice, December 1, 2007; 13(4): 207 - 221. [Abstract] [PDF]

				F. Fagioli, M. Aglietta, A. Tienghi, S. Ferrari, A. Brach del Prever, E. Vassallo, A. Palmero, E. Biasin, G. Bacci, P. Picci, et al. High-Dose Chemotherapy in the Treatment of Relapsed Osteosarcoma: An Italian Sarcoma Group Study J. Clin. Oncol., April 15, 2002; 20(8): 2150 - 2156. [Abstract] [Full Text] [PDF]

				Y. Y. Hon and W. E. Evans Making TDM work to optimize cancer chemotherapy: a multidisciplinary team approach Clin. Chem., February 1, 1998; 44(2): 388 - 400. [Abstract] [Full Text] [PDF]