High-dose methotrexate pharmacokinetics and outcome of children and young adults with osteosarcoma.

High-dose methotrexate (HDMTX) is used frequently in combination regimens that include nephrotoxic chemotherapy. The authors evaluated the impact of factors such as age and prior nephrotoxic agents on MTX pharmacokinetics in children and young adults with osteosarcoma and examined whether MTX pharmacokinetic parameters were associated with outcome. The authors evaluated MTX pharmacokinetics in 140 patients who were treated with 1083 courses of HDMTX on 3 consecutive studies of multiagent chemotherapy at a single institution. The influence of MTX pharmacokinetics on the outcome of 107 patients with localized disease was examined. Mean peak MTX concentrations > or = 1000 microM were achieved in 135 patients (96%). MTX clearance was decreased after cisplatin therapy (P = 0.01), after cisplatin in combination with ifosfamide therapy (P < 0.0001), and after MTX therapy (P = 0.003). In patients with localized osteosarcoma, a higher mean MTX area under the curve, a higher mean peak concentration of MTX, a longer mean time above a threshold concentration (500 microM), and a lower mean MTX clearance were associated with lower probability of event-free survival (EFS). Patients who had a mean peak MTX plasma concentration > 1500 microM were found to have a worse outcome (estimated 5-year EFS, 58.5% +/- 6.7%) compared with patients who had a mean peak concentration < or = 1500 microM (estimated 5-year EFS, 75.5% +/- 6.6%; P = 0.02). When HDMTX (12 g/m(2)) was used with multiagent therapy for patients with osteosarcoma, very high MTX exposures were associated with poorer outcome. The prospective evaluation of MTX pharmacokinetics and their relation to outcome in a large study is warranted to further substantiate the current findings and to elucidate the causative mechanism.

Crews KR ，Liu T ，Rodriguez-Galindo C ，Tan M ，Meyer WH ，Panetta JC ，Link MP ，Daw NC ... -  《CANCER》

Delayed methotrexate clearance in osteosarcoma patients treated with multiagent regimens of neoadjuvant chemotherapy.

Bacci G ，Ferrari S ，Longhi A ，Forni C ，Loro L ，Beghelli C ，Tremosini M ，Versari M ... -  《ONCOLOGY REPORTS》

Methotrexate levels and outcome in osteosarcoma.

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. 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. 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). 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 S ，Kellick M ，Wexler LH ，Shi W ，Sankaran M ，Lo S ，Healey J ，Huvos AG ，Meyers PA ，Gorlick R ... -  《-》

Dose escalation with pharmacokinetics monitoring in methotrexate chemotherapy of osteosarcoma.

Delepine N ，Delepine G ，Cornille H ，Brion F ，Arnaud P ，Desbois JC ... -  《-》

Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups.

Ferrari S ，Smeland S ，Mercuri M ，Bertoni F ，Longhi A ，Ruggieri P ，Alvegard TA ，Picci P ，Capanna R ，Bernini G ，Müller C ，Tienghi A ，Wiebe T ，Comandone A ，Böhling T ，Del Prever AB ，Brosjö O ，Bacci G ，Saeter G ，Italian and Scandinavian Sarcoma Groups ... -  《JOURNAL OF CLINICAL ONCOLOGY》