TY - JOUR
T1 - Delayed methotrexate clearance in osteosarcoma patients treated with multiagent regimens of neoadjuvant chemotherapy
AU - Bacci, Gaetano
AU - Ferrari, Stefano
AU - Longhi, Alessandra
AU - Forni, Cristiana
AU - Loro, Loretta
AU - Beghelli, Claudio
AU - Tremosini, Morena
AU - Versari, Michela
PY - 2003/7
Y1 - 2003/7
N2 - We retrospectively studied 790 patients with osteosarcoma treated by neoadjuvant chemotherapy at a single institution between 1983 and 2000 according to different protocols, all including a high dose of methotrexate (HDMTX), to determine the incidence of delayed clearance of HDMTX, and identify patients at high risk for this kind of toxicity. Chemotherapy was administered according to 7 different protocols, successively activated, in which HDMTX was associated with other drugs (cisplatin, adriamycin, ifosfamide) in different combinations. The doses of MTX ranged between 7.5 to 12 g/m2and patients received from 1 to 10 cycles with MTX for a total number of 4219 cycles. The incidence of delayed clearance of MTX (plasma values of the drug at 24 h >5 μM/l) was 8.6% per patient and 1.6% per cycle of treatment. In 51 cases the delayed clearance of MTX was 'mild' (plasma values of MTX at 24 h between 5 and 19 μM/l) and in 18 cases 'severe' (plasma values of MTX at the 24 h >20 μM/l). The delayed clearance of MTX was significantly correlated with the age of patients (16% for patients over 20 vs. 6% for younger patients: p=0.0001) and was significantly more frequent during the first cycles of chemotherapy (7% during the first 3 cycles of treatment vs. 2% during subsequent cycles). There was also a significant correlation (p=0.0001) between the plasma values of MTX at the end of the infusion and at 18 h and the delayed clearance of the drug. In addition to support treatment by increased hydration and sodium bicarbonate, all patients who experienced the delayed clearance of MTX were treated solely with a high dose of leucovorin (HDLV), which was started at the first 18 h. Significant neutropenia and/or thrombocythopenia, increase of serum creatinine, mucositis of varying degrees and vomiting occurred in most cases of severe delayed clearance of MTX, but all patients completely recovered. We conclude that in spite of adequate hydration and urine alkalinization and the use of pharmacokinetically guided leucoverin rescue, delayed clearance of MTX may still occur and that its incidence is higher in older patients and during the first cycles of treatment. However, if 'rescue' treatment is started early, the consequent morbility is tolerable and these patients can be rescued using only HDLV, without the need for extracorporeal removal.
AB - We retrospectively studied 790 patients with osteosarcoma treated by neoadjuvant chemotherapy at a single institution between 1983 and 2000 according to different protocols, all including a high dose of methotrexate (HDMTX), to determine the incidence of delayed clearance of HDMTX, and identify patients at high risk for this kind of toxicity. Chemotherapy was administered according to 7 different protocols, successively activated, in which HDMTX was associated with other drugs (cisplatin, adriamycin, ifosfamide) in different combinations. The doses of MTX ranged between 7.5 to 12 g/m2and patients received from 1 to 10 cycles with MTX for a total number of 4219 cycles. The incidence of delayed clearance of MTX (plasma values of the drug at 24 h >5 μM/l) was 8.6% per patient and 1.6% per cycle of treatment. In 51 cases the delayed clearance of MTX was 'mild' (plasma values of MTX at 24 h between 5 and 19 μM/l) and in 18 cases 'severe' (plasma values of MTX at the 24 h >20 μM/l). The delayed clearance of MTX was significantly correlated with the age of patients (16% for patients over 20 vs. 6% for younger patients: p=0.0001) and was significantly more frequent during the first cycles of chemotherapy (7% during the first 3 cycles of treatment vs. 2% during subsequent cycles). There was also a significant correlation (p=0.0001) between the plasma values of MTX at the end of the infusion and at 18 h and the delayed clearance of the drug. In addition to support treatment by increased hydration and sodium bicarbonate, all patients who experienced the delayed clearance of MTX were treated solely with a high dose of leucovorin (HDLV), which was started at the first 18 h. Significant neutropenia and/or thrombocythopenia, increase of serum creatinine, mucositis of varying degrees and vomiting occurred in most cases of severe delayed clearance of MTX, but all patients completely recovered. We conclude that in spite of adequate hydration and urine alkalinization and the use of pharmacokinetically guided leucoverin rescue, delayed clearance of MTX may still occur and that its incidence is higher in older patients and during the first cycles of treatment. However, if 'rescue' treatment is started early, the consequent morbility is tolerable and these patients can be rescued using only HDLV, without the need for extracorporeal removal.
KW - Methotrexate
KW - Neoadjuvant chemotherapy
KW - Osteosarcoma
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M3 - Article
C2 - 12792734
AN - SCOPUS:1542472976
VL - 10
SP - 851
EP - 857
JO - Oncology Reports
JF - Oncology Reports
SN - 1021-335X
IS - 4
ER -