High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma: Incidence, treatment, and outcome

• Published in: Cancer 2004-05, Vol.100 (10), p.2222-2232
• Main Authors: WIDEMANN, Brigitte C, BALIS, Frank M, KEMPF-BIELACK, Beate, BIELACK, Stefan, PRATT, Charles B, FERRARI, Stefano, BACCI, Gaetano, CRAFT, Alan W, ADAMSON, Peter C
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Diseases of the osteoarticular system; Medical sciences; Tumors of striated muscle and skeleton
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.20255

High-dose methotrexate (HDMTX)-induced renal dysfunction can be life threatening, because it delays methotrexate (MTX) excretion, thereby exacerbating the other toxicities of MTX. HDMTX-induced nephrotoxicity has been managed with high-dose leucovorin, dialysis-based methods of MTX removal, thymidine, and with the recombinant enzyme, carboxypeptidase-G sub(2) (CPDG sub(2)), which cleaves MTX to inactive metabolites. The objectives of the current study were to estimate the current incidence of HDMTX-induced renal dysfunction in patients with osteosarcoma and to compare the efficacy and recovery of renal function for dialysis-based methods of MTX removal with treatment using CPDG sub(2). The literature was reviewed for osteosarcoma trials, use of dialysis- based methods for MTX removal, and reports of MTX-induced nephrotoxicity, including information regarding recovery of renal function. Clinical trial databases of select osteosarcoma studies were reviewed. The efficacy of CPDG sub(2) and renal recovery after CPDG sub(2) rescue was obtained from the database of a compassionate-release trial. Approximately 1.8% of patients with osteosarcoma (68 of 3887 patients) who received HDMTX developed nephrotoxicity Grade => 2. The mortality rate among those patients was 4.4% (3 of 68 patients). Dialysis-based methods of MTX removal were used frequently but had limited effectiveness in removing MTX compared with the rapid reductions > 98% in plasma MTX concentrations achieved with CPDG sub(2). CPDG sub(2) did not appear to increase the time to recovery of renal function compared with supportive treatment that included dialysis-based methods. HDMTX-induced renal dysfunction continues to occur in approximately 1.8% of patients with osteosarcoma who are treated on clinical protocols with optimal supportive care. For patients with delayed MTX excretion and high plasma MTX concentrations, CPDG sub(2) should be considered over hemodialysis to lower plasma MTX concentrations rapidly and efficiently.