High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma.
BACKGROUND
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-G2 (CPDG2), 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 CPDG2.


METHODS
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 CPDG2 and renal recovery after CPDG2 rescue was obtained from the database of a compassionate-release trial.


RESULTS
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 CPDG2. CPDG2 did not appear to increase the time to recovery of renal function compared with supportive treatment that included dialysis-based methods.


CONCLUSIONS
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, CPDG2 should be considered over hemodialysis to lower plasma MTX concentrations rapidly and efficiently.
Widemann
Brigitte C
BC
Pediatric Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892-1920, USA. bw42y@nih.gov
Balis
Frank M
FM
Kempf-Bielack
Beate
B
Bielack
Stefan
S
Pratt
Charles B
CB
Ferrari
Stefano
S
Bacci
Gaetano
G
Craft
Alan W
AW
Adamson
Peter C
PC
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D001859:Bone Neoplasms / Q000188:drug therapy; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects*; D012516:Osteosarcoma / Q000188:drug therapy*; D006435:Renal Dialysis; D011623:gamma-Glutamyl Hydrolase / Q000627:therapeutic use
D000964:Antimetabolites, Antineoplastic; D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate