Difficulty Measuring Methotrexate in a Patient with High-Dose Methotrexate-Induced Nephrotoxicity

Abstract

An 18-year-old male presented with pain and swelling in his left leg that he noted after playing football. An x-ray of the affected leg showed a destructive lesion that prompted a concern for malignancy. Subsequent tests, including magnetic resonance imaging, a bone scan, and a needle biopsy of the lesion, confirmed nonmetastatic osteosarcoma in the left proximal tibia. The patient was started on a standard regimen of chemotherapy. He received 4 cycles of high-dose methotrexate (HDMTX)3 with leucovorin rescue and 2 cycles of cisplatin and doxorubicin, which he tolerated well. Each HDMTX course involved the intravenous administration of 20 g methotrexate (MTX) over 4 h. The patient experienced delayed MTX clearance after the first cycle but showed typical clearance after the subsequent 3 cycles. He then underwent a planned radical resection of the tumor with allograft placement. After the patient recovered from surgery, chemotherapy resumed, and the patient received 2 additional cycles of cisplatin and doxorubicin and 1 additional cycle of HDMTX. His treatment was interrupted when he had to undergo surgery for a wound infection in the affected leg. After recovery from the second surgery, the patient received a sixth HDMTX cycle. After this cycle, the patient developed acute nephrotoxicity, which was manifested by marked renal dysfunction and delayed MTX clearance. His plasma creatinine concentration increased from 0.8 mg/dL (8 mg/L) at the start of the cycle to 6.8 mg/dL (68 mg/L) after he received HDMTX. Plasma MTX concentrations were 1700 μmol/L at 24 h after infusion, 450 μmol/L at 48 h, and 350 μmol/L at 72 h. The patient was treated with aggressive hydration, diuresis, and 1500 mg leucovorin intravenously every 6 h for several days. These measures did not reduce MTX below the toxic concentration, however, and the decision was made to give the patient glucarpidase …