Methotrexate (MTX) is one of the most widely used anti-cancer agents, and administration of high-dose methotrexate (HDMTX) followed by leucovorin (LV) rescue is an important component in the treatment of a variety of childhood and adult cancers. HDMTX can be safely administered to patients with normal renal function by the use of alkalinization, hydration, and pharmacokinetically guided LV rescue. Despite these measures, HDMTX-induced renal dysfunction continues to occur in approximately 1.8% of patients with osteosarcoma treated on clinical trials. Prompt recognition and treatment of MTX-induced renal dysfunction are essential to prevent potentially life-threatening MTX-associated toxicities, especially myelosuppression, mucositis, and dermatitis. In addition to conventional treatment approaches, dialysis-based methods have been used to remove MTX with limited effectiveness. More recently carboxypeptidase-G(2) (CPDG(2)), a recombinant bacterial enzyme that rapidly hydrolyzes MTX to inactive metabolites, has become available for the treatment of HDMTX-induced renal dysfunction. CPDG(2) administration has been well tolerated and resulted in consistent and rapid reductions in plasma MTX concentrations by a median of 98.7% (range, 84%-99.5%). The early administration of CPDG(2) in addition to LV may be beneficial for patients with MTX-induced renal dysfunction and significantly elevated plasma MTX concentrations.

Understanding and Managing Methotrexate Nephrotoxicity

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. Cancer 2004. © 2004 American Cancer Society.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.20255

High-Dose Methotrexate-Induced Nephrotoxicity in Patients with Osteosarcoma: Incidence, Treatment, and Outcome

PURPOSEFollowing high-dose methotrexate (HD-MTX) treatment, delayed MTX elimination is an important problem because it necessitates increased leucovorin rescue and additional hospitalization for hydration and urinary alkalinization. Our purpose was to identify factors associated with high-risk MTX plasma concentrations (defined by plasma concentration > or = 1.0 mumol/L at 42 hours from the start of MTX) and with toxicity.PATIENTS AND METHODSVariables associated with MTX concentrations and toxicity were assessed in 134 children treated with one to five courses of HD-MTX (900 to 3,700 mg/m2 intravenously [i.v.] over 24 hours for a total of 481 courses) for acute lymphoblastic leukemia (ALL).RESULTSHigh-risk MTX concentrations, toxicity (usually mild mucositis), and delay in resuming continuation chemotherapy occurred in 106 (22%), 123 (26%), and 66 (14%) of 481 courses, respectively. Using a mixed effects model for repeated measures, high-risk MTX concentrations were significantly associated with a higher ...

Patient characteristics associated with high-risk methotrexate concentrations and toxicity.

Objective Chemotherapy doses are limited by toxicity to normal tissues. Intravenous glutamine protects liver cells from oxidant injury by increasing intracellular glutathione (GSH) content. The authors hypothesized that supplemental oral glutamine (GLN) would increase the therapeutic index of methotrexate (MTX) by improving host tolerance through changes in glutathione metabolism. The authors examined the effects of oral glutamine on tumor and host glutathione metabolism and response to methotrexate. Methods Thirty-six 300-g Fischer 344 rats were implanted with fibrosarcomas. On day 21 after implantation, rats were randomized to receive isonitrogenous isocaloric diets containing 1 g/kg/day glutamine or glycine (GLY) by gavage. On day 23 after 2 days of prefeeding, rats were randomized to one of the following four groups receiving an intraperitoneal injection of methotrexate (20 mg/kg) or saline (CON) : GLN + MTX, GLY + MTX, GLN-CON, or GLY-CON. On day 24, rats were killed and studied for arterial glutamine concentration, tumor volume, tumor, kidney and gut glutaminase activity, and glutathione content (tumor, gut, heart, liver, muscle, kidney, and lung). Results Provision of the glutamine-enriched diets to rats receiving MTX decreased tumor glutathione (2.38 ± 0.17 in GLN + MTX vs. 2.92 ± 0.20 in GLY + MTX, p < 0.05), whereas increasing or maintaining host glutathione stores (in gut, 2.60 ± 0.28 in GLN + MTX vs. 1.93 ± 0.18 ; in GLY + MTX, p < 0.05). Depressed glutathione levels in tumor cells increases susceptibility to chemotherapy. Significantly decreased glutathione content in tumor cells in the GLN + MTX group correlated with enhanced tumor volume loss (-0.8 ± 1.0 mL in GLN + MTX vs. +9.5 ± 2.0 mL in GLY + MTX, p < 0.05). Conclusion These data suggest that oral glutamine supplementation will enhance the selectivity of antitumor drugs by protecting normal tissues from and possibly sensitizing tumor cells to chemotherapy treatment-related injury.

Glutamine enhances selectivity of chemotherapy through changes in glutathione metabolism.

The administration of high-dose methotrexate (HDMTX) with leucovorin rescue carries with it a risk of severe toxicity which may be fatal. In the present study, patients with a 24-h serum concentration of 5 x10- M and an elimination half-life (T1/2) of 3.5 h during the first 24 h after the infusion were considered at low risk for toxicity and received conventional lowdose leucovorin rescue. Patients not meeting these criteria were considered at high risk for toxicity and received an escalated and extended course of leucovorin. The low-risk criteria were met following 109 of 114 HDMTX infusions administered to 30 patients. None of these patients developed toxicity with low-dose leucovorin. The 24-h serum concentration and the t1/2 exceeded the low-risk criteria following five HDMTX infusions administered to three patients. In two of these three patients leucovorin was continued until the MTX concentration was 10-8 M (168–265 h) and no toxicity developed. The third high-risk patient discontinued his leucovorin 11 days prior to a MTX serum concentration 10-8 M and developed moderate toxicity. Clinical features present in the three high-risk patients, which were not present in the low-risk group, included a pleural effusion in one patient and gastrointestinal obstruction in the other two patients. The identification of 3/30 high-risk patients in the present study was consistent with a historical control group in which 6/65 patients developed severe toxicity. These data indicate that patients meeting the criteria described herein are at low risk to develop toxicity with conventional leucovorin rescue and that high-risk patients may be identified early enough to reduce or prevent toxicity.

Pratt Cb

Papers

Recovery from toxicity associated with high-dose methotrexate: prognostic factors.