The Memorial Sloan Kettering Cancer Center experience with outpatient administration of high dose methotrexate with leucovorin rescue.

We describe the safety and feasibility of an outpatient high dose methotrexate (HDMTX) regimen. HDMTX (12 g/m(2)) is administered in a pediatric day hospital (PDH) intravenously (IV) over 4 hrs. Urinary alkalinization is achieved using an IV bolus of sodium bicarbonate and oral bicarbonate tablets. Daily visits to the PDH follow. Leucovorin is begun 24 hrs. after MTX at a standard dose of 10 mg orally (po) every 6 hrs. (q6h). The leucovorin dose is escalated between a range of 20 mg po q6h to 1 g as a continuous IV drip over 24 hrs. according to an institutional algorithm for levels above 10, 1, and 0.1 micromol/L at 24, 48, and 72 hrs. post-MTX. To evaluate our approach, we conducted a retrospective review of all HDMTX courses administered at the Memorial Sloan Kettering Cancer Center between 1996 and 2002. Out of a total of 708 MTX courses, 82% were successfully completed as an outpatient. Forty-nine percent of the MTX courses were treated with standard dose leucovorin while 49% required a dose escalation, the majority of which was to 20-30 mg po q6h. Observed toxicity included mild (Grade 0-I) nephrotoxicity and reversible transaminitis in the majority of patients. Myelosuppression was manifested mainly as neutropenia, with Grade III-IV toxicity in 16% of patients. Outpatient administration of HDMTX and the required supportive therapy is safe and feasible using the described approach. Approximately half of the patients will require leucovorin dose modification based on serial monitoring of MTX levels.

Zelcer S ，Kellick M ，Wexler LH ，Gorlick R ，Meyers PA ... -  《-》

Ambulatory high-dose methotrexate administration among pediatric osteosarcoma patients in an urban, underserved setting is feasible, safe, and cost-effective.

We describe the safety, feasibility, and provide a cost-estimate of outpatient high-dose methotrexate administration (HDMTX) among an urban, underserved population. A retrospective analysis of ambulatory HDMTX administration among osteosarcoma patients, at Montefiore Medical Center's Children's Hospital (Bronx, NY) was performed. HDMTX (12 g/m(2)) was given intravenously (IV) over 4 hr after urine alkalinization. Patients were discharged home to continue IV hydration and alkalinization delivered via a home infusion pump. Families were instructed to monitor urine pH overnight and management was adjusted according to our institution's treatment algorithm until MTX level ≤ 0.1 µmol/L. A cost estimate was performed to assess the difference in costs for outpatient versus hypothetical inpatient administrations. Of the 97 ambulatory HDMTX administrations, 99% were successfully completed. One patient failed outpatient administration secondary to home infusion pump malfunction. This patient successfully completed subsequent courses as an outpatient. Most patients (72%) had a MTX level of < 10 µmol/L at 24 hr post-HDMTX. No patients were found to have a MTX level of > 50 µmol/L at 24 hr. About 26% of courses were associated with grade III or IV neutropenia, 4% were associated with grade III or IV thrombocytopenia and 1% were associated with grade III/IV leukopenia. Compared to a hypothetical hospital inpatient stay, the hospital costs for ambulatory HDMTX were an average of $1400 less per cycle. Ambulatory HDMTX administration among an underserved, urban population is safe, feasible, and cost-effective.

Mahadeo KM ，Santizo R ，Baker L ，Curry JO ，Gorlick R ，Levy AS ... -  《-》

High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma.

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. 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. 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. 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 BC ，Balis FM ，Kempf-Bielack B ，Bielack S ，Pratt CB ，Ferrari S ，Bacci G ，Craft AW ，Adamson PC ... -  《CANCER》

Hyper-alkalinization without hyper-hydration for the prevention of high-dose methotrexate acute nephrotoxicity in patients with osteosarcoma.

Mir O ，Ropert S ，Babinet A ，Alexandre J ，Larousserie F ，Durand JP ，Enkaoua E ，Anract P ，Goldwasser F ... -  《-》

[Effects of hydration on plasma concentrations of methotrexate in patients with osteosarcoma treated with high doses of methotrexate].

Ferrari S ，Orlandi M ，Avella M ，Caldora P ，Ferraro A ，Ravazzolo G ，Bacci G ... -  《MINERVA MEDICA》