Substitution of l-leucovorin for d,l-leucovorin in the rescue from high-dose methotrexate treatment in patients with osteosarcoma.

Studies in which high-dose methotrexate (HDMTX) is used for the treatment of osteosarcoma have utilized commercial formulations of d,l-leucovorin (leucovorin calcium) for rescue from potential methotrexate (MTX) toxicity. These formulations are racemic mixtures containing equal amounts of d and l isomers of leucovorin. All of the available data indicate that the l isomer is the pharmacologically active diastereomer. A clinical study was conducted to determine if l-leucovorin was as safe and efficacious as d,l-leucovorin in the rescue of patients with osteosarcoma who were treated with HDMTX (12.5 g/m2 over 6 h). Because d,l-leucovorin consists of equal proportions of d and l isomers, l-leucovorin was administered at half the usual dose of d,l-leucovorin. In patients with delayed methotrexate excretion, l-leucovorin doses were escalated from 7.5 to 50 mg every 3 h until the MTX level was 0.3 mumol/l or less. Due to the low incidence of osteosarcoma, a control group of patients previously treated with d,l-leucovorin was utilized for comparison. Efficacy of l-leucovorin was determined by its ability to prevent HDMTX-associated toxicity. Demographic and clinical toxicity data from three patients who received 22 courses of MTX rescued with l-leucovorin were compared with data from six patients who had received 42 MTX courses rescued with d,l-leucovorin. Some liver function abnormalities and leukocyte elevations were found in both groups and were attributed to MTX administration. No clinical toxicity attributable to l-leucovorin was observed. l-Leucovorin in half the d,l-leucovorin dose was (equally) effective as a rescue treatment.