High-dose trimetrexate and minimal-dose leucovorin: a case for selective protection?
Our objective was to find the minimum dose of leucovorin (LV; 5-formyltetrahydrofolate) needed to potentially provide selective protection of normal tissue in patients with tumors resistant to methotrexate (MTX) by virtue of transport during prolonged therapy with high-dose trimetrexate (TMTX). Based upon the known daily requirement for folate, that tumors are often resistant to methotrexate via a transport-based mechanism, and that large doses of trimetrexate can be given with large doses of leucovorin for the treatment of patients with Pneumocystis carinii, a protocol was designed to find the minimum LV dose required to allow the administration of large doses of TMTX. Patients were treated in 28-day cycles consisting of 14 consecutive days of oral TMTX (45 mg/m2 every 12 h), followed by 14 days of rest. The dose of concurrent LV was started at 5 mg/m2 twice daily. Cohorts of patients received successive half doses of LV so long as three consecutive patients had less than or equal to grade 3 toxicity. Ten patients received 29 courses of therapy. The most common toxicities encountered were thrombocytopenia (38%), mucositis (14%), and neutropenia (10%). At a LV dose of 2.5 mg/m2, toxicities were consistently limited to less than or equal to grade 3 and only one episode of grade 4 hematological toxicity. Although there was marked interpatient variability, the minimally effective LV dose for selective protection seems to be 2.5 mg/m2. If tumors are resistant to methotrexate because of decreased transport of drug (and also folate), then the same pharmacological principle used to develop TMTX/LV for the treatment of P. carinii may be applied to treatment of some patients with cancer.
Hum
M
M
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235-9063, USA.
Holcenberg
J S
JS
Tkaczewski
I
I
Weaver
J W
JW
Wilson
J
J
Kamen
B A
BA
D000293:Adolescent; D000328:Adult; D000931:Antidotes; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D005240:Feasibility Studies; D006801:Humans; D007223:Infant; D002955:Leucovorin / Q000627:therapeutic use*; D008111:Liver Function Tests; D009092:Mucous Membrane / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy*; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D016597:Trimetrexate / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000931:Antidotes; D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D016597:Trimetrexate