Abstract
Individual tolerance to single or widely spaced doses of methotrexate was explored in 49 patients with advanced cancer with normal serum creatinine and/or blood urea nitrogen. Methotrexate was given as an intravenous infusion over 1 hour at initial doses of 80-120 mg./m(2) body surface area. The doses were increased by 50% increments every 2 weeks until moderate toxicity occurred, arbitrarily defined as leukopenia <5000/mm.(3), and/or thrombocytopenia <100,000/mm.(3), and/or the appearance of oral mucous or intestinal toxicity.The individual dose required to produce initial evidence of toxicity varied by a factor of 18 between 50 and 900 mg./m(2). Starting doses above 80 mg./m(2) were potentially hazardous. Dose limiting toxicity consisted of leukopenia with or without stomatitis in 81% of the patients, and stomatitis without leukopenia, in 19%. Thrombocytopenia was seen in 19% of the patients, but was never a dose limiting factor alone. Leukopenia always preceded thrombocytopenia. The nadir for haematologic toxicity varied considerably between day 5-15 and 9-14 for leukocytes and platelets, respectively, while oral ulcerations, when they occurred, consistently began between days 3-6 after drug administration. Other toxic manifestations included dermatologic changes in 8 patients, hepatic dysfunction in 7, conjunctivitis in 7, nausea and vomiting in 6, alopecia in 4, and diarrhea in 3 patients.The only factor which predicted toxicity was the patient's age. Drug tolerance was independent of previous chemotherapy or radiotherapy, weight loss, serum albumin or pretreatment serum folic acid levels.
Highlights
The individual dose required to produce initial evidence of toxicity varied by a factor of 18 between 50 and 900 mg./m2
Similar variation of drug tolerance has been observed by Papac, Lefkowitz and Bertino (1967) in a small series of patients using a schedule of MTX or 0-8 mg./kg. or 30 mg./m2 every 4 days until stomatitis and leukopenia developed
One possible explanation for this phenomenon is the decreased glomerular filtration rate as measured by endogenous creatinine clearance occurring {in elderly patients (Hansen, Kampmann and Laursen, 1970) which is not recognized by standard parameters of renal function tests such as blood urea nitrogen (BUN) and/or serum creatinine
Summary
SINCE the folic acid analogues were introduced as antineoplastic agents in 1948 by Farber et al, a variety of dose schedules have been explored Goldin and his colleages reported 2 methods of improving the therapeutic index of methotrexate (MTX) as measured by the prolongation of survival of CDBA hybrid mice with Leukaemia 1210. The first method consisted of administration of MTX every fourth day rather than twice daily, once daily, or every second day (Goldin, Venditti, Humphreys and Mantel, 1956). The superiority of this dose schedule of MTX over daily medication was confirmed for maintenance of remission in childhood leukaemia (Acute Leukaemia Group B, 1965). The present study was designed to define the individual tolerance to single or widely spaced doses of MTX, as a baseline for exploration of the optimal time interval and dose ratio of MTX followed by leukovorin (Selawry, 1970)
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