A phase I study of methotrexate administration following 5-fluorouracil

A priming dose of 5-fluorouracil can decrease the toxicity and retain the efficacy of high-dose methotrexate in laboratory models. This Phase I study determined the maximum tolerated dose of methotrexate that can be administered after a dose of 5-fluorouracil without leucovorin rescue. Forty-two patients received 5-fluorouracil (500 mg/m2) by bolus injection followed in 2 h by methotrexate infused over 1 h; treatment was repeated every 3 weeks. Patients received five doses of leucovorin (10 mg/m2 every 6 h); this was reduced to two doses and then to zero doses (no rescue) if less than grade 2 toxicity occurred in prior treatments. If safe, at least two patients received no leucovorin rescue with their first treatment. The dose of methotrexate was escalated in cohorts of patients, starting with a methotrexate dose of 200 mg/m2. Previously untreated patients maximally tolerated 1600 mg/m2 of methotrexate with 5-fluorouracil pretreatment. Leukopenia combined with stomatitis prevented deescalation of leucovorin doses. Fourteen percent of total courses and 15% of courses without leucovorin rescue resulted in dose limiting toxicity. MTX levels exceeded levels that require leucovorin rescue. Four of the 33 (12%) advanced head and neck cancer patients had objective responses to therapy; median survival was 10 months. Previously treated patients were less tolerant; oral and hematological toxicities were troublesome; 400 mg/m2 of methotrexate was the approximate maximum tolerated dose. Forty-seven percent of total courses and 60% of courses without leucovorin rescue resulted in dose limiting toxicity. There were no responses. Although the antineoplastic activity is poor, prior 5-fluorouracil exposure does protect tissues susceptible to methotrexate toxicity.