A phase I study of FAP (5-Fluorouracil, α-interferon and cisplatin) combined with methotrexate for the treatment of advanced urothelial malignancies.

Combination chemotherapy using 5-fluorouracil and α-interferon is active against advanced urothelial cancers. Its toxcity profile appears favorable such that addition of other active agents (i.e., cisplatin and methotrexate) may improve its therapeutic window. Our goal was to identify the starting dose of FAP (5-fluorouracil-α-interferon-cisplatin) that will permit delivery of methotrexate in patients with advanced chemotherapy-refractory urothelial cancers. This is a phase 1 study in which the dose level of FAP that permitted delivery of two doses of methotrexate in 28 days will be considered the maximum tolerated dose (MTD). This is based on experiences with MVAC chemotherapy in which only half of the patients received two doses of methotrexate in a 28 days cycle. The dose level identified as the MTD is as follows: 5-FU 500 mg/m(2) by intravenous continuous infusion daily for 5 days in weeks 1 and 4; α-interferon 5 MU/m(2) subcutaneously daily for 5 days simultaneously with 5-FU infusion in weeks 1 and 4 and thrice weekly during weeks 2 and 3; and cisplatin 25 mg/m(2) plus methotrexate 30 mg/m(2) intravenously once weekly for 4 weeks. The treatment will be repeated every 6 weeks. Most of the significant toxic effects, including mucositis, neutropenia, and thrombocytopenia, are encountered during weeks 3 and 4. This study showed that the MTD for FAP combined with methotrexate has been determined for phase II studies. Exploration of alterative regimen such as FAP in the treatment of advanced urothelial cancer is warranted. FAP has a unique mechanism of action and acceptable toxicity profile that may allow novel drug combinations and improved therapeutic efficacy.