5-Fluorouracil and methotrexate administered simultaneously as a continuous infusion. A phase I study.

Area of Science:

• Oncology
• Pharmacology
• Clinical Trials

Background:

• Continuous infusion chemotherapy is used for various agents.
• Combining 5-fluorouracil (5-FU) and methotrexate (MTX) requires establishing optimal dosing and schedules.
• Ambulatory infusion delivery systems allow for outpatient chemotherapy administration.

Purpose of the Study:

• To establish a safe and effective dose schedule for combined continuous infusion of 5-fluorouracil (5-FU) and methotrexate (MTX) in an ambulatory setting.
• To evaluate dose-limiting toxicities associated with different schedules of 5-FU and MTX admixture.
• To determine the optimal administration regimen for this combination chemotherapy.

Main Methods:

• A Phase I trial design was employed to test varying dose rates of MTX (0.75-2.0 mg/M2/day) with a fixed dose rate of 5-FU (300 mg/M2/day).
• Two administration schedules were compared: continuous admixture (Schedule A) and sequential 14-day cycles of MTX added to continuous 5-FU (Schedule B).
• Infusion was delivered via subclavian venous access using portable pumps in an ambulatory setting, with 29 patients receiving 38 treatment courses.

Main Results:

• Dose-limiting toxicities were primarily MTX-related, including stomatitis and thrombocytopenia on Schedule A, and thrombocytopenia/hepatitis on Schedule B.
• Higher MTX doses (1.5-2.0 mg/M2/day) on Schedule A led to stomatitis, while lower doses (1.0 mg/M2/day) caused thrombocytopenia.
• On Schedule B, MTX toxicities resolved upon interruption, even with continued 5-FU infusion, suggesting a manageable toxicity profile.

Conclusions:

• A recommended dose schedule for combined 5-FU and MTX continuous infusion is 5-FU 300 mg/M2/day for 28 days, with MTX 0.75 mg/M2/day for days 1-14, repeated every 28 days.
• This regimen allows for effective delivery of both chemotherapeutic agents in an ambulatory setting.
• The study successfully identified a useful dose schedule and highlighted the importance of monitoring MTX-related toxicities.