Role of fluoropyrimidine schedule and (6R,S)leucovorin dose in a preclinical animal model of colorectal carcinoma

Background: Fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd), used alone or in combination with other cytotoxic agents, exhibit limited efficacy in the treatment of advanced gastrointestinal cancer. (6R,S)Leucovorin (LV), a source of reduced folate cofactor, can modulate (i.e., enhance) the therapeutic efficacy of treatment with these fluoropyrimidines (FPs). The role of FP schedule and LV dose in modulating FP antitumor activity, using clinically relevant drug doses and schedules, has not been fully documented. Purpose: We evaluated the antitumor activities and the toxic effects of 5-FU and FdUrd, used either alone or in combination with LV, by following three clinically relevant treatment schedules in rats bearing advanced Ward colorectal carcinomas. Methods: Maximum tolerated doses (MTDs), i.e., doses producing a reversible body weight loss of no more than 20% with no lethality, of 5-FU and FdUrd, either individually or in combination with LV, were used in the following treatment schedules: (I) 4 days of continuous intravenous FP infusion (with or without a daily 2-hour LV infusion); (II) a daily FP intravenous push for 4 days (LV, when given, was administered as a 2-hour infusion, with the FP push given after the first hour of LV treatment); and (III) an FP intravenous push given weekly for 3 weeks (the coadministration of LV and FP was performed as in schedule II). In these studies, LV was given at either a low dose (20 mg/kg [body weight] per day) or a high dose (200 mg/kg per day). The MTDs of 5-FU and FdUrd, with or without LV, were defined in normal rats. Antitumor activities were assessed in animals 12-14 days after they received subcutaneous tumor implants. Toxic effects at the MTD were evaluated in both normal and tumor-bearing animals. Results: With schedules I and II, the MTD of 5-FU alone was 35 mg/kg per day; with schedule III, it was 100 mg/kg per week. For FdUrd alone, the MTD was 100 mg/kg per day with schedules I and II and 400 mg/kg per week with schedule III. Coadministration of LV reduced the MTD of both 5-FU and FdUrd by approximately 25%-30%, irrespective of the LV dose used. The dose-limiting toxic effects of treatment with 5-FU and FdUrd were diarrhea and/or stomatitis, the relative severity of which depended on the schedule of FP administration. The profile of toxic effects was not altered by LV when used at either dose. FP antitumor activity was modulated by LV in all three treatment schedules, but the greatest effects were seen using schedule III, where more complete tumor regression was seen with high-dose LV than with low-dose LV. LV potentiated the antitumor activity of FdUrd to a greater extent than that observed with 5-FU. Conclusions: In this rat model of colorectal carcinoma, the extent to which FP antitumor activity is modulated by LV depends on the schedule of FP administration and the dose of LV used.