5-fluorouracil scheduling

Fluorouracil-based chemotherapy is the standard of care for the adjuvant treatment of colorectal cancer either as a single agent or, more commonly, in combination with other agents. 5-Fluorouracil (5-FU) alone results in a small improvement in survival that can vary based on the method of 5-FU administration. Studies suggest that protracted or continuous intravenous (IV) 5-FU infusion treatment schedules are more effective than bolus therapy.20... 

Bevacizumab 5 mg/kg IV every 2 weeks plus fluorouracil and leucovorin (given in any schedule below) or IFL or FOLFOX or FOLFIRI... 

In phase II studies with topotecan alone, there is cytotoxic activity in lung cancer with intermittent dose schedules (33), as well as in lung cancer patients with topoisomerase II refractory disease (34). In advanced head and neck cancer topotecan is well-tolerated and has single-agent activity similar to that of cisplatin, 5-fluorouracil, and methotrexate... 

Rich TA. Irradiation Plus 5-Fluorouracil Cellular Mechanisms of Action and Treatment Schedules. Semin Radiat Oncol 1997 7(4) 267-273. 

So far, the available evidence probably supports the use of either the GOG weekly cisplatin regimen or the RTOG schedule of cisplatin and fluorouracil. As yet, no data support the use of weekly cisplatin at doses below the 40 mg/m2/wk given in the GOG studies. The only randomized trial to investigate a lower dose of weekly cisplatin was an early study reported by Wong et al. (32) They were unable to demonstrate a benefit when 25 mg/m2/wk of cisplatin plus radiation therapy was compared to radiation therapy alone. It must be noted, though, that the study was compromised by the small number of patients (fewer than 30 in each arm). 

The toxicities of 5-fluorouracil vary with the schedule and mode of administration. Nausea is usually mild if it occurs at all. Myelosuppression is most severe after intravenous bolus administration, with leukopenia and thrombocytopenia appearing 7 to 14 days after an injection. Daily injection or continuous infusion is most likely to produce oral mucositis, pharyngitis, diarrhea, and alopecia. Skin rashes and nail discoloration have been reported, as have photosensitivity and increased skin pigmentation on sun exposure. Neurological toxicity is manifested as acute cerebellar ataxia that may occur within a few days of beginning treatment. 

Aschele C, Sobrero A, Faderan MA et al. Novel mechanism(s) of resistance to 5-fluorouracil in human colon cancer (HCT-8) sublines following exposure to two different clinically relevant dose schedules. Cancer Res 1992 52 1855-1864. 

Patients with poorly controlled diabetes are at risk of greater or more severe fluorouracil toxicity, causing hyperglycemia, which has been fatal. This effect seems to be independent of previous diabetic control and or fluorouracil dosage schedules (414)... 

Schwarz LR. Elimination of dose limiting toxicities of cis-platin, 5-fluorouracil, and leucovorin using a weekly 24-hour infusion schedule for the treatment of patients with nasopharyngeal carcinoma. Cancer 1996 78(3) 566-7. 

Fluorouracil has also been associated with a number of vascular effects, particularly thromboembolic or circulatory in nature (27). Although Raynaud s phenomenon has been reported after cisplatin-based chemotherapy, the first case of digital ischemia and Raynaud s phenomenon has been reported with fluorouracil given in a De Gramond type schedule (28). 

Fluorouracil can cause neurotoxicity (48), with an incidence of 5-15% and with all schedules of administration in common use (49,50). The toxicity is acute in onset and cumulative dose-dependency has not been observed. 

The neurotoxicity is usually reversible by withdrawing fluorouracil. Since there is no cumulative effect, therapy can be resumed later if desired, usually with either a lower dose or a less frequent dosing schedule to prevent recurrence. 

The hematological toxicity of fluorouracil is dose- and schedule-related (80). Leukocytes and platelets are affected, althongh the latter less so. Myelosuppression begins 4—7 days after the first dose, with recovery nsnally 14 days after the last dose (2). With continned treatment, anemia can develop in 3-4 months (81). Severe bone marrow depression causing death has been reported (82). 

Lokich JJ, Ahlgren JD, Gullo JJ, Philips JA, Fryer JG. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma a Mid-Atlantic Oncology Program Study. J Clin Oncol 1989 7(4) 425-32. 

Friberg LE, Freijs A, Sandstrom M, et al. Semiphysiological model for the time course of leukocytes after varying schedules of 5-fluorouracil in rats. / Pharmacol Exp Ther. 2000 295(2) 734-740. 

Simonsen LE, Wahlby U, Sandstrom M, et al. Haematological toxicity following different dosing schedules of 5-fluorouracil and epirubicin in rats. Anticancer Res. 2000 20(3A) 1519-1525. 

A variety of continuous TV infusion fluorouracil regimens have been developed to increase the duration of drug exposure during the S phase of the cell cycle and increase DNA-dependent cytotoxicity. Some of these schedules involve short (24- to 48-hour) weekly or biweekly or protracted continuous fluorouracil infusions for up to 12 weeks. Doses of fluorouracil employed in 24 to 48 hour infusions generally range from 1000 to 2000 mg/m per day. A regimen utilizing 300 mg/m per day for 10 weeks is considered the maximally tolerated dose for protracted continuous infusion. Based on the assumption that a dose-response relationship exists for colorectal cancer, this approach is one of the most efficacious methods of dose intensification for fluorouracil. The maximum cumulative fluorouracil dose that can be administered via continuous IV infusion in... 

Overall, response rates and survival outcomes with weekly and daily regimens of bolus fluorouracil plus LD- or HD-leucovorin appear comparable. Leucovorin doses greater than 20 mg/m do not appear to increase overall survival, but rather add to the toxicity of either daily or weekly regimens of fluorouracil. Weekly (HD-leucovorin) treatment schedules are associated with a higher incidence of diarrhea, the primary dose-limiting toxicity, whereas mucositis and leukopenia are relatively infrequent. Mucositis tends to be dose-limiting and leukopenia is more common with the daily (LD-leucovorin) treatment schedule. 

The Meta-Analysis Group in Cancer. Toxicity of fluorouracil in patients with advanced colorectal cancer Effect of administration schedule and prognostic factors. J CUn Oncol 1998 16 3537-3541. 

Buroker TR, O Connell MJ, Wieand HS, et al. Randomized comparison of two schedules of fluorouracil and leucovorin in flie treatment of advanced colorectal cancer. J Clin Oncol 1994 12 14-20. 

Port et al. (1991) administered 5-fluorouracil (5-FU) treatments to 26 patients with advanced carcinomas of various origin under a variety of doses and treatment schedules. Monotherapy was given as 5-day... 

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