Fluorouracil FU

Fluorouracil (FU), discovered in 1957 [1], has been considered to be the standard therapy for the palliative treatment of metastatic colorectal cancer for about 40 years. The overall response rate when used as the single agent is about 20% and complete responses are extremely rare with a median survival less than 12 months. One review of trials of new agents in colorectal cancer between 1960 and 1990 found that none of the 72 compounds evaluated pro duced a higher response rate than FU [2]. One way to attempt to increase the mechanisms of action of FU was biomodulation. A number of biomodulation strategies have been used with FU: methotrexate with a higher response rate (19% vs. 10%) and a 1.6-month survival advantage (p=0.024) [3]; interferon-a without any documented advantage [4]; and finally leucovorin calcium (LV), which has been the most widely used agent for biomodulation. When compared with the best supportive care, the combination FU-LV showed a significantly longer survival (11 vs. 5 months) [5].

The best known regimens, Machover (a dailyX5 schedule of FU 370 mg/m2 with LV 200 mg/m2 every 4 weeks), Roswell Park (a weekly schedule of FU 600 mg/m2 with LV 500 mg/m2) and Mayo Clinic (a dailyx5 schedule of FU 425 mg/m2 with LV 20 mg/m2 every 4 weeks), showed 20-30% increased response rates with different kinds of toxicity: mucositis in the first and diarrhoea in the second [6, 7].

At least a dozen randomised trials have addressed the question of whether FU plus LV is superior to FU alone. The updated meta-analysis has show the advantage of FU-LV over FU alone is not limited to tumour response (21% for the combination and 11% for FU alone) but also applies to overall survival, with a median survival time of 10.5 months for patients treated with FU alone and 11.7 months for patients treated with FU-LV (p=0.004) [8].

A North Central Cancer Treatment Group study compared two leucovorin schedules: Mayo Clinic low-dose, dailyX5 and the Roswell Park weekly high dose. There were no significant differences in therapeutic efficacy between the two regimens tested with respect to the following parameters: objective tumour response (35% vs. 31%), survival (median 9.3 vs. 10.7 months) and palliative effects (as assessed by relief of symptoms, improved performance status and weight gain). There were significant (p<0.05) differences in toxicity, with more leukopenia and stomatitis seen with the intensive-course regimen, and more diarrhoea and requirement for hospitalisation to manage toxicity with the weekly regimen. Finan

Table 1. FU evolution in the treatment of metastatic colorectal cancer

Author

Trial

Response rate

Median survival

1 -year survival

(%)

(months)

(%)

Scheitauer et al. [5]

FU+LV

11 pS

_

BSC

5

-

Meta-analysis [3]

FU+LV

21 pS

11.7

47 pS

FU

11

10.5

37

Buroker et al. [9]

FU+HDLV

35

9.3

-

FU+LDLV

31

10.7

-

Meta-analysis [10]

FU CI

22 pS

12.1 pS

-

FU

14

11.3

-

De Gramont et al. [11]

FU+LV2

32 pS

15.5

-

FU+LV

14.5

14.2

-

pS, p value statistically significant pS, p value statistically significant cial cost was also higher with the weekly regimen [9].

FU has been shown to have a short plasma half-life of 8-20 min following a bolus injection and these observations led to the development of different infusional schedules classically divided in two categories: protracted intravenous (IV) and high-dose intermittent infusions. These have been compared with bolus schedules in randomised trials.

FU continuous infusion (CI) is superior to FU bolus in terms of tumour response and achieves a slight increase of overall survival. The haematologic toxicity is much less important in patients who receive FU CI, but hand-foot syndrome is frequent in this group of patients [10].

The intermittent high dose was more effective and less toxic than the monthly regimen and definitely increased the therapeutic ratio. However, there was no evidence of increased survival [11] (Table 1).

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