Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer.

Abstract

In a previous study (J Clin Oncol 7:1407-1417, 1989), we identified two dosage administration schedules of fluorouracil (5FU) combined with leucovorin that were superior to single-agent 5FU for the treatment of advanced colorectal cancer. In this same study, a regimen of 5FU plus high-dose methotrexate (MTX) demonstrated a suggestive advantage over 5FU alone. To permit a more definitive comparison, we have extended our evaluation of these three regimens to involve an additional 259 patients. In all, 457 patients with advanced colorectal cancer were randomly assigned to one of the following regimens: 5FU plus low-dose leucovorin, 5FU plus high-dose leucovorin, or 5FU plus high-dose MTX with leucovorin rescue. We have found that each of the 5FU/leucovorin regimens demonstrates a significant (P less than or equal to .01) advantage over 5FU plus high-dose MTX for objective tumor response and interval to tumor progression. Moreover, 5FU plus low-dose leucovorin confers a significant survival benefit (P less than or equal to .01) compared with 5FU plus high-dose MTX. The 5FU plus high-dose leucovorin regimen shows a survival benefit only in unadjusted analyses (P = .04), but this difference is not significant when adjusted for imbalances in prognostic variables (P = .44). Evaluation of the two 5FU/leucovorin regimens rules out a 10% decrease in death rate for the high-dose leucovorin regimen compared with the low-dose leucovorin regimen (P less than .05). The regimen of 5FU plus low-dose leucovorin has now been shown to offer a statistically significant survival advantage versus 5FU alone and versus 5FU plus high-dose MTX, a regimen that had shown promise in earlier trials. These data confirm the efficacy of leucovorin combined with 5FU in patients with advanced colorectal cancer and establish that it is not necessary to use high doses of leucovorin to achieve these results.

The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer

“…2 Clinical studies have clearly demonstrated the interest of this association allowing improved TS inhibition. 3 Despite the improved response rates with the addition of oxaliplatin or irinotecan, 5-FU remains a major drug in treatment of CRC. 4 However, many questions persist such as: how can we enhance the response rate and efficacy in terms of survival?…”

High-dose folinic acid and 5-fluorouracil bolus and continuous infusion in advanced colorectal cancer: poor response rate in unselected patients

“…The response rate to single-agent 5-FU in bolus form is only 11% (Advanced Colorectal Meta-Analysis Report, 1992), but this can be improved when 5-FU is given in combination with folinic acid (Poon et al, 1991), albeit at the expense of increased toxicity.…”

A novel biweekly multidrug regimen of gemcitabine, oxaliplatin, 5-fluorouracil (5-FU), and folinic acid (FA) in pretreated patients with advanced colorectal carcinoma

“…The most optimistic studies testing 5-FU for first-line in colo-rectal carcinoma reported overall response rate lower than 15%, with a median survival of 12 -18 months. Clinical evidence suggests that the use of protracted intravenous infusion of 5-FU may be more efficacious and better tolerated than bolus dosing (Cancer, 1998), and that modulation of 5-FU may lead to higher response rates (Poon et al, 1989(Poon et al, , 1991. Oxaliplatin is a novel diaminocyclohexane platinum agent that mainly acts by causing inter-and intrastrand DNA crosslinks (Mathe et al, 1989;Soulie et al, 1997;Wiseman et al, 1999;Culy et al, 2000).…”