Due to the lack of conclusive evidence to identify the optimum dose of calcium folinate (Leucovorin®), it is the consensus of the eviQ reference committee to adopt flat dosing of calcium folinate (Leucovorin®) as a 50 mg IV bolus when used with bolus 5FU across all colorectal and upper gastrointestinal protocols. A discussion regarding the effect of dosing on outcome can be found in the calcium folinate (Leucovorin®) dose document.
The evidence supporting this regimen of weekly fluorouracil (5-FU) and leucovorin is provided by the QUASARr trial which was a large trial (in a 2x2 factorial design) to investigate whether a higher dose of folinic acid or the addition of levamisole to fluorouracil (5-FU) and folinic acid improved survival in adjuvant colorectal cancer.
Between May 1994 and October 1997, a total of 4927 patients were enrolled and randomly assigned to receive 5-FU 370 mg/m2 and either high-dose (175 mg/m2) or low-dose (25 mg) folinic acid and either levamisole or placebo.
The schedule of administration was determined by the clinician as either a 5 days, every 4 weeks for 6 cycles or weekly for 30 weeks.
The primary end point of the study was all- cause mortality and secondary end points included death from colorectal cancer and recurrence.
Patel et al., 2004r
Patel et al., 2004 presented data for the use of a weekly fluorouracil (5-FU) and folinic acid (FA) regimen that was aimed to provide moderately dose-intense treatment with low toxicity.
Between November 1999 and February 2003, a total of 162 patients received weekly 5-FU 425 mg/m2 with FA 45 mg for 24 weeks.
Efficacy
At 3 years, survival was similar with high-dose and low-dose folinic acid (70.1% versus 71%; p=0.43) as were recurrence rates (36% versus 35.8%; p=0.94).r
Risk of recurrence and survival for high-dose versus low-dose folinic acidr
© Lancet 2000
Patel et al., (2004)r
Dose intensity (DI) was used to evaluate the efficacy of this weekly 5-FU/FA regimen. Median DI was 96% of planned (407 mg/m2/week) during treatment, and 91% of planned (385 mg/m2/week) over the full 24 week treatment plan. Compared to the QUASAR's 5-day monthly schedule, this weekly 5-FU/FA regimen was found to deliver a similar DI.
Toxicity
The toxicity data is summarised in the table below. The only significant difference in toxic effects seen between the high-dose and low-dose folinic acid groups was stomatitis. There was only 0.1% treatment related mortality seen, showing that the QUASAR regimens were safer.
Numbers of toxic events reported by treatmentr
© Lancet 2000
Patel et al., 2004r
Treatment was generally well-tolerated, with only 20% patients experiencing any toxicity greater or equal to grade 3 and only 2% experiencing any grade 4 toxicity. Most common was diarrhoea, which occurred in 14% of patients.
Maximum toxicities per patientr
© Annals of Oncology 2004
Dose reductions were made in 35% of patients (although only 21 % required 20 % or more reduction); and a decision to stop treatment before 24 weeks because of toxicity was 16 % of patients.