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.
Prior to the availability of irinotecan, oxaliplatin and bevacizumab, single agent weekly fluorouracil was the preferred treatment option for patients with metastatic colorectal cancer. Combination therapies which include fluorouracil have improved response rates and survival compared with weekly fluorouracil. For this reason, combination therapy is usually the treatment of choice for first line therapy in patients with good performance scores.
Capecitabine is an alternative to intravenous fluorouracil. Two trials have compared capecitabine with 5FU/Leucovorin (Mayo regimen) in first line metastatic setting.rr These studies showed higher response rates in capecitabine arms and no signficant difference in TTP, PFS and OS. There was less grade 3/4 stomatitis, neutropenia, diarrhoea, nausea and vomiting and more hand and foot syndrome in the capecitabine arms.
The weekly fluorouracil (5-FU) plus leucovorin QUASAR regimen, is sometimes used instead of the Roswell Park regimen. The highest level of evidence supporting the activity of weekly fluorouracil (5-FU) plus leucovorin (QUASAR) comes from studies conducted in the adjuvant setting.r It is this evidence that is used to support the use of QUASAR in the metastatic setting.
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.
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.
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 safe.r
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.