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 for using this regimen comes from the results of the French Intergroup Study comparing monthly low dose leucovorin and fluorouracil (5-FU) bolus with bimonthly high dose leucovorin and 5-FU bolus plus continuous infusion in advanced colorectal cancer.r
Between February 1991 to April 1994, a total of 433 patients were randomly assigned to:
- Arm A (n=216): leucovorin 20mg/m2/day (IV bolus) and 5-FU 425mg/m2/day (IV bolus) for 5 consecutive days. Cycles were administered every 4 weeks
- Arm B (n=217): leucovorin 200mg/m2/day (IV infusion), 5-FU 400mg/m2/day (IV bolus) and 5-FU 600mg/m2/day as 22 hour continuous infusion, all repeated for 2 consecutive days. Cycles were administered every 2 weeks
The end points of this study was to compare the therapeutic ratio, efficacy and toxicity of the above 2 regimens.
The modified de Gramont regimen is a simplified version of the standard regimen which avoids day 3 administration of 5FU/LV bolus. It has been shown to be a less costly option with equivalent efficacy and toxicity as the standard regimen.rr
A lower dose of folinic acid has also been used in this protocol as there is no evidence to suggest any differences in efficacy resulting from alterations in the folinic acid dosing.
The addition of oxaliplatin to the de Gramont regimen has demonstrated significantly longer progression-free survival and a better response rate but is associated with more grade 3/4 neutropenia, diarrhoea and neurosensory toxicity.r As such, the de Gramont regimen remains an option for those who have discontinued oxaliplatin due to toxicity .
Efficacy
The objective response rate was significantly greater in the bimonthly regimen (arm B ) compared with the monthly regimen (arm A) (32.6% versus 14.5%; p= 0.0004).
However the median duration of responses were similar between both groups (48.5 weeks in arm A and 47 weeks in arm B).
de Gramontr |
arm A (monthly regimen)
n=216 |
arm B (bi-monthly regimen)
n=217 |
p-value |
Response rates |
14.5 % |
32.6% |
0.0004 |
Median progression free survival |
22 weeks |
27.6 weeks |
0.0012 |
Median survival |
56.8 weeks |
62 weeks |
0.067 |
Toxicity
In the monthly arm, more patients (23.9%) experienced grade 3/4 toxicities compared with the bimonthly arm (11.1%; p=0.0004). There was one therapy related death in the study in the monthly arm.
Toxicityr
Grade 3/4 |
arm A (Monthly regimen)
n=205
% |
arm B (Bi-monthly regimen)
n=208
% |
p-value |
Neutropenia |
7.3 |
1.9 |
0.0052 |
Nausea |
3.4 |
3.9 |
0.95 |
Diarrhoea |
7.3 |
2.9 |
0.039 |
Mucositis |
12.7 |
1.9 |
0.0001 |
Angina |
0 |
0 |
- |
Cutaneous |
0 |
1.0 |
- |
Alopecia |
1.5 |
0.5 |
0.37 |
Conjunctivitis |
0 |
0 |
- |
Neurologic |
0 |
0.5 |
- |