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 comes from 2 randomised controlled trials by Tournigand et alr and Colucci et al.r
Tournigand et alr:
Between December 1997 and September 1999, 226 patients were randomised to either FOLFIRI followed by FOLFOX6 (arm A; n=113) or FOLFOX6 followed by FOLFIRI (arm B; n=113). The design required cross over on progression and 60% of patients received second-line treatment per protocol.
The primary end point was the second progression free survival (PFS); time duration from randomisation until progression after the second-line chemotherapy. Secondary end points were overall survival (OS), response rates (RR) and safety.
Colucci et alr:
Between March 1999 and November 2002, 360 patients were randomised to either FOLFIRI (arm A; n=178) or FOLFOX4 (arm B; n=182). The primary endpoint was RR and the secondary end points were time to treatment progression (TTP), OS and toxicity.
It is important to note that a number of other studies have compared the use of oxaliplatin/5FU with irinotecan/5FU. The results of these studies are not shown below as bolus 5FU rather than infusional 5FU was used in some of the treatment arms. It is likely that the efficacy of combination regimens is influenced by the method (bolus versus infusional) and scheduling of 5FU administration. This should be borne in mind when interpreting the results of clinical studies using 5FU as a component of treatment.
Although the FOLFIRI regimen used in these trials was not FOLFIRI (modified), there is no evidence to suggest any differences in efficacy resulting from alterations in the folinic acid dosing.
Efficacy
Tournigand et alr:
After a median follow up of 43.9 months, median PFS after first line therapy was 8.5 months for arm A and 8.0 months for arm B (p=0.26).
Following second-line therapy, the median second PFS from randomisation was 14.2 months in arm A vs 10.9 months in arm B (p=0.64).
The median OS was 21.5 months for arm A vs 20.6 months for arm B (p=0.99).
After first-line therapy, the RR was 56% with FOLFIRI vs 54% with FOLFOX6 (p=not significant) and after second-line therapy, the RR was 15% with FOLFOX6 vs 4% with FOLFIRI.
Tournigandr |
arm A
(n=113) |
arm B
(n=113) |
p-value |
PFS (after first-line therapy) |
8.5 months |
8.0 months |
0.26 |
Second PFS (from randomisation) |
14.2 months |
10.9 months |
0.64 |
OS |
21.5 months |
20.6 months |
0.99 |
arm A: FOLFIRI followed by FOLFOX6
arm B: FOLFOX6 followed by FOLFIRI
Kaplan-meier curves of Progression-free survivalr
© J Clin Oncol 2004
Colucci et alr:
After a median follow up of 31 months, the overall response rates (ORR) were 31% in arm A and 34% in arm B (p=0.6) according to intent to treat analysis. Median time to progression, duration of response and OS were not statistically different between both arms.
Coluccir |
FOLFIRI
(n=178) |
FOLFOX4
(n=182) |
p-value |
ORR |
31% |
34% |
0.60 |
Time to progression |
7 months |
7 months |
0.64 |
OS |
14 months |
15 months |
0.28 |
Toxicity
Tournigand et alr:
In first-line therapy, grade 3 or 4 mucositis , nausea/vomiting and grade 2 alopecia were more frequent with FOLFIRI whilst grade 3 or 4 neutropenia and neurotoxicity were more frequent with FOLFOX6.
Toxicityr
grade 3/4 |
First-line |
p-value |
FOLFIRI
(%) |
FOLFOX6
(%) |
Mucositis |
10 |
1 |
0.003 |
Diarrhoea |
14 |
11 |
NS |
Nausea |
13 |
3 |
0.005 |
Vomiting |
10 |
3 |
0.027 |
Alopecia* |
24 |
9 |
0.003 |
Neurological |
0 |
34 |
<0.001 |
* grade 2
Colucci et alr:
Toxicity was mild in both groups: alopecia and gastrointestinal disturbances were the most common toxicities in arm A; thrombocytopenia and neurosensory were the most common toxicities in arm B. Grade 3 to 4 toxicities were uncommon in both arms, and no statistical significant difference was observed.
Toxicityr
grade 1/2 |
FOLFIRI
(%) |
FOLFOX4
(%) |
Alopecia |
42 |
19 |
Diarrhoea |
53 |
41 |
Mucositis |
34 |
29 |
Neurological |
5 |
41 |
Thrombocytopenia |
15 |
42 |