Although there are no RCTs which provide a comparison between FOLFOX regimens, the FOLFOX6 (modified) regimen is widely accepted and is currently used as the control arm in most clinical trials (link to discussion on FOLFOX protocols).
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.
In metastatic colorectal cancer, regimens which add oxaliplatin (FOLFOX) to 5 fluorouracil and leucovorin have been shown to be superior to 5 fluorouracil and leucovorin alone.r
There are several different dosing schedules for FOLFOX regimens and a retrospective analysis in 2000 of phase II studies suggested more dose intense oxaliplatin at 100 mg/m2 such as unmodified FOLFOX6 are associated with better response and progression free survival rates.r This evidence provides justification for increasing the dose of oxaliplatin from 85mg/m2 to 100mg/m2 on an individual patient basis. However, most clinical trials now use mFOLFOX6 as the control arm.
The evidence supporting the use of the FOLFOX6 regimen comes from one phase III randomised controlled trial of previously untreated patients with metastatic colorectal cancer.r In this study 226 patients were randomised to either FOLFIRI followed by FOLFOX6 (113 patients) or FOLFOX6 followed by FOLFIRI (113 patients).
Both regimens were proven to be active when used as the initial treatment for metastatic colorectal cancer or as second line therapy. A comparison of the optimal sequencing of FOLFOX6 and FOLFIRI revealed no difference in efficacy whether FOLFOX is given first or second but a difference in side effects, as previously reported.r
Efficacy
Response rates for first-line and second-line treatments of FOLFIRI-FOLFOX6 and FOLFOX6-FOLFIRI r
Outcome |
First Line |
Second Line |
FOLFIRI |
FOLFOX6 |
Absolute Risk Difference
(95% CI) |
FOLFIRI |
FOLFOX6 |
Absolute Risk Difference
(95% CI) |
Complete Response |
3% |
4% |
2%
(-7%,3%) |
0% |
0% |
0%
(-3%,3%) |
Partial Response |
53% |
49% |
5%
(-9%,18%) |
15% |
4% |
10% (1%, 20%) |
Stable Disease |
23% |
27% |
4%
(-16%,7%) |
48% |
30% |
18% (2%, 33%) |
Progressive Disease |
14% |
13% |
1%
(-8%,10%) |
18% |
51% |
32% (-47%, 18%) |
Not Assessable |
7% |
7% |
0%
(-7%,7%) |
18% |
14% |
4% (-8%, 16%) |
Median Time to Recurrence/Progression |
8.5 months |
8.0 months |
HR:NR |
4.2 months |
2.5 months |
HR:NR |
Source: Tournigandr
CI = confidence interval, ARD = absolute risk difference, HR = hazard ratio, NR = not reported
Survivalr
© Journal of Clinical Oncology 2004
Toxicity
In terms of the use of the FOLFOX6 regimen in the first-line setting, significantly fewer patients randomised to FOLFOX6 experienced febrile neutropenia, nausea, vomiting and mucositis, whereas more patients experienced neutropenia compared to those randomised to FOLFIRI. No significant differences in the numbers of deaths, diarrhoea or fatigue were observed between the two groups. The author’s state that in the context of first-line treatment, overall, more patients experienced grade 3 or 4 toxicities with FOLFOX6 than FOLFIRI (74% and 53%, respectively, p=0.001), however, more patients had serious adverse events with FOLFIRI than with FOLFOX6 (14% and 5%, respectively, p=0.03). During the first 60 days on treatment, there were 4 deaths in the FOLFIRI group and 3 in the FOLFOX6 group.
In terms of the use of FOLFOX6 in the second-line setting, no significant differences in any of the reported adverse events were observed between patients randomised to FOLFOX6 or FOLFIRI. During the first 60 days on treatment, there were 3 deaths in each treatment group.
There were no reports of discontinuation due to toxicities.
Grade 3 & 4 Toxicities (%) |
First Line |
Second Line |
FOLFIRI |
FOLFOX6 |
Absolute Risk Difference (95% CI) |
FOLFIRI |
FOLFOX6 |
Absolute Risk Difference (95% CI) |
Neutropenia |
24 |
44 |
-18%
(-30%,6%) |
20 |
30 |
-10% (-24%, 4%) |
Anaemia |
3 |
3 |
0%
(-4%,4%) |
4 |
4 |
-1% (-7%, 6%) |
Febrile Neutropenia |
7 |
0 |
6%
(2%,11%) |
0 |
1 |
-1% (-5%, 2%) |
Nausea |
12 |
3 |
9%
(2%,16%) |
6 |
0 |
7% (1%, 13%) |
Vomiting |
10 |
3 |
6%
(0%,13%) |
5 |
4 |
2% (-5%, 9%) |
Diarrhoea |
14 |
11 |
3%
(-6%,11%) |
5 |
12 |
-6% (-15%, 4%) |
Mucositis |
10 |
1 |
8%
(3%,14%) |
4 |
4 |
0% (-6%, 7%) |
Fatigue |
4 |
3 |
1%
(-4%,6%) |
5 |
1 |
5% (-1%, 11%) |