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 the use of FOLFIRI and cetuximab in the first-line treatment for metastatic colorectal cancer is based on the CRYSTAL study, a randomized, open-label, multicentre study that compared cetuximab plus FOLFIRI and FOLFIRI alone in 1,198 patients. The patients receiving cetuximab plus FOLFIRI received cetuximab at 400 mg/m2 on day 1 and subsequently received cetuximab at 250 mg/m2 weekly. This was given together with FOLFIRI on a 14 day cycle.r
Monoclonal antibodies (mABs) targeting the epidermal growth factor receptor (EGFR) prolong survival in patients with metastatic colorectal cancer (mCRC) harbouring KRAS exon 2 wild type tumours. Recent evidence suggest that other RAS mutations (exon 3 and 4 of KRAS and exons 2, 3, 4 of NRAS) may also be predictive of resistancer,r and some studies even suggest that anti-EGFR mAB treatment may have a detrimental effect on PFS and OS.r As such, cetuximab should not be used in patients with any RAS mutations.
Several studies have shown that the 2 weekly schedule of cetuximab has similar efficacy and safety as the weekly schedule and is sometimes preferred as it is more convenient for the patient.r However, at present there are no published phase III studies to confirm this.
In the controlled phase 2 APEC study, it was shown that there was similar efficacy and safety profile for 2 weekly cetuximab compared with historical data on weekly schedules.r
In the CECOG randomised multicentre phase II study the combination of cetuximab every second week with FOLFOX4 demonstrated activity and a manageable safety profile comparable with that observed for FOLFOX4 plus standard weekly cetuximab.r
Another phase 2 study by Martin-Martorelli et al also showed similar efficacy for cetuximab every two weeks in combination with irinotecan.r
In the second part of the Phase 1 dose escalation study by Tabernero et al, cetuximab two weekly was administered in combination with FOLFIRI. The primary end-point of this study was to determine the maximum tolerated dose of cetuximab administered two weekly, however efficacy data was reported and did not show any significant differences to the weekly regimen.r
The expert reference panel supported publication of the protocol on the basis of the information summarised below.
Source |
Study & Year Published |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trials
|
Cheng et al 2013r |
Yes |
Yes |
- |
Martin-Martorelli et al 2008r |
Yes |
No |
Irinotecan/Cetuximab |
Brodowicz et al 2013r |
Yes |
No |
FOLFOX + cetuximab weekly vs FOLFOX + cetuximab 2 weekly |
Phase I trial |
Tabernero et al 2010r |
Yes |
Yes |
Population pK/pD dose escalation study |
Observational studies |
- |
N/A |
- |
- |
Case series |
Pfeiffer et al 2008r |
Yes |
No |
Irinotecan/Cetuximab |
Guidelines |
Date published/revised |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
v2. 2015 |
Yes |
Yes |
- |
BCCA |
- |
N/A |
- |
- |
CCO |
- |
N/A |
- |
- |
Efficacy
In a small phase 1 dose escalation study of cetuximab monotherapy using bi-weekly dosing, efficacy data was looked at and there were comparable results for cetuximab every two weeks.r
Cetuximab weekly/FOLFIRI
After a median follow up of 46.8 months, the addition of cetuximab to FOLFIRI resulted in an improvement in overall survival time from 18.6 months to 19.9 months (HR 0.878, 95% CI, 0.774 to 0.995; P = 0.0419).r
A post-hoc analysis investigating the impact of RAS mutations other than KRAS codon 12 or 13 in relation to treatment effects showed that there was no clear evidence that the addition of cetuximab to FOLFIRI modified efficacy outcome in the evaluable patients with other tumour RAS mutations. In patients with RAS wild-type tumors, a clear cetuximab benefit was seen across efficacy end points.r
Kaplan-Meier plots for overall survival according to treatment group in RAS populations. (A) KRAS codon 12 or 13 wild type, evaluable for other RAS mutations. (B) RAS wild type (all loci). (C) KRAS codon 12 or 13 wild type; other RAS mutations. (D) RAS mutation (any locus)r
© Journal of Clinical Oncology 2015
Hazard ratios for (A) overall survival and (B) progression-free survival according to tumour KRAS exon 2 and RAS mutation status
© Journal of Clinical Oncology 2015
Toxicity
In the studies looking at the biweekly cetuximab combination regimens, there were no increased adverse events, including allergic reactions and skin toxicity associated with the double dose.r
Toxicity of Cetuximab (Weekly) plus FOLFIRI vs FOLFIRI Aloner
© New England Journal of Medicine 2009