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.
Although the FOFIRI 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
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
Toxicityr
© New England Journal of Medicine 2009