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.
The evidence supporting the addition of cetuximab to modified FOLFOX6 chemotherapy in the first-line setting in metastatic KRAS wt colorectal cancer comes from the randomised phase III trial by Venook et al.r
Between September 2005 and March 2012, a total of 1137 patients were randomly assigned to receive cetuximab (n=578) or bevacizumab (n=559) with chosen FOLFIRI/mFOLFOX6 chemotherapy regimen.
The primary end point of the trial was overall survival (OS) with secondary end points including progression-free survival (PFS) and overall response rate (ORR), site-reported confirmed or unconfirmed complete or partial response.
The trial concluded there was no significant difference in OS between adding cetuximab or bevacizumab to mFOLFOX6 or FOLFIRI for patients with KRAS wt metastatic colorectal cancer.
After a median follow-up of 47.4 months, median OS was 30.0 months for the cetuximab-chemotherapy group and 29.0 months for the bevacizumab-chemotherapy group (stratified HR 0.88, 95% CI, 0.77 - 1.01; p=0.08). The median PFS was 10.5 months and 10.6 months respectively. RR were 59.6% in the cetuximab group and 55.2% in the bevacizumab group.r
Post hoc subgroup analysis conducted in the expanded RAS wt cohort (KRAS exon 2-4 and NRAS exon 2-4 wt) showed that the addition of cetuximab was associated with better OS compared to bevacizumab amongst patients receiving mFOLFOX6. r
||Cetuximab + chemotherapy (mFOLFOX6 or FOLFIRI)
|Bevacizumab + chemotherapy (mFOLFOX6 or FOLFIRI)
© JAMA 2017
Kaplan-Meier graph of overall survival
© JAMA 2017
The overall incidence of grade 3 or higher adverse events occurred in 53% of patients, with 14% of patients experiencing grade 4 or higher adverse events.r
Adverse events reported in greater than 10% of the patients were similar across both groups. Although lower than grade 3 events, acneiform rash was more common in the cetuximab group while hypertension was more common in the bevacizumab group.r
© JAMA 2017