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 this protocol is provided by a phase III multicentre international randomised trial ‘PRIME’ involving 1183 patients comparing panitumumab-FOLFOX4 with FOLFOX4 alone in patients with metastatic colorectal cancer.
Between August 2006 and February 2008, 593 patients were randomised to receive panitumumab 6mg/kg IV every two weeks along with FOLFOX4 and 590 patients were randomised to receive FOLFOX4 alone every two weeks.
The primary end point was PFS and secondary end point was OS, objective response rate and safety.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 many studies suggest that anti-EGFR mAB treatment may have a detrimental effect on PFS and OS in patients with NRAS mutations.r As such, panitumumab should not be used in patients with any RAS mutations.
The trial was originally designed to test the treatment effect on all randomised patients but was amended to compare PFS and OS according K-RAS status before any efficacy analyses. 656 patients (60%) had wild type K-RAS in this trial.
In the wild type K-RAS population, after a median follow up of 13.2 months, the median PFS was 9.6 months in the panitumumab+FOLFOX4 group vs 8.0 months in the FOLFOX4 group (HR=0.80; CI 95% 0.66 to 0.97 ; p=0.02).r
In an updated analysis, panitumumab+FOLFOX4, compared with FOLFOX4 alone, was associated with a 4.4-month improvement in overall survival (23.8 months vs. 19.4 months; p=0.03).r
Among patients without RAS mutations, the overall survival was 26.0 months in the panitumumab-FOLFOX group vs 20.2 months in the FOLFOX4 alone group (HR=0.78; 95% CI, 0.62 to 0.99; p=0.04). Patients with non-mutated KRAS exon 2 who had other RAS mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX treatment.r
(A) Kaplan-Meier Estimates of Progression-free Survival and (B) Overall Survival in the Primary Analysis Populationr
© New England Journal of Medicine 2013
Grade 3 and 4 Adverse Eventsr
© Journal of Clinical Oncology 2010