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, randomised, open-label, multicenter trial (TRIBE) involving 508 patients comparing FOLFIRI plus bevacizumab with FOLFOXIRI plus bevacizumab in patients with untreated metastatic colorectal cancer.r
Between July 2008 and May 2011, 256 patients were randomised to receive FOLFIRI plus bevacizumab (bevacizumab 5 mg/kg, irinotecan 180 mg/m2, leucovorin 200 mg/m2, fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion over 46 hours. Cycles were repeated every 14 days up to 12 cycles) and 252 patients were randomised to receive FOLFOXIRI plus bevacizumab (bevacizumab 5 mg/kg, irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, fluorouracil 3200 mg/m2 continuous infusion over 48 hours. Cycles were repeated every 14 days up to 12 cycles).r Maintenance treatment with fluorouracil plus bevacizumab was then continued until disease progression in both arms.
There was a significantly higher proportion of right-sided tumours in the experimental group compared to the control group; all other characteristics were balanced. KRAS and BRAF mutation status was known in 80% of enrolled patients: 39.4% had KRAS mutations, 5.5% had BRAF mutations.
The primary end point was progression-free survival and secondary end points were response rate, overall survival rate, resection rate of metastases, and rate of adverse events.r
After a median follow up of 32.2 months, the median progression-free survival was 12.1 months for the FOLFOXIRI plus bevacizumab group and 9.7 months for the FOLFIRI plus bevacizumab group (HR=0.75; CI 95% 0.62 to 0.90 ; p=0.003).r This PFS benefit was maintained across all subgroups, including both mutant and wild-type KRAS and BRAF, except in those patients who had received prior adjuvant chemotherapy where there was an association with worse PFS on FOLFOXIRI plus bevacizumab compared to FOLFIRI plus bevacizumab (p=0.04).
The objective response rate was 65% in the FOLFOXIRI plus bevacizumab group and 53% in the FOLFIRI plus bevacizumab group (Odds Ratio=1.64; 95% CI 1.15 to 2.35; p= 0.006). Overall survival was longer, but not significantly in the FOLFOXIRI plus bevacizumab group (31.0 vs. 25.8 months; hazard ratio for death=0.79; 95% CI, 0.63 to 1.00; p = 0.054).r The rate of R0 resection of metastases was not significantly different between the groups (12% vs. 15%; p=0.33).
Updated but yet unpublished data with a median follow up of 48.1 months confirms the continued PFS advantage (12.3 vs. 9.7 months; HR = 0.77; p=0.006), as well as a significant OS advantage with FOLFOXIRI plus bevacizumab compared to FOLFIRI plus bevacizumab (29.8 vs. 25.8 months, HR = 0.80; p=0.03).r
No quality of life data was collected in this trial.
Kaplan-Meier Estimates (A) Progression-free Survival (B) Overall Survivalr
© New England Journal of Medicine 2014
The incidence of grade 3 or 4 neutropenia, diarrhoea, stomatitis, and neurotoxicity (i.e., peripheral neuropathy) was significantly higher in the FOLFOXIRI plus bevacizumab group than in the FOLFIRI plus bevacizumab group. The rates of serious adverse events were similar in the two groups (19.7% vs. 20.4%; p=0.91); four patients in the control group and 6 patients in the experimental group died as a result of adverse events.r There were no significant differences observed in the rates of bevacizumab related toxicity.
|Most Common Adverse Eventsr
(Grade 3 or 4)
|FOLFIRI plus Bevacizumab
|FOLFOXIRI plus Bevacizumab
|Serious adverse events