Due to the lack of conclusive evidence to identify the optimum dose of Leucovorin®, it is the consensus of the eviQ reference committee to adopt flat dosing of 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 (NAPOLI-1) involving 417 patients.r This study compared nanoliposomal irinotecan and fluorouracil/leucovorin with either nanoliposomal irinotecan or fluorouracil/leucovorin alone in patients with stage IV pancreatic adenocarcinoma (who had previously received gemcitabine containing regimen).
Between January 2012 and September 2013, 117 patients were randomised to receive nanoliposomal irinotecan and fluorouracil/leucovorin fortnightly until progression, 151 patients received nanoliposomal irinotecan alone and 149 patients received fluorouracil/leucovorin alone.
The primary end point was overall survival.
Median overall survival was 6.1 months in the combined therapy arm, (95% CI 4.8–8.9) compared with 4.2 months in the fluorouracil/leucovorin arm (95% CI 3.3–5.3) (unstratified HR 0.67, 95% CI 0.49–0.92; p=0.012).r
Median overall survival was 4.9 months (95% CI 4.2–5.6) in the nanoliposomal irinotecan monotherapy arm compared with 4.2 months in the fluorouracil/leucovorin control in that arm of the study (95% CI 3.6–4.9) (unstratified HR 0.99, 95% CI 0.77–1.28; p=0.94).r
© Lancet 2017
There was no difference in quality of life data between the treatment arms, however compliance with self-reported data was low (60% completed pain questionnaires). r
Treatment-related deaths were rare in the nanoliposomal irinotecan combined with 5-FU arm and in the comparator, 5FU monotherapy. Of note, the nanoliposomal irinotecan single agent arm was more toxic with treatment-related deaths in 4 out of 147 patients.r
Discontinuation due to an adverse event was slightly more common in the combined therapy arm (11%) compared with the 5-FU monotherapy arm (7%). Rates of serious adverse events were similar (48 vs 45%).
Of note, grade 3 and 4 gastrointestinal toxicities and neutropenia were much more common in the combined therapy arm (see table below).
||Nanoliposomal irinotecan and fluorouracil (n=117)
||Fluorouracil alone (n=134)
||1 (0.9%, death due to septic shock)
|Serious adverse events
|Discontinuation due to adverse event
|Grade 3 and 4 toxicities