FOLFIRINOX is an effective yet toxic protocol against gastro-intestinal cancers. We report final updated global results from a randomised international trial aiming to identify the least toxic time of Irinotecan (I) combined with Oxaliplatin (O), 5-Fluorouracil (F) and Leucovorin (L).
199 MCC pts were randomised to receive chronomodulated I (180 mg/m2 over 6-h) on day 1 (d1) with peak delivery at 1:00, 5:00, 9:00, 13:00, 16:00 or 21:00, followed by 4-d fixed-time chronomodulated O (20 mg/m2/d) over 11.5 h, with peak delivery at 16:00, alternating with F (700 mg/m2/d) and L (300 mg/m2/d) over 11.5 h, with peak delivery at 4:00. ChronoIFLO was administered every 3rd week using an automatic programmable-in-time pump.
136 males (68%) and 63 females (32%) were registered at 18 centers. They had a median age of 61 years (range: 30-81), a WHO PS of 0 (73%), 1 (23%) or 2 (4%). ChronoIFLO4 was given as 1st (154 pts, 77%) or 2nd line (45 pts, 23%; 14 pts had previously received I and 20 pts, O). Pt features were similar in the 6 treatment groups. Median number of cycles was 6 (1-18), and mean relative dose intensities were 88% for I, 88% for O, 89% for F. Overall grade 3-4 toxicity occurred in 136/199 pts (68%) and 248/1158 cycles (21%). The most common severe toxicities were diarrhoea (43% of pts), nausea (19%), neutropenia (17%), fatigue (13%) and anorexia (11%). 1st line chronoIFLO achieved an objective response rate (ORR) of 61% [95% Confidence Limits: 53-69], a disease control rate (DCR) of 90% [85-95], a median progression-free survival (PFS) of 8.7 months (mo) [7.6-9.8], and a median overall survival (OS) of 19.5 mo [14.8-24.2]. Respective figures for 2nd line were: ORR, 39% [24-54]; DCR, 76% [63-89]; PFS, 7.4 mo [5.4-9.3]; OS, 16.6 mo [12.5-20.7].
Chronomodulated triplet showed favourable safety and activity profiles both as frontline or salvage treatment of MCC, in comparison to previous reports of conventional delivery. The therapeutic index of chronoIFLO could benefit from the personalisation of drug delivery patterns to match individual differences in internal clock phase.
Clinical trial identification
Legal entity responsible for the study
Warwick Medical School
Warwick Medical School
All authors have declared no conflicts of interest.