Optimizing FOLFIRINOX tolerability in patients with colorectal cancer through dosing irinotecan in the morning for men and in the afternoon for women.

Abstract

120 Background: Irinotecan (IRI) toxicity was worse in female (F) than in male (M) patients (pts) on FOLFIRI for metastatic colorectal cancer (MCC). This finding could reflect different optimal administration timing of IRI in M and F pts along the 24 hours. IRI pharmacology is regulated by the circadian clock, and its least toxic daily time (LTT) occurred ~6 hours later in F as compared to M mice. The relevance of sex for the LTT of IRI is addressed here using data from an international randomized trial, whose primary endpoint was not met for all the 193 pts with MCC (EORTC 05011). Methods: 130 M and 63 F were randomized to receive chronomodulated IRI (180 mg/m2 over 6-h, with peak delivery in the morning (at 5:00 or 9:00), in the afternoon (at 13:00 or 17:00) or at night (at 21:00 or 01:00) on day (d) 1, followed by fixed-time chronomodulated oxaliplatin-5-fluorouracil-leucovorin for 4 d. Triplet combination was given q3 weeks as 1st or 2nd line, without prophylactic G-CSF. The relevance of IRI timing for main toxicities was determined separately in M and F, using Cosinor and Fisher Exact tests. Results: Baseline characteristics of M or F pts did not differ significantly according to IRI timing group. Main worse grade 3-4 toxicities per pt after 6 courses were diarrhea (M, 40.2%; F, 51.9%) neutropenia (M, 12.6%; F, 18.4%), fatigue (M, 13.4%; F, 17.3%) and anorexia (M, 8.2%; F, 9.6%). These toxicities were reduced following IRI delivery in the morning for M, but in the afternoon for F, with statistically significant rhythms (p < 0.05 from cosinor) and sex*timing interactions (Fischer Exact, diarrhea, p = 0.023; neutropenia, p = 0.015; fatigue, p = 0.062; anorexia, p = 0.032). IRI timing was most critical for F, with Grade 3-4 toxicities ranging from 55.2% of the pts (morning) to 29.4% (afternoon) for diarrhea, and from 25.9% (morning) to 0% (afternoon) for neutropenia. IRI timing did not significantly influence efficacy. Conclusions: The present study results supports the administration of irinotecan in the morning for M and in the afternoon for F in order to minimize adverse events of triplet chemotherapy without impairing efficacy. Prospective trials testing sex specific timing issues are warranted. Clinical trial information: 05011.