Efficacy and safety of chronomodulated irinotecan, oxaliplatin, 5‐fluorouracil and leucovorin combination as first‐ or second‐line treatment against metastatic colorectal cancer: Results from the International EORTC 05011 Trial

Abstract

The triplet combination of irinotecan, oxaliplatin and fluorouracil is an active frontline regimen in metastatic colorectal cancer, but scarce data exist on its use as salvage treatment. We aimed at assessing its safety and efficacy profiles with its circadian‐based administration (chronoIFLO5) as either first‐ or second‐line treatment, within the time‐finding EORTC 05011 trial. Five‐day chronoIFLO5 was administered every 3 weeks in patients with PS 0, 1 or 2. It consisted of chronomodulated irinotecan (180 mg/sqm), oxaliplatin (80 mg/sqm) and fluorouracil‐leucovorin (2800 and 1200 mg/sqm, respectively). For our study, toxicity and antitumour activity were evaluated separately in first‐ and second‐line settings. Primary endpoints included Grade 3‐4 toxicity rates, best objective response rate (ORR), progression‐free survival (PFS) and overall survival (OS). One‐hundred forty‐nine and 44 patients were treated in first‐line and second‐line settings, respectively, with a total of 1138 cycles with median relative dose intensities of about 90%. Demographics were comparable in the two groups. Thirty‐six (24.7%) and 10 (22.2%) patients experienced at least one episode of severe toxicity in first line and second line, respectively. Frontline chronoIFLO5 yielded an ORR of 62.3% [95% CI: 54.2‐70.4] and resulted in median PFS and OS of 8.7 months [7.5‐9.9] and 19.9 months [15.4‐24.5]. Corresponding figures in second line were 37.5% [22.5‐52.5], 6.7 months [4.8‐8.9] and 16.3 months [11.8‐20.8]. International and prospective evaluation revealed the favourable safety and efficacy profiles of chronoIFLO5, both as frontline and as salvage treatment against metastatic colorectal cancer. In particular, encouraging activity in second line was observed, with limited haematological toxicity.

A mathematical model of the circadian clock and drug pharmacology to optimize irinotecan administration timing in colorectal cancer

“…Thus, timing drug administration may also impact drug pharmacodynamics (PD) and eventually treatment outcome. In the field of cancer management, several clinical studies have addressed the effect of timing medications for treatment optimization – chronotherapy – with promising results [8] , [12] , [13] , [14] . Giacchetti and colleagues reported data from three international Phase III clinical trials involving 842 patients (345 females and 497 males) treated with 5-fluorouracil, leucovorin and oxaliplatin administered as chronomodulated or conventional infusions [15] .…”

Circadian rhythms and cancers: the intrinsic links and therapeutic potentials

“…Another study on 186 metastatic colorectal cancer patients in a randomized multicenter phase III trial also reported that oxaliplatin, 5-FU, and chronoFLO delivered by chrono-modulated infusion reduced ~ fivefold the rate of severe mucosal toxicity and ~ 50% functional impairment from peripheral sensitive neuropathy compared with constant drug delivery (14% vs. 76% and 16% vs. 31%, respectively) [ 329 ]. Furthermore, timed administration of irinotecan was performed in 31 cancer patients and demonstrated that chrono-mediated infusion of irinotecan from 2:00 a.m. to 8:00 a.m. induced less severe diarrhea and interpatient variability compared with the conventional 30-min infusion in the morning [ 351 ]. A very recent clinical study evaluated the effect of immunotherapy time-of-day infusion on the overall survival of patients with advanced melanoma.…”

Circadian Rhythms, Disease and Chronotherapy

“…at 1800 before or after doxorubicin) caused fewer complications and renal toxicity than administration of doxorubicin in the evening and cisplatin in the morning (Hrushesky, 1985;Sothern et al, 1989;Levi et al, 1990). Likewise, chronotherapy trials of patients with metastatic colorectal cancer showed that timed combination therapy with irinotecan, oxaliplatin, 5-fluorouracil (5-FU), and leucovorin resulted in delayed time to progression and increased overall survival with increased tolerance and safety, compared to routine chemotherapy (Levi et al, 1997;Gholam et al, 2006;Innominato et al, 2020b).…”