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Poster display session

3760 - Sex-related differences in circadian-dependent tolerance of Irinotecan (I) added to chronomodulated (chrono) 5-Fluorouracil (F), Leucovorin (L) and Oxaliplatin (O): final results from international randomised time-finding study in patients with metastatic colorectal cancer (MCC).

Date

09 Sep 2017

Session

Poster display session

Presenters

Francis Levi

Citation

Annals of Oncology (2017) 28 (suppl_5): v158-v208. 10.1093/annonc/mdx393

Authors

F. Levi1, C. Garufi2, A. Karaboué3, C. Focan4, P. Chollet5, X. Li6, P. INNOMINATO1

Author affiliations

  • 1 Medical School, University of Warwick, CV4 7AL - Coventry/GB
  • 2 Medical Oncology, Ospedale Di Pescara, Pescara/IT
  • 3 Research & Therapeutic Innovation, AK-SCIENCE, Vitry-sur-Seine/FR
  • 4 Oncology, Centre Hospitalier Chrétien (CHC), 4000 - Liège/BE
  • 5 Oncology, Centre Jean Perrin, 63011 - Clermont-Ferrand/FR
  • 6 Team-3 Chronotherapy Of Liver Cancers And Optimization Of Liver Function, INSERM U935, 94800 - Villejuif/FR
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Resources

Abstract 3760

Background

The least toxic time (LTT) of I varied by up to 8 hours according to sex in mice (Li et al. Cancer Res 2013). The translational relevance was investigated through a post-hoc analysis of a randomised trial, where the planned methodology did not identify the LTT of I combined with F, L and O (chronoIFLO) in the whole population.

Methods

199 MCC patients at 18 EU centers were randomised to receive chrono I (180 mg/m2 over 6-h, with peak delivery at 1:00, 5:00, 9:00, 13:00, 17:00 or 21:00) on day (d) 1, followed by fixed-time chrono O (20 mg/m2/d over 11.5 h; peak delivery at 16:00) and F-L (700 and 300 mg/m2/d, respectively, over 11.5h, with peak delivery at 4:00), for 4 d. ChronoIFLO was administered q3 weeks as 1st or 2nd line. The main endpoints were the circadian profiles of Grade (G) 3-4 toxicity and best objective response (OR), according to sex. Rhythmic trends were determined with cosinor using smoothed data through moving average.

Results

The trial included 136 males (m; 68%) and 63 females (f; 32%), with similar characteristics among the 6 treatment groups. The rates of all G3-4 toxicities ranged from 64% to 69.6% in m, and from 50% to 93.3% in f according to I timing. The LTT was at 12:30 [95% CI, 11:30-13:30] in m (p = 0.002), and at 15:55 [12:40-19:08] in f (p = 0.05) for all G3-4 toxicities. G3-4 neutropenia varied >3-fold as a function of I timing (10 to 33.3% in m; 0 to 38.5% in f), and the least corresponded to I peak delivery at 11:00 [08:00-13:08] in m (p = 0.045) and 18:07 [15:07-21:08] (p = 0.047) in f. Similar circadian trends were found for mucosal G3-4 toxicities in both sexes. No timing effect was found for G3-4 diarrhoea. OR rates ranged from 38.9% to 80% in m, and 37.5% to 83.3% in f between groups, with most effective timing of I overlapping with LTT in m (14:50 [11:52-17:26], p = 0.039), but not in f (02:17, p = 0.074).

Conclusions

Optimal timing of I tolerability occurred 4 to 7 h earlier in m as compared to f, in agreement with prior mouse data. The relevance of sex for the determination of optimal efficacy timing is further supported here.

Clinical trial identification

EORTC 05011

Legal entity responsible for the study

Warwick Medical School

Funding

Warwick Medical School

Disclosure

All authors have declared no conflicts of interest.

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