Innominato, Pasquale F., Ballesta, Annabelle, Huang, Qi, Focan, Christian, Chollet, Philippe, Karaboué, Abdoulaye, Giacchetti, Sylvie, Bouchahda, Mohamed, Adam, René, Garufi, Carlo and Lévi, Francis A. (2020) Sex-dependent least toxic timing of irinotecan combined with chronomodulated chemotherapy for metastatic colorectal cancer : randomized multicenter. Cancer Medicine, 9 (12). pp. 4148-4159. doi:10.1002/cam4.3056 ISSN 2045-7634.

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Abstract

The least toxic time (LTT) of irinotecan varied by up to 8 hours according to sex and genetic background in mice. The translational relevance was investigated within a randomized trial dataset, where no LTT stood out significantly in the whole population.

130 male and 63 female eligible patients with metastatic colorectal cancer were randomized to receive chronomodulated Irinotecan with peak delivery rate at 1 of 6 clock hours staggered by 4 hours on day 1, then fixed‐time chronomodulated Fluorouracil‐Leucovorin‐Oxaliplatin for 4 days, q3 weeks. The sex‐specific circadian characteristics of grade (G) 3‐4 toxicities were mapped with cosinor and time*sex interactions confirmed with Fisher's exact test.

Baseline characteristics of male or female patients were similar in the six treatment groups. Main grade 3‐4 toxicities over six courses were diarrhea (males vs females, 39.2%; vs 46.0%), neutropenia (15.6% vs 15.0%), fatigue (11.5% vs 15.9%), and anorexia (10.0% vs 7.8%). They were reduced following irinotecan peak delivery in the morning for males, but in the afternoon for females, with statistically significant rhythms (P < .05 from cosinor) and sex*timing interactions (Fisher's exact test, diarrhea, P = .023; neutropenia, P = .015; fatigue, P = .062; anorexia, P = .032). Irinotecan timing was most critical for females, with grades 3‐4 ranging from 55.2% of the patients (morning) to 29.4% (afternoon) for diarrhea, and from 25.9% (morning) to 0% (afternoon) for neutropenia.

The study results support irinotecan administration in the morning for males and in the afternoon for females, in order to minimize adverse events without impairing efficacy.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions:	Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Colon (Anatomy) -- Cancer -- Chemotherapy, Circadian rhythms -- Therapeutic use, Rectum -- Cancer -- Treatment, Cancer -- Treatment
Journal or Publication Title:	Cancer Medicine
Publisher:	Wiley
ISSN:	2045-7634
Official Date:	June 2020
Dates:	Date Event June 2020 Published 22 April 2020 Available 30 March 2020 Accepted
Volume:	9
Number:	12
Page Range:	pp. 4148-4159
DOI:	10.1002/cam4.3056
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	10 September 2020
Date of first compliant Open Access:	10 September 2020
RIOXX Funder/Project Grant:	Project/Grant ID RIOXX Funder Name Funder ID UNSPECIFIED International Association for Research on Time in Biology and Chronotherapy UNSPECIFIED MR/M013170/1 Medical Research Council http://dx.doi.org/10.13039/501100000265 C53561/A19933 Cancer Research UK http://dx.doi.org/10.13039/501100000289
Is Part Of:	1
Related URLs:	Publisher

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