Sex moderates circadian chemotherapy effects on survival of patients with metastatic colorectal cancer: A meta-analysis

S. Giacchetti, P. A. Dugué, P. F. Innominato, G. A. Bjarnason, C. Focan, C. Garufi, S. Tumolo, B. Coudert, S. Iacobelli, R. Smaaland, M. Tampellini, R. Adam, T. Moreau, F. Lévi

Research output: Contribution to journalArticlepeer-review


Background: Molecular circadian clocks can modify cancer chemotherapy effects, with a possible moderation according to sex differences. We investigated whether sex determine the optimal delivery schedule of chemotherapy for metastatic colorectal cancer. Patients and methods: A meta-analysis was performed using individual data from three international Phase III trials comparing 5-fluorouracil, leucovorin and oxaliplatin administered in chronomodulated (chronoFLO) or conventional (CONV) infusions. The data from 345 females and 497 males were updated at 9 years. The main end point was survival. Results: Overall survival was improved in males on chronoFLO when compared with CONV (P = 0.009), with respective median values of 20.8 (95% CL, 18.7 to 22.9) and 17.5 months (16.1 to 18.8). Conversely, median survival was 16.6 months (13.9 to 19.3) on chronoFLO and 18.4 months (16.6 to 20.2) on CONV in females (P=0.012). The sex versus schedule interaction was a strong predictive factor of optimal treatment schedule, with a hazard ratio of 1.59 (1.30 to 1.75) for overall survival (P = 0.002) in multivariate analysis. Conclusions: Males lived significantly longer on chronomodulated chemotherapy rather than on conventional chemotherapy. The current chronoFLO schedule deserves prospective assessment as a safe and more effective first-line treatment option than conventional delivery for male patients.

Original languageEnglish
Article numbermds148
Pages (from-to)3110-3116
Number of pages7
JournalAnnals of Oncology
Issue number12
Publication statusPublished - Dec 2012


  • Chronotherapy
  • Colorectal cancer
  • Drug delivery
  • Folfox
  • Gender
  • Meta-analysis

ASJC Scopus subject areas

  • Oncology
  • Hematology


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