title: Sex moderates circadian chemotherapy effects on survival of patients with metastatic colorectal cancer: a meta-analysis.
abstract: 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.
  
  
  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.
authors: INSERM, UMRS776 'Biological Rhythms and Cancers', Villejuif; Paris South University, UMR-S0776, Orsay; APHP, Chronotherapy Unit, Department of Oncology, Paul Brousse hospital, Villejuif; Faculty of Medicine, Paris XI University, le Kremlin-Bicêtre, France.
authors: S
authors: S
authors: Giacchetti
authors: INSERM, UMRS776 'Biological Rhythms and Cancers', Villejuif; Paris South University, UMR-S0776, Orsay; APHP, Chronotherapy Unit, Department of Oncology, Paul Brousse hospital, Villejuif; Faculty of Medicine, Paris XI University, le Kremlin-Bicêtre, France.
authors: P A
authors: PA
authors: Dugué
authors: INSERM, UMRS776 'Biological Rhythms and Cancers', Villejuif; Paris South University, UMR-S0776, Orsay; APHP, Chronotherapy Unit, Department of Oncology, Paul Brousse hospital, Villejuif; Faculty of Medicine, Paris XI University, le Kremlin-Bicêtre, France.
authors: P F
authors: PF
authors: Innominato
authors: Division of Medical Oncology, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Canada.
authors: G A
authors: GA
authors: Bjarnason
authors: Department of Medical Oncology, Centre Hospitalier Chrétien, Clinique Saint-Joseph, Liège, Belgium.
authors: C
authors: C
authors: Focan
authors: Department of Medical Oncology C, Istituto Regina Elena, Roma.
authors: C
authors: C
authors: Garufi
authors: Department of Medical Oncology, Azienda Ospedaliera Santa Maria Degli Angeli, Pordenone, Italy.
authors: S
authors: S
authors: Tumolo
authors: Department of Medical Oncology, Georges-François Leclerc Center, Dijon, France.
authors: B
authors: B
authors: Coudert
authors: Department of Medical Oncology, G. D'Annunzio di Chieti University, Chieti, Italy.
authors: S
authors: S
authors: Iacobelli
authors: Department of Hematology and Oncology, Stavanger University Hospital, Stavanger; University of Bergen, Norway.
authors: R
authors: R
authors: Smaaland
authors: Department of Medical and Biological Sciences, University of Torino, San Luigi Gonzaga Hospital, Orbassano, Torino, Italy.
authors: M
authors: M
authors: Tampellini
authors: INSERM, UMRS776 'Biological Rhythms and Cancers', Villejuif; Paris South University, UMR-S0776, Orsay; APHP, Chronotherapy Unit, Department of Oncology, Paul Brousse hospital, Villejuif; Faculty of Medicine, Paris XI University, le Kremlin-Bicêtre, France; Onco-surgery Unit, Hepato-biliary Center, France.
authors: R
authors: R
authors: Adam
authors: Department of Biostatistics, INSERM U1018, Paul Brousse Hospital, Villejuif, France.
authors: T
authors: T
authors: Moreau
authors: INSERM, UMRS776 'Biological Rhythms and Cancers', Villejuif; Paris South University, UMR-S0776, Orsay; APHP, Chronotherapy Unit, Department of Oncology, Paul Brousse hospital, Villejuif; Faculty of Medicine, Paris XI University, le Kremlin-Bicêtre, France. Electronic address: monique.levi@inserm.fr.
authors: F
authors: F
authors: Lévi
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019454:Chronotherapy; D057906:Circadian Clocks; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality*; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D012737:Sex Factors; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil