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

Ann Oncol. 2012 Dec;23(12):3110-3116. doi: 10.1093/annonc/mds148. Epub 2012 Jun 27.


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.

Publication types

  • Clinical Trial, Phase III
  • Meta-Analysis
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Chronotherapy
  • Circadian Clocks*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / mortality*
  • Drug Administration Schedule
  • Female
  • Fluorouracil / therapeutic use
  • Humans
  • Leucovorin / therapeutic use
  • Male
  • Middle Aged
  • Neoplasm Metastasis / drug therapy
  • Neoplasm Recurrence, Local / drug therapy
  • Organoplatinum Compounds / therapeutic use
  • Sex Factors
  • Survival Rate
  • Treatment Outcome


  • Organoplatinum Compounds
  • Leucovorin
  • Fluorouracil

Supplementary concepts

  • Folfox protocol