title: Subjective sleep and overall survival in chemotherapy-naïve patients with metastatic colorectal cancer.
abstract: BACKGROUND
  Sleep disorders are prevalent in patients with advanced cancer. Their impact on clinical outcomes is not well understood.
  
  
  METHODS
  A post-hoc analysis was conducted in 361 chemo-naïve patients with metastatic colorectal cancer completing twice the EORTC QLQ-C30 questionnaire within a randomized international phase III trial. The study assessed the effect on overall survival (OS) of subjective sleep complaint, used as a normal or a time-dependent covariate (TDC), using a multivariate Cox proportional hazard model. Prognostic analysis was conducted on the whole study population and separately in each treatment arm (conventional FOLFOX2, or chronomodulated chronoFLO4).
  
  
  RESULTS
  Sleep problems were reported by 202 patients (56%) at baseline and by 188 (52%) on treatment. Sleep problems at baseline were independently associated with a higher risk of earlier death (HR: 1.36; p = 0.011), progression (HR: 1.43; p = 0.002) and poor treatment response (RR: 0.58; p = 0.016). TDC analysis confirmed the independent prognostic effect of sleep problems on OS (HR: 1.37; p = 0.008), while on treatment this effect was only observed using univariate analysis. The negative prognostic value of sleep problems on OS at baseline, on treatment, and as a TDC was greatest on chronoFLO4 compared to FOLFOX2.
  
  
  CONCLUSIONS
  Subjective sleep problems are associated with poor clinical outcomes in metastatic colorectal cancer patients and affect chronotherapy effectiveness. There is a need for a well-tuned circadian timing system in order to increase chronotherapy activity. Prospective studies are needed for determining the impact of therapeutic approaches on sleep disorders upon quality of life and survival of cancer patients.
authors: Assistance Publique - Hôpitaux de Paris, Department of Oncology, Paul Brousse Hospital, Villejuif, France; INSERM, UMRS 776 'Rythmes Biologiques et Cancers', Villejuif, France. Electronic address: pasquale.innominato@inserm.fr.
authors: Pasquale F
authors: PF
authors: Innominato
authors: Center for Stress and Health, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford, CA, USA.
authors: David
authors: D
authors: Spiegel
authors: Assistance Publique - Hôpitaux de Paris, Department of Oncology, Paul Brousse Hospital, Villejuif, France; INSERM, UMRS 776 'Rythmes Biologiques et Cancers', Villejuif, France.
authors: Ayhan
authors: A
authors: Ulusakarya
authors: INSERM, UMRS 776 'Rythmes Biologiques et Cancers', Villejuif, France; Breast Diseases Unit, Department of Medical Oncology, Assistance Publique - Hôpitaux de Paris, St. Louis Hospital, Paris, France.
authors: Sylvie
authors: S
authors: Giacchetti
authors: Division of Medical Oncology, Sunnybrook Odette Cancer Center, Toronto, Ontario, Canada.
authors: Georg A
authors: GA
authors: Bjarnason
authors: Assistance Publique - Hôpitaux de Paris, Department of Oncology, Paul Brousse Hospital, Villejuif, France; INSERM, UMRS 776 'Rythmes Biologiques et Cancers', Villejuif, France; Université Paris Sud 11, UMR-S0776, Orsay, France; Cancer Chronotherapy Unit, Warwick Medical School, Warwick University, Coventry, Warwickshire, UK.
authors: Francis
authors: F
authors: Lévi
authors: Center for Stress and Health, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford, CA, USA.
authors: Oxana
authors: O
authors: Palesh
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D019454:Chronotherapy; D015179:Colorectal Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000401:mortality* / Q000556:secondary; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D011379:Prognosis; D016016:Proportional Hazards Models; D011788:Quality of Life; D012893:Sleep Wake Disorders / Q000175:diagnosis / Q000453:epidemiology*; D011795:Surveys and Questionnaires; D015996:Survival Rate; D055815:Young Adult
chemical_list: D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil
keywords: Chronotherapy; Circadian; Colorectal cancer; Sleep; Survival; Time-dependent covariates