title: The circadian rest-activity rhythm, a potential safety pharmacology endpoint of cancer chemotherapy.
abstract: The robustness of the circadian timing system (CTS) was correlated to quality of life and predicted for improved survival in cancer patients. However, chemotherapy disrupted the CTS according to dose and circadian timing in mice. A continuous and repeated measures longitudinal design was implemented here to characterize CTS dynamics in patients receiving a fixed circadian-based chemotherapy protocol. The rest-activity rhythm of 49 patients with advanced cancer was monitored using a wrist actigraph for 13 days split into four consecutive spans of 3-4 days each, i.e., before, during, right after and late after a fixed chronotherapy course. The relative amount of activity in bed vs. out of bed (I<O, main endpoint), the autocorrelation coefficient r24, the relative 24-hr amplitude (Amp), interdaily stability (IS) and intradaily variability (IV) were compared according to study span. Circadian disruption (I<O ≤ 97.5%) resulted from the administration of the fixed chronotherapy protocols, with all five rest-activity rhythm parameters being worsened in the whole group of patients (p < 0.05). Mean parameter values subsequently recovered to near baseline values. The occurrence of circadian disruption on chemotherapy was associated with a higher risk of clinically relevant fatigue (p = 0.028) or body weight loss (p = 0.05). Four CTS dynamic patterns characterized treatment response including no change (9.5% of the patients); improvement (14.3%); alteration and complete recovery (31%) or sustained deterioration (45%), possibly due to inadequate chronotherapy dosing and/or timing. Improved clinical tolerability could result from the minimization of circadian disruption through the personalization of chronotherapy delivery.
authors: Department of Physiology Chronobiology Laboratory, University of Murcia, Murcia, Spain; INSERM, UMRS776, Biological Rhythms and Cancers, Villejuif, France.
authors: Elisabet
authors: E
authors: Ortiz-Tudela
authors: Ida
authors: I
authors: Iurisci
authors: Jacques
authors: J
authors: Beau
authors: Abdoulaye
authors: A
authors: Karaboue
authors: Thierry
authors: T
authors: Moreau
authors: Maria Angeles
authors: MA
authors: Rol
authors: Juan Antonio
authors: JA
authors: Madrid
authors: Francis
authors: F
authors: Lévi
authors: Pasquale F
authors: PF
authors: Innominato
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002940:Circadian Rhythm / Q000187:drug effects*; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D008991:Monitoring, Physiologic; D009043:Motor Activity / Q000187:drug effects*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D011446:Prospective Studies; D012146:Rest / Q000502:physiology*; D015431:Weight Loss / Q000187:drug effects
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: actigraphy; cancer chemotherapy; circadian disruption; rest-activity rhythm; toxicity