Relevance of internal time and circadian robustness for cancer patients.
BACKGROUND
Adequate circadian timing of cancer treatment schedules (chronotherapy) can enhance tolerance and efficacy several-fold in experimental and clinical situations. However, the optimal timing varies according to sex, genetic background and lifestyle. Here, we compute the individual phase of the Circadian Timing System to decipher the internal timing of each patient and find the optimal treatment timing.


METHODS
Twenty-four patients (11 male; 13 female), aged 36 to 77 years, with advanced or metastatic gastro-intestinal cancer were recruited. Inner wrist surface Temperature, arm Activity and Position (TAP) were recorded every 10 min for 12 days, divided into three 4-day spans before, during and after a course of a set chronotherapy schedule. Pertinent indexes, I < O and a new biomarker, DI (degree of temporal internal order maintenance), were computed for each patient and period.


RESULTS
Three circadian rhythms and the TAP rhythm grew less stable and more fragmented in response to treatment. Furthermore, large inter- and intra-individual changes were found for T, A, P and TAP patterns, with phase differences of up to 12 hours among patients. A moderate perturbation of temporal internal order was observed, but the administration of fixed chronomodulated chemotherapy partially resynchronized temperature and activity rhythms by the end of the study.


CONCLUSIONS
The integrated variable TAP, together with the asynchrony among rhythms revealed by the new biomarker DI, would help in the personalization of cancer chronotherapy, taking into account individual circadian phase markers.
Chronobiology Laboratory, Department of Physiology, University of Murcia, IMIB-Arrixaca, Murcia, Spain.|INSERM, UMRS 776 « Biological Rhythms and Cancers », Villejuif, France.|Warwick Medical School, Cancer Chronotherapy Unit, Coventry, UK.
Elisabet
E
Ortiz-Tudela
INSERM, UMRS 776 « Biological Rhythms and Cancers », Villejuif, France.|APHP, Chronotherapy Unit, Department of Oncology, Paul Brousse Hospital, Villejuif, France.
Pasquale F
PF
Innominato
Chronobiology Laboratory, Department of Physiology, University of Murcia, IMIB-Arrixaca, Murcia, Spain. angerol@um.es.|Chronobiology Laboratory, Department of Physiology, Faculty of Biology, University of Murcia, Campus de Espinardo, Espinardo, Murcia, Zip Code 30100, Spain. angerol@um.es.
Maria Angeles
MA
Rol
INSERM, UMRS 776 « Biological Rhythms and Cancers », Villejuif, France.|APHP, Chronotherapy Unit, Department of Oncology, Paul Brousse Hospital, Villejuif, France.|Warwick Medical School, Cancer Chronotherapy Unit, Coventry, UK.
Francis
F
Lévi
Chronobiology Laboratory, Department of Physiology, University of Murcia, IMIB-Arrixaca, Murcia, Spain.
Juan Antonio
JA
Madrid
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000502:physiology; D019454:Chronotherapy; D002940:Circadian Rhythm / Q000235:genetics* / Q000502:physiology; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009043:Motor Activity / Q000502:physiology; D057285:Precision Medicine; D014953:Wrist / Q000502:physiology
D014408:Biomarkers, Tumor
Circadian; TAP; chemotherapy; gastro-intestinal cancer; personalization