Circadian Rhythm in Rest and Activity: A Biological Correlate of Quality of Life and a Predictor of Survival in Patients with Metastatic Colorectal Cancer

¹INSERM, U776 «Biological Rhythms and Cancers»; ²Assistance Publique-Hôpitaux de Paris, Chronotherapy Unit, Department of Oncology, hôpital Paul Brousse, P V. Couturier; ³Univ Paris-Sud, UMR-S0776, Orsay, France; ⁴CHC-Clinique Saint Joseph, Liege, Belgium; ⁵European Organisation for Research and Treatment of Cancer Data Center, AISBL-IVZW, Brussels, Belgium; ⁶INSERM, U780 "Research in Epidemiology and Biostatistic," Villejuif, France; ⁷Istituto Regina Elena, Roma, Italy; ⁸Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom; ⁹Centre Georges-François Leclerc, Dijon, France; ¹⁰Department of Oncology & Neurosciences, University «G. d'Annunzio» Medical School, Chieti, Italy; ¹¹Service d'Oncologie Médicale, CHU Dupuytren, Limoges, France; ¹²Ospedale San Luigi Gonzaga, Orbassano, Italy; ¹³Centre Jean Perrin, Clermont-Ferrand, France; and ¹⁴Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada

^* To whom correspondence should be addressed. E-mail: georg.bjarnason{at}sri.utoronto.ca.

	Abstract

The rest-activity circadian rhythm (CircAct) reflects the function of the circadian timing system. In a prior single-institution study, the extent of CircAct perturbation independently predicted for survival and tumor response in 192 patients receiving chemotherapy for metastatic colorectal cancer. Moreover, the main CircAct parameters correlated with several health-related quality of life (HRQoL) scales. In this prospective study, we attempted to extend these results to an independent cohort of chemotherapy-naive metastatic colorectal cancer patients participating in an international randomized phase III trial (European Organisation for Research and Treatment of Cancer 05963). Patients were randomized to receive chronomodulated or conventional infusion of 5-fluorouracil, leucovorin, and oxaliplatin as first-line treatment for metastatic colorectal cancer. Patients from nine institutions completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and wore a wrist accelerometer (actigraph) for 3 days before chemotherapy delivery. Two validated parameters (I<O and r24) were used to estimate CircAct. Of 130 patients with baseline CircAct assessments, 96 had baseline HRQoL data. I<O was confirmed to correlate with global quality of life, physical functioning, social functioning, fatigue, and appetite loss (r > |0.25|; P < 0.01). I<O further independently predicted for overall survival with a hazard ratio of 0.94 (P < 0.0001). The associations between CircAct parameters, HRQoL, and survival, which were shown in this international study involving previously untreated metastatic colorectal cancer patients, confirm prior single-institution findings in mostly pretreated metastatic colorectal cancer patients. The circadian timing system constitutes a novel therapeutic target. Interventions that normalize circadian timing system dysfunction may affect quality of life and survival in cancer patients. [Cancer Res 2009;69(11):4700–7]

Key Words: Circadian, Actigraphy, Health-Related Quality of Life, Colorectal Cancer, Chronotherapy, Survival