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

Abstract

The rest-activity circadian rhythm (CircAct) reflects the function of the circadian timing system. In a prior singleinstitution 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]

Circadian Disruption, Fatigue, and Anorexia Clustering in Advanced Cancer Patients: Implications for Innovative Therapeutic Approaches

“…56.61 In the remaining 11 studies, performed in patients with different types of cancer, using different actigraphy devices and different fatigue scales, the degree of fatigue was found to be associated with circadian disruption, poor sleep, or lower daytime physical activity. 13,14,[49][50][51][52][53][54][55][57][58][59][60] Current data thus support the hypothesis that a disturbance in circadian function, as estimated by a locomotor activity biomarker, is associated with increased fatigue. The heterogeneity of the methodological approaches and reporting procedures used worldwide calls for collaborative efforts, as has been pointed out by other authors.…”

“…Table 1 summarizes the data for 1129 cancer patients for whom actigraphy data were correlated with data from fatigue questionnaires. 13,14,[49][50][51][52][53][54][55][56][57][58][59][60][61] In 2 out of 13 studies, no significant correlation between actigraphy parameters and fatigue was described. 56.61 In the remaining 11 studies, performed in patients with different types of cancer, using different actigraphy devices and different fatigue scales, the degree of fatigue was found to be associated with circadian disruption, poor sleep, or lower daytime physical activity.…”

“…13,14 In these 2 cohorts, those parameters were also negatively correlated with fatigue (subjective measure). 13,14 Here, we report for the first time the results of the combined analysis of these 2 data sets. 13,14 This data set consists of 251 patients with metastatic colorectal cancer, who each wore the actigraph for 72 consecutive hours and who also completed the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of life Questionnaire C30) questionnaire 63 to estimate their subjective fatigue and anorexia.…”

“…Disruption of the circadian pattern can be visually observed and objectively quantified with robust and validated parameters (eg, r24, I<O, and mean activity). [9][10][11][12][13][14] Wrist actigraphy recordings provide a noninvasive and reliable marker rhythm of the functioning of the circadian system that affects the temporal patterns of locomotor activity 15,16 and organizes some other physiological rhythms. [1][2][3] Given the heterogeneity in the methodological procedures used to assess circadian function in cancer patients in published reports, it is difficult to precisely estimate the prevalence of circadian disruption, but it likely affects at least 25% to 50% of, if not most, patients with metastatic disease.…”

Prognosis Prediction Models and their Clinical Utility in Palliative Care

“…Phase angle, which is measured via bioelectrical impedance analysis (BIA), relects the amount of water in tissues (resistance) and cellular membrane (capacitance) and could be a prognostic factor [11]. Circadian rhythm is also found to be an independent prognostic factor [12,32].…”