Symptoms associated with circadian rest-activity rhythm disruption in 237 patients with metastatic colorectal cancer.

1 Background: The circadian timing system exerts temporal control over physiology, generating rhythms of about 24 hours. Its alteration in benign conditions has been associated with several systemic symptoms, including fatigue, appetite loss and poor sleep. However, the clinical impact of circadian disruption in cancer patients remains overlooked. We hypothesized that patients with circadian disruption would report more severe symptoms than those with robust circadian function. Methods: Data were available for 237 patients with metastatic colorectal cancer: M/F ratio: 1.66; median age: 60.4 years; range: 20.7-77.6; WHO Performance Status (PS) = 0/1: 59.7%/33.5%. We estimated the occurrence of circadian disruption using a validated parameter (the dichotomy index I < O), derived from wrist-actigraphy for at least 72 consecutive hours. Symptoms were self-reported by the patients using the EORTC QLQ-C30 questionnaire. Mann-Whitney U test was used to compare symptom severity according to the presence or absence of circadian disruption. Cohen’s d effect sizes were computed to evaluate the clinical meaningfulness of the observed differences. Subgroup analyses were performed according to gender, age, and WHO Performance Status (PS). Results: Circadian disruption (I < O lower than or equal to 97.5%) occurred in 130 (54.9%) patients. Fatigue (p < 0.0001), appetite loss (p < 0.0001), difficulty sleeping (p = 0.009), pain (p < 0.0001) and dyspnea (p = 0.001) were significantly more severe in patients with circadian disruption than in those with robust circadian function. Largest effect sizes were observed for fatigue (0.64), appetite loss (0.59) and pain (0.57). Subgroup analyses showed similar results, regardless of gender, age or PS. Conclusions: In this large international study, the presence of circadian disruption was associated with a clinically meaningfully higher severity of fatigue, appetite loss, pain, dyspnea and sleep problems. Correcting circadian dysfunction with the use of pharmacological and/or behavioural interventions could improve these often difficult-to-manage systemic symptoms.