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

Abstract

A disruption of the circadian timing system, as identified by monitoring of marker biorhythms, is common in cancer patients. The recording of the rest-activity rhythm with a wrist actigraph has been commonly used. This noninvasive monitoring allows a robust estimation of circadian disruption. The authors have previously found that altered patterns of circadian rest-activity rhythms are significantly and independently associated with the severity of fatigue and anorexia in patients with metastatic colorectal cancer. Elevated proinflammatory cytokines could partly account for this circadian disruption and its associated constitutional symptoms. Here, the authors present and discuss the data supporting the hypothesis that circadian disruption is often associated with fatigue and anorexia, which in turn further alter and dampen circadian synchronization, thus, creating a vicious cycle. This body of evidence paves the path for innovative therapeutic approaches targeting the circadian timing system in an effort to diminish constitutional symptoms induced by cancer and some anticancer treatments.

Subjective sleep and overall survival in chemotherapy-naïve patients with metastatic colorectal cancer

“…Our subgroup analyses furthermore substantiate the hypothesis that excessive toxicity could hamper the efficacy of circadian-based chronomodulated chemotherapy 8,30,32,33,35,36 . In this study, we found that the complaint of sleep troubles at the last ontreatment assessment was correlated with shorter overall survival in patients treated with chronoFLO4, but not on FOLFOX2.…”

“…Thus, our findings underscore the hypothesis that optimal efficacy of circadian-based chronotherapy is associated with optimal tolerability 32,33,37 . Indeed, the persistence of robust circadian function during chemotherapy, a recently documented phenomenon 38 , associated with lower incidence and/or severity of chemotherapy toxicity, has been shown to predict for better efficacy of chronotherapy 8,30,32,33,35,36 . Thus, as for severe neutropenia or clinically meaningful fatigue and/or weight loss, subjective sleep complaints during treatment might reflect disrupted circadian function, decreasing chronotherapy effectiveness.…”

“…Berger et al also noted substantial evidence of circadian disruption in that sample, suggesting that patients diagnosed with these types of cancer experience lack of distinction between nighttime and daytime in their activities 6 . This phenomenon was previously described in patients with advanced cancers where substantial amount of time spent asleep during the day and awake during the night effectively blurs the line between day and nighttime [7][8][9] . The observed association between altered rest-activity rhythm and subjectively-reported sleep problems in two independent cohorts of patients with metastatic colorectal cancer 10,11 further supported the hypothesis that disruption of circadian rhythms in cancer patients plays a role in the occurrence of sleep problems.…”

Wrist actimetry circadian rhythm as a robust predictor of colorectal cancer patients survival

“…This measure is in fact associated with all four variables, which are under circadian control (Mormont et al, 2000, Innominato et al, Innominato et al, 2009aInnominato et al, 2009b). These common cancer-related problems may interact and reinforce one another (Spiegel, 2008).…”

Melatonin and Circadian Rhythm: Aging, Cancer, and Mechanism

“…A disruption of the circadian timing system, as identified by monitoring maker biorhythms, is common in cancer patients [44]. A body of evidence paves the path for innovative therapeutic approaches targeting the circadian timing system in an effort to diminish constitutional symptoms induced by cancer and some anticancer treatments.…”