Circadian rest-activity rhythm as an objective biomarker of patient-reported outcomes in patients with advanced cancer

Background Psychosocial symptoms often cluster together, are refractory to treatment, and impair health‐related quality of life (HR‐QoL) in cancer patients. The contribution of circadian rhythm alterations to systemic symptoms has been overlooked in cancer, despite a causal link shown under jet lag and shift work conditions. We investigated whether the circadian rest‐activity rhythm provides a reliable and objective estimate of the most frequent patient‐reported outcome measures (PROMs). Methods Two datasets were used, each involving concomitant 3‐day time series of wrist actigraphy and HR‐QoL questionnaires: EORTC QLQ‐C30 was completed once by 237 patients with metastatic colorectal cancer; MD Anderson Symptom Inventory (MDASI) was completed daily by 31 patients with advanced cancer on continuous actigraphy monitoring, providing 1015 paired data points. Circadian function was assessed using the clinically validated dichotomy index I < O. Nonparametric tests compared PROMs and I < O. Effect sizes were computed. Sensitivity subgroup and temporal dynamics analyses were also performed. Results I < O values were significantly lower with increasing symptom severity and worsening HR‐QoL domains. Fatigue and anorexia were worse in patients with circadian disruption. The differences were both statistically and clinically significant (P < 0.001; d ≥ 0.33). Physical and social functioning, and global quality/enjoyment of life were significantly better in patients with robust circadian rhythm (P < 0.001; d ≥ 0.26). Sensitivity analyses validated these findings. Conclusion Objectively determined circadian disruption was consistently and robustly associated with clinically meaningfully severe fatigue, anorexia, and interference with physical and social functioning. This supports an important role of the circadian system in the determination of cancer patients’ HR‐QoL and symptoms that deserves therapeutic exploitation

The circadian timing system in clinical oncology

The circadian timing system (CTS) controls several critical molecular pathways for cancer processes and treatment effects over the 24 hours, including drug metabolism, cell cycle, apoptosis, and DNA damage repair mechanisms. This results in the circadian time dependency of whole-body and cellular pharmacokinetics and pharmacodynamics of anticancer agents. However, CTS robustness and phase varies among cancer patients, based on circadian monitoring of rest– activity, body temperature, sleep, and/or hormonal secretion rhythms. Circadian disruption has been further found in up to 50% of patients with metastatic cancer. Such disruption was associated with poor outcomes, including fatigue, anorexia, sleep disorders, and short progression-free and overall survival. Novel, minimally invasive devices have enabled continuous CTS assessment in non-hospitalized cancer patients. They revealed up to 12-hour differences in individual circadian phase. Taken together, the data support the personalization of chronotherapy. This treatment method aims at the adjustment of cancer treatment delivery according to circadian rhythms, using programmable-in-time pumps or novel release formulations, in order to increase both efficacy and tolerability. A fixed oxaliplatin, 5-fluorouracil and leucovorin chronotherapy protocol prolonged median overall survival in men with metastatic colorectal cancer by 3.3 months as compared to conventional delivery, according to a meta-analysis (P = 0.009). Further analyses revealed the need for the prevention of circadian disruption or the restoration of robust circadian function in patients on chronotherapy, in order to further optimize treatment effects. The strengthening of external synchronizers could meet such a goal, through programmed exercise, meal timing, light exposure, improved social support, sleep scheduling, and the properly timed administration of drugs that target circadian clocks. Chrono-rehabilitation warrants clinical testing for improving quality of life and survival in cancer patients

The day after : correlates of patient-reported outcomes with actigraphy-assessed sleep in cancer patients at home (inCASA project)

Subjective sleep assessment in cancer patients poorly correlates with actigraphy parameters that usually encompass multiple nights. We aimed to determine the objective actigraphy measures that best correlated with subjective sleep ratings on a night-by-night basis in cancer patients. Thirty-one cancer patients daily self-rated sleep disturbances using the single dedicated item of the MD Anderson Symptom Inventory (0–10 scale) with 18 other items, and continuously wore a wrist actigraph for 30 days. Objective sleep parameters were computed from the actigraphy nighttime series, and correlated with subjective sleep disturbances reported on the following day, using repeated measures correlations. Multilevel Poisson regression analysis was performed to identify the objective and subjective parameters that affected subjective sleep rating. Poor subjective sleep score was correlated with poor sleep efficiency (rrm = −0.13, p = 0.002) and large number of wake episodes (rrm = 0.12, p = 0.005) on the rated night. Multilevel analysis demonstrated that the expected sleep disturbance score was affected by the joint contribution of the wake episodes (exp(β) = 1.01, 95% confidence interval = 1.00 to 1.02, p = 0.016), fatigue (exp(β) = 1.35, 95% confidence interval = 1.15 to 1.55, p < 0.001) and drowsiness (exp(β) = 1.70, 95% confidence interval = 1.19 to 2.62, p = 0.018), self-rated the following evening, and sleep disturbance experienced one night before (exp(β) = 1.77, 95% confidence interval = 1.41 to 2.22, p < 0.001). The night-by-night approach within a multidimensional home tele-monitoring framework mainly identified the objective number of wake episodes computed from actigraphy records as the main determinant of the severity of sleep complaint in cancer patients on chemotherapy. This quantitative information remotely obtained in real time from cancer patients provides a novel framework for streamlining and evaluating interventions toward sleep improvement in cancer patients

Cancer-Related Fatigue and Sleep Disorders

Abstract Sleep disorders, such as difficulty falling asleep, problems maintaining sleep, poor sleep efficiency, early awakening, and excessive daytime sleepiness, are prevalent in patients with cancer. Such problems can become chronic in some patients, persisting for many months or years after completion of cancer therapy. For patients with cancer, sleep is potentially affected by a variety of factors, including the biochemical changes associated with the process of neoplastic growth and anticancer treatments, and symptoms that frequently accompany cancer, such as pain, fatigue, and depression. Fatigue is highly prevalent and persistent in patients with cancer and cancer survivors. Although cancerrelated fatigue and cancer-related sleep disorders are distinct, a strong interrelationship exists between these symptoms, and a strong possibility exists that they may be reciprocally related. The majority of studies that have assessed both sleep and fatigue in patients with cancer provide evidence supporting a strong correlation between cancer-related fatigue and various sleep parameters, including poor sleep quality, disrupted initiation and maintenance of sleep, nighttime awakening, restless sleep, and excessive daytime sleepiness. This paper reviews the data from these studies with a view toward suggesting further research that could advance our scientific understanding both of potential interrelationships between sleep disturbance and cancer-related fatigue and of clinical interventions to help with both fatigue and sleep disturbance. The Oncologist 2007;12(suppl 1)