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

Abstract

BackgroundPsychosocial 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).MethodsTwo 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.ConclusionObjectively 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 importance of determining circadian parameters in pharmacological studies

“…However, mice are nocturnal animals, and as a consequence, their rhythms differ substantially from those of humans. Moreover, knowing that each individual chronotype can affect treatment response (Innominato et al, ), there is a need to find approaches that can be used to accurately measure circadian rhythms in humans.…”

“…These can easily be assessed through patient‐reported outcome measures, but such questionnaires are rather subjective. Wristbands are currently the most common device used for measuring activity in humans and have been validated as an objective biomarker of circadian function (Ancoli‐Israel et al, ; Innominato et al, ). Other wearable biosensors have also been correlated with the circadian rhythms of patients (Innominato et al, ).…”

“…Wristbands are currently the most common device used for measuring activity in humans and have been validated as an objective biomarker of circadian function (Ancoli‐Israel et al, ; Innominato et al, ). Other wearable biosensors have also been correlated with the circadian rhythms of patients (Innominato et al, ). For example, a recent study studied the circadian rhythms in individuals of different ages and measured several parameters such as distal skin temperature, activity, body position, light exposure, and environmental temperature, using various wearable biosensors (Martinez‐Nicolas et al, ).…”

Inter- and intra-patient circadian variabilities in eight urinary modified nucleosides excretion in patients with metastatic colorectal cancer

“…We also computed the autocorrelation at 24-h (r24), a measure of the regularity of the 24-h restactivity pattern from day to day, as well as the dichotomy index (I < O), defined as the percentage of activity in-bed (I) that was less than the median activity out-of-bed (O) [28,35]. Furthermore, we also computed for each patient the dominant period using the spectrum-resampling (SR) algorithm of Costa et al [36], as well as the acrophase and amplitude using a cosinor model.…”

Relevance of a Mobile Internet Platform for Capturing Inter- and Intrasubject Variabilities in Circadian Coordination During Daily Routine: Pilot Study (Preprint)

“…Anderson Symptom Inventory (MDASI) questionnaires in cancer patients with locally advanced or metastatic disease [23,24]. Furthermore, circadian rest-activity disruption, as measured with an I<O of 97.5% or less, in patients receiving cancer chemotherapy could indeed represent an early warning signal of deterioration and emergency hospitalisation [25,26].…”