Thoracic surface temperature rhythms as circadian biomarkers for cancer chronotherapy

Abstract

The disruption of the temperature circadian rhythm has been associated with cancer progression, while its amplification resulted in cancer inhibition in experimental tumor models. The current study investigated the relevance of skin surface temperature rhythms as biomarkers of the Circadian Timing System (CTS) in order to optimize chronotherapy timing in individual cancer patients. Baseline skin surface temperature at four sites and wrist accelerations were measured every minute for 4 days in 16 patients with metastatic gastro-intestinal cancer before chronotherapy administration. Temperature and rest-activity were recorded, respectively, with wireless skin surface temperature patches (Respironics, Phillips) and an actigraph (Ambulatory Monitoring). Both variables were further monitored in 10 of these patients during and after a 4-day course of a fixed chronotherapy protocol. Collected at baseline, during and after therapy longitudinal data sets were processed using Fast Fourier Transform Cosinor and Linear Discriminant Analyses methods. A circadian rhythm was statistically validated with a period of 24 h (p<0.05) for 49/61 temperature time series (80.3%), and 15/16 rest-activity patterns (93.7%) at baseline. However, individual circadian amplitudes varied from 0.04 °C to 2.86 °C for skin surface temperature (median, 0.72 °C), and from 16.6 to 146.1 acc/min for rest-activity (median, 88.9 acc/min). Thirty-nine pairs of baseline temperature and rest-activity time series (75%) were correlated (r>|0.7|; p<0.05). Individual circadian acrophases at baseline were scattered from 15:18 to 6:05 for skin surface temperature, and from 12:19 to 15:18 for rest-activity, with respective median values of 01:10 (25–75% quartiles, 22:35–3:07) and 14:12 (13:14–14:31). The circadian patterns in skin surface temperature and rest-activity persisted or were amplified during and after fixed chronotherapy delivery for 5/10 patients. In contrast, transient or sustained disruption of these biomarkers was found for the five other patients, as indicated by the lack of any statistically significant dominant period in the circadian range. No consistent correlation (r<|0.7|, p ≥ 0.05) was found between paired rest-activity and temperature time series during fixed chronotherapy delivery. In conclusion, large inter-patient differences in circadian amplitudes and acrophases of skin surface temperature were demonstrated for the first time in cancer patients, despite rather similar rest-activity acrophases. The patient-dependent coupling between both CTS biomarkers, and its possible alteration on a fixed chronotherapy protocol, support the concept of personalized cancer chronotherapy.

Physical activity, and not fat mass is a primary predictor of circadian parameters in young men

“…Analysis of wrist temperature has been used in the circadian assessment of human subjects in studies measuring sleep quality, blood pressure, aging, cancer therapeutics, and weight loss (Bandin et al, 2014; Blazquez et al, 2012; Corbalán-Tutau et al, 2011; Gompper et al, 2010; Roche et al, 2014; Romeijn & Van Someren, 2011; Sarabia et al, 2008; Yoon et al, 2003). These temperature rhythms have been shown to correlate with changes in dim light melatonin onset, a standard for determining circadian phase in people (Nováková et al, 2013).…”

Circadian rhythms measured by actigraphy during oncological treatments: a systematic review

“…Moreover, night time inactivity and removal of the device can be difficult to distinguish. Some recent studies suggested that core temperature is more robust biomarker for circadian rhythms than rest-activity spans, and hence (wireless) skin temperature measurement may provide a more precise measurement of circadian rhythms (Scully et al 2011;Roche et al 2014). However this method is still challenged by signal dropouts, ambient temperature interferences, and high costs.…”

Identification of Circadian Determinants of Cancer Chronotherapy through In Vitro Chronopharmacology and Mathematical Modeling

“…Moreover, the administration of anticancer agents at the circadian time when they were the safest also achieved best efficacy both in rodents (4) and in cancer patients (5)(6)(7)(8). Large intersubject differences in CTS further need to be taken into account for the personalization of circadian delivery of cancer treatments (9,10). Thus, a systematic mapping of the critical pathways of anticancer drug chronopharmacology and their molecular clock control is required for optimizing treatment effects through tailoring circadian drug delivery to individual CTS.…”