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.

FIGURE 1

Location of the skin temperature patches and the wristwatch accelerometer. (A) Identification of two warmer and two cooler areas in the anterior thorax of patients, through height resolution infrared (IR) imaging. (B) Patches placement on the four sites. (C) Wrist watch accelerometer worn on the non-dominant arm.

FIGURE 2

Twenty-four-hour patterns in multisite skin surface temperature and wrist activity measured every minute before, during and after chronotherapy in two cancer patients (pt 1 and pt 2). (A and C) Chronograms of skin temperature at both upper thoracic sites (U1, blue; U2, red) and at both lower thoracic sites (L1, green; L2, purple) in patient 1 who obviously maintained robust circadian patterns throughout the 12 days record and patient 2 with obvious disrupted rhythms. (B and D) Corresponding power spectra note dominant 24-h period for all temperature patches and rest-activity with halved amplitudes during chronotherapy delivery, as compared to baseline and post-chronotherapy spans for pt 1, and the lack of dominant period with relevant amplitudes for pt 2. (E) LDA scores plot in which each variable represents all individual temperature data collected before (blue), during (green) of after (red) chronotherapy delivery for patient 1 (left) and patient 2 (right). Chronotherapy delivery clearly modified the baseline time series. Indeed, the blue scatter plot corresponding to the baseline study span is farther from the red (during) and green (after) ones for the pt 1 than the pt 2, meaning the robustness of the pt 1 rhythms and the desynchronization observed in pt 2. Furthermore, scatter plots corresponding to during (red) and after (green) are closer justifying the previous sentence. However, red and green scatter plots are closer for pt 2 explaining his difficulty to recover.

FIGURE 3

Inter- and intra-patient variability over the three study spans regarding temperature and activity amplitudes. U1/U2, data from patches situated on the upper front chest; L1/L2, data from patches situated on the lower front chest, as shown on Figure 1. (A and C) Twenty-four-hour temperature amplitudes for each time series for each patient. In (A) are the patients’ temperature amplitudes before chronotherapy from the four sites (U1/2 and L1/2) and in (C) are the patients’ temperature amplitudes evolution during and after chronotherapy delivery. (B and D) Activity amplitude corresponding to each patient and each span is shown on the right of the temperature graph. Median and Interquartile are represented right next to each corresponding marked scatter.

FIGURE 4

Inter-patient differences in temperature and rest-activity acrophases at baseline, during and after chronotherapy. Upper thoracic sites (U1, blue lozenge; U2, red triangle), lower thoracic sites (L1, green round; L2, purple asterisk), activity (yellow square). (A) Baseline, (B) during, (C) after chronotherapy. Individual acrophases were spread over a range of ≈14 h for skin surface temperature and ≈3 h for rest-activity at each study span. Median and Interquartile ranges are represented in black right next to the corresponding marker scatter.

FIGURE 5

Individual patient survival according to median value of highest skin surface temperature amplitude (among the four sites of recording). (A) At baseline, (B) during and (C) after chronotherapy. Higher was the individual skin surface temperature amplitude, longer was the survival.