Circadian actigraphic rest–activity rhythms following surgery for endometrial cancer: A prospective, longitudinal study
Introduction
A host of biological processes occur within living organisms in circadian cycles over an approximately 24-hour period. Circadian rhythms are orchestrated endogenously by the central clock in the suprachiasmatic nucleus (SCN) within the hypothalamus and also are behaviorally based in that they are sensitive to external input such as light–dark exposure, which sends signals directly from the eyes to the SCN [1]. Consistent circadian rhythms (i.e., staying within synchronization of an approximately 24-hour day) through biological and behavioral processes are related to more positive health outcomes, whereas circadian dysregulation has been linked with poorer health outcomes [2]. In the context of cancer, circadian dysregulation, as measured by melatonin suppression, cortisol flattening, and history of shift work, has been related to increased risk of tumor initiation and progression (reviewed in Eismann et al.[3]).
An alternative marker of circadian rhythm dysregulation is the diurnal pattern of rest and activity as measured by wrist-worn actigraphy. This objective and non-invasive measure involves a watch-like device that is typically worn on the non-dominant wrist and measures activity level through accelerometry in small intervals (e.g., 1 min) continuously over 24-hour periods. Resulting data are then analyzed to quantify several indices of the rest–activity cycle including mean activity level, differences between highest and lowest activity levels, the regularity of the rest–activity cycle, and the timing of peak activity.
Cross-sectional actigraphic studies in breast, metastatic colorectal, and non-small cell lung cancer populations have demonstrated associations between indices indicating greater dysregulation of circadian rest–activity rhythms (including lower mean activity level, less differentiated highest and lowest activity values, and delayed timing of peak activity) and greater sleep disturbance, fatigue, depressive symptoms, anxiety symptoms, and body mass index (BMI) [4], [5], [6], [7], [8]. Less rest–activity consistency has also been associated with flattened cortisol rhythms in breast and metastatic colorectal patients and increased inflammation and tumor-related symptoms in metastatic colorectal patients [9], [10]. Longitudinal studies of breast and metastatic colorectal cancer patients demonstrate changes in rest–activity rhythms during the course of treatment and recovery [11], [12], [13], [14], [15], [16]. For example, women with breast cancer showed increasingly dysregulated rest–activity rhythms as chemotherapy progressed, with a return to rhythms comparable to a healthy reference group by 1 year post-chemotherapy. Longitudinal studies of women with breast cancer also further support a relationship between impaired rhythms and greater fatigue, depressive symptoms, and BMI. Longitudinal studies of metastatic colorectal patients showed that more irregular rhythms predicted tumor response as evaluated by CT scans, and, ultimately, survival. Thus, rest–activity regulation/dysregulation shows promise as a biobehavioral measure of functioning, recovery, and overall quality of life in cancer patients.
Women with endometrial cancer comprise the largest population of female cancer survivors after breast cancer. The sequelae of surgery and adjuvant therapy, psychological stress, disrupted daily routines, physiological changes (e.g., inflammation and hormonal alterations), and pre-morbid increased risk for obesity that accompany an endometrial cancer diagnosis are likely to be associated with changes in rest–activity patterns. However, no studies have examined rest–activity patterns in endometrial cancer patients specifically, and there is only one previous study of a mixed sample of gynecologic cancer patients [17]. This study found that patients on multiple agent chemotherapy were more likely to have a higher dichotomy index (i.e., the ratio of nighttime activity to daytime activity) than those on single agent chemotherapy. A higher dichotomy index was associated with greater fatigue, less efficient sleep, and more depressive symptoms during post-chemotherapy intervals. Our study sought to investigate circadian rhythm disturbances among endometrial cancer patients. To address the limitations of prior work in this area, we utilized a prospective, longitudinal study that allowed us to examine changes in rest–activity patterns at specific post-surgical milestones, and we compared findings to a reference group of women with no cancer history.
The current study had three objectives. First, we examined changes in rest–activity patterns during the 4 months following surgery for endometrial cancer. Second, we investigated the extent to which rest–activity rhythms of women with endometrial cancer differed from rhythms of a historical reference sample of women with no history of cancer. We hypothesized that women with endometrial cancer would have significantly more dysregulated rest–activity patterns but that rhythms would normalize as surgical recovery progressed. Our final objective was to examine health- and treatment-related predictors (age, body mass index, cancer stage, surgery type, adjuvant chemotherapy, and adjuvant radiation therapy) of dysregulated rhythms. We hypothesized that women undergoing more invasive surgery and more extensive adjuvant therapy and those with obesity would have more dysregulated rest–activity patterns and a slower recovery of rhythms.
Section snippets
Participants
Participants were 60 women who were enrolled in a larger study of sleep disturbance and quality of life following surgery for endometrial cancer. Women who underwent surgery for an endometrial malignancy of any stage at the University of Wisconsin Carbone Cancer Center were eligible. Women with a prior history of cancer or those with recurrent cancer were excluded. Those included in the present analyses had completed at least one valid actigraphic assessment.
A historical reference sample of 60
Participants
Table 1 provides demographic and medical variables for the patient and reference groups. The groups were similar on all demographic variables except BMI. Women with endometrial cancer had a higher BMI (M = 38.7; SD = 10.9; median = 38.1) than the reference group (M = 30.3; SD = 11.2; median = 28.4; t(118) = − 4.2, p < 0.0001). Of note, the majority of patients who underwent adjuvant chemotherapy (95%; 18/19) received a standard 6 cycle carboplatin/taxol regimen. The remaining patient was on a clinical trial
Discussion
Results of the present study highlight significant disturbances in rest–activity rhythms experienced by endometrial cancer patients during the initial months following surgery. Specifically, the endometrial cancer group showed lower mean activity level (mesor) and weaker rhythms (amplitude) at 1 week post-surgery relative to an age-matched reference group. Both mesor and amplitude improved significantly to levels commensurate with the community-based reference group by 4 months post-surgery.
Conflict of interest statement
Dr. Rumble reports grants from UW Carbone Cancer Center, during the conduct of the study and grants from Merck, Inc., outside the submitted work. Dr. Gehrman reports grants from Merck, Inc., outside the submitted work. Dr. Benca reports grants and personal fees from Merck, Inc. and personal fees from Jazz, outside the submitted work. Dr. Costanzo and Ms. Moore report grants from NIH — National Cancer Institute and grants from University of Wisconsin Carbone Cancer Center, during the conduct of
Acknowledgments
This research was supported by grants K07 CA136966 (to ESC) and P30 CA014520 (UW Carbone Cancer Center Support Grant) from the National Cancer Institute, which funded the investigator-initiated trial award for the current study. We would like to acknowledge the UW Center for Sleep Medicine and Research for donating wrist actigraphs for data collection within the cancer sample. We would also like to acknowledge Gayle Love, PhD, Kristofer Hansen, and Carol Ryff, PhD for their collaboration on
References (22)
- et al.
Health consequences of circadian disruption in humans and animal models
Prog. Mol. Biol. Transl. Sci.
(2013) - et al.
Circadian effects in cancer-relevant psychoneuroendocrine and immune pathways
Psychoneuroendocrinology
(Aug 2010) - et al.
Central and peripheral circadian clocks in mammals
Annu. Rev. Neurosci.
(2012) - et al.
Fatigue, sleep, and circadian rhythms prior to chemotherapy for breast cancer
Support Care Cancer
(Mar 2006) - et al.
Circadian rhythms, symptoms, physical functioning, and body mass index in breast cancer survivors
J. Cancer Surviv.
(Sep 2012) - et al.
Actigraphic assessment of daily sleep–activity pattern abnormalities reflects self-assessed depression and anxiety in outpatients with advanced non-small cell lung cancer
Psychooncology
(Feb 2010) - et al.
The association of quality of life with potentially remediable disruptions of circadian sleep/activity rhythms in patients with advanced lung cancer
BMC Cancer
(2011) - et al.
Validation of actigraphy to assess circadian organization and sleep quality in patients with advanced lung cancer
J. Circadian Rhythms
(2011) - et al.
Stress, coping, and circadian disruption among women awaiting breast cancer surgery
Ann. Behav. Med.
(Aug 2012) - et al.
Elevated serum cytokines correlated with altered behavior, serum cortisol rhythm, and dampened 24-hour rest–activity patterns in patients with metastatic colorectal cancer
Clin. Cancer Res.
(2005)
Sleep, fatigue, depression, and circadian activity rhythms in women with breast cancer before and after treatment: a 1-year longitudinal study
Support Care Cancer
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2022, Contemporary Clinical Trials CommunicationsCitation Excerpt :The Actiwatch-2 (Philips Respironics), a wrist-worn actigraphy device, will be used to objectively quantify circadian rest-activity patterns over a continuous 7-day period at three time points: prior to hospital admission for HCT and 9 weeks (mid-intervention) and 18 weeks (post-intervention) post-HCT [40]. Data processing will yield the following indices: mesor (mean activity level), amplitude (rhythm height), acrophase (time of day the rhythm peaks), and R-squared (goodness-of-fit or robustness of the rhythm), as described in Rumble et al., 2015 [41]. These rest-activity indices will be the primary actigraphy outcomes of interest.
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