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Losing Sleep Over Cancer

Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA

Cancer is something to lose sleep over. It causes understandable anxiety that might well disrupt sleep. But losing sleep, and the disruption of associated circadian patterns of hormones such as cortisol and melatonin, may well have more pervasive effects on the body, ranging from the expectable—such as fatigue and depression—to increases in the rate of cancer progression and risk of cancer incidence. Good sleep is necessary and restorative for people in good health. There is growing evidence that sleep plays an even more important role in the health of cancer patients.

In their article in this issue of the Journal of Clinical Oncology, Parker et al¹ utilized 24-hour ambulatory polysomnography to precisely study sleep/wake patterns among 114 patients with advanced solid tumors. They documented considerable sleep disruption, including poor quality and quantity of sleep at night and excessive sleep episodes during the day. Demographic factors that mitigated this sleep disturbance included being female, married or partnered, white, and more highly educated. As is the case in many situations, "them as has, gets." Those with less in the way of social support, education, and the associated socioeconomic advantages, suffered combined effects of cancer-related and social stress at night as well as during the day.

The detailed sleep analysis demonstrated that these cancer patients’ sleep was anything but normal. They had an average of 60 brief arousals per hour and some six awakenings lasting a minute or more per hour at night, and they slept an hour and a half during the day. This included 6.7% rapid eye movement (REM) sleep, which is rare during the day and is a sign of chronic sleep and REM deprivation. One bit of good news is that antineoplastic agents seemed, if anything, to be associated with increased sleep efficiency. Also, those patients taking antidepressants had better sleep, presumably through effective treatment of depression, which is often accompanied by sleep disruption, especially early morning wakening.

A key observation from the study is the erosion of distinction between night and day in sleep among cancer patients: They were awake approximately a quarter of the time and night, and slept approximately one fifth of the time during the day. This is consistent with daytime fatigue, and presumably with dysregulation of hormones, such as cortisol, melatonin, human growth hormone, and thyroid-stimulating hormone, that have pronounced circadian patterns. Disruption of these patterns could have adverse effects on both quality of life and the disease itself.

Circadian rhythm disruption is associated with poorer quality of life among cancer patients, including increased fatigue and depression.² Notably and not surprisingly, daytime fatigue is associated with disturbed sleep and phase-advanced circadian rhythms among primary breast cancer patients, even before chemotherapy.³ There are similar observations of sleep disruption among patients with non–small-cell lung cancer.⁴ Mediating factors associated with circadian disruption and fatigue include reduced daytime light exposure⁵ and elevated cytokine levels, notably 8-AM levels of transforming growth factor-alpha, tumor necrosis factor-alpha, and interleukin 6.⁶ Cytokines such as these have been associated with "sickness behavior" and depressive symptoms in cancer patients.^7,8

Cancer can be understood as a series of stressors—the diagnosis and its implications, including fears of death, arduous treatments, and changes in one's social and physical environment. Reactivity to stressors involves not only the initial response of the central and autonomic nervous systems and the hypothalamic-pituitary-adrenal axis, but also the body's ability to restore equilibrium after stress. Older organisms seem to be less flexible in this regard,⁹ leaving stress responsive systems more tonically upregulated for longer periods of time. Cancer particularly affects older people, and chronic disease-related stressors are perhaps likely to further decrease the flexibility of stress-response mechanisms. Stressing older animals leads not only to persistently elevated cortisol levels, but also much more rapid growth of implanted tumors.^9-11

There is an exquisitely sensitive circadian clock that regulates variation in levels of cortisol and other hormones throughout the day.¹² There is evidence that abnormal circadian clock gene expression is associated with cancer.^13-16 Breast and ovarian cancer patients have abnormalities in the circadian rhythm of cortisol.¹⁷ Among breast cancer patients, these abnormalities include high levels throughout the 24-hour cycle.^17,18 Loss of normal circadian variation in cortisol, similar to that observed in depression, predicts earlier mortality among metastatic breast cancer patients, independent of other known risk factors including estrogen/progesterone receptor status, age at diagnosis, and disease-free interval.¹⁹ This loss of normal diurnal variation in cortisol is associated with more awakenings during the night, and with reduced feedback inhibition of cortisol secretion by the pituitary.²⁰ It would be very interesting to see whether the degree of sleep disruption observed by Parker et al turns out to predict the rate of disease progression in their sample. A clear physiologic distinction between an active daytime and a restful nighttime has been associated with longer survival, better quality of life, and less severe fatigue, anorexia, and depression in metastatic colorectal cancer patients.²¹ Female night-shift workers are at higher risk for developing breast, colon, and endometrial cancers.^22,23 This effect could be a result of sleep loss and associated disruption of circadian cortisol rhythms²⁴ as well as suppressed melatonin levels.²⁵

Why might circadian cycle disruption affect the course of cancer? In certain prostate cancer cell lines, the androgen receptor becomes cortisol sensitive, thereby allowing physiological levels of cortisol to stimulate tumor growth.²⁶ In mice, surgical ablation of the central biologic clock, the suprachiasmatic nucleus in mice, which blunts the circadian cortisol rhythm, resulted in a two-fold increase in the rate of growth of implanted osteosarcomas, and pancreatic adenocarcinomas.²⁷

Thus, sleep disruption is a potentially modifiable mediating risk factor for cancer and its progression. There is accumulating evidence that attention to the circadian cycle in the administration of chemotherapy, so-called chronomodulation, may improve the efficacy of chemotherapy while reducing adverse effects.^28-31 Losing sleep over cancer may mean losing ground to cancer. Restoring sleep and taking circadian rhythms into account in cancer treatment may not only improve quality of life but also treatment effectiveness. That's something to sleep on.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

Supported by Grants No. 5 RO1CA118567-02 from NCI and 5 PO1 18784 from the National Cancer Institute and National Institute on Aging. I thank Sonia Ancoli-Israel, Jamie Zeitzer, and Pasquale Innominato for review and suggestions.

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