Inflammation and behavioral symptoms after breast cancer treatment: do fatigue, depression, and sleep disturbance share a common underlying mechanism?

PURPOSE Fatigue, depression, and sleep disturbance are common adverse effects of cancer treatment and frequently co-occur. However, the possibility that inflammatory processes may underlie this constellation of symptoms has not been examined. PATIENTS AND METHODS Women (N = 103) who had recently finished primary treatment (ie, surgery, radiation, chemotherapy) for early-stage breast cancer completed self-report scales and provided blood samples for determination of plasma levels of inflammatory markers: soluble tumor necrosis factor (TNF) receptor II (sTNF-RII), interleukin-1 receptor antagonist, and C-reactive protein. RESULTS Symptoms were elevated at the end of treatment; greater than 60% of participants reported clinically significant problems with fatigue and sleep, and 25% reported elevated depressive symptoms. Women treated with chemotherapy endorsed higher levels of all symptoms and also had higher plasma levels of sTNF-RII than women who did not receive chemotherapy (all P < .05). Fatigue was positively associated with sTNF-RII, particularly in the chemotherapy-treated group (P < .05). Depressive symptoms and sleep problems were correlated with fatigue but not with inflammatory markers. CONCLUSION This study confirms high rates of behavioral symptoms in breast cancer survivors, particularly those treated with chemotherapy, and indicates a role for TNF-α signaling as a contributor to postchemotherapy fatigue. Results also suggest that fatigue, sleep disturbance, and depression may stem from distinct biologic processes in post-treatment survivors, with inflammatory signaling contributing relatively specifically to fatigue.

[1]  B. Mausbach,et al.  Sleep and Biomarkers of Atherosclerosis in Elderly Alzheimer Caregivers and Controls , 2009, Gerontology.

[2]  P. Jacobsen,et al.  The Fatigue Symptom Inventory: a systematic review of its psychometric properties , 2011, Supportive Care in Cancer.

[3]  J. Dimsdale,et al.  The association between interleukin-6, sleep, and demographic characteristics , 2005, Brain, Behavior, and Immunity.

[4]  S. Ancoli-Israel,et al.  The Effects of Standard Anthracycline-Based Chemotherapy on Soluble ICAM-1 and Vascular Endothelial Growth Factor Levels in Breast Cancer , 2004, Clinical Cancer Research.

[5]  P. Ganz,et al.  Fatigue in long‐term breast carcinoma survivors , 2006, Cancer.

[6]  G. Lyman,et al.  Measurement of Fatigue in Cancer Patients: Development and Validation of the Fatigue Symptom Inventory , 1998, Quality of Life Research.

[7]  S. Fosså,et al.  Predictors and course of chronic fatigue in long-term breast cancer survivors , 2010, Journal of cancer survivorship : research and practice.

[8]  G. Lyman,et al.  Fatigue in women receiving adjuvant chemotherapy for breast cancer: characteristics, course, and correlates. , 1999, Journal of pain and symptom management.

[9]  M. Irwin,et al.  Inflammatory biomarkers for persistent fatigue in breast cancer survivors , 2006, Brain, Behavior, and Immunity.

[10]  P. Ganz,et al.  Inflammatory Biomarkers and Fatigue during Radiation Therapy for Breast and Prostate Cancer , 2009, Clinical Cancer Research.

[11]  J. Bower Behavioral symptoms in patients with breast cancer and survivors. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  E. Suarez Self-reported symptoms of sleep disturbance and inflammation, coagulation, insulin resistance and psychosocial distress: Evidence for gender disparity , 2008, Brain, Behavior, and Immunity.

[13]  L. Natarajan,et al.  Inflammation and sleep in healthy individuals. , 2007, Sleep.

[14]  D. Butterfield,et al.  Adriamycin-induced, TNF-alpha-mediated central nervous system toxicity. , 2006, Neurobiology of disease.

[15]  R. Dantzer,et al.  A Cytokine-Based Neuroimmunologic Mechanism of Cancer-Related Symptoms , 2004, Neuroimmunomodulation.

[16]  C. Morin,et al.  Prevalence, clinical characteristics, and risk factors for insomnia in the context of breast cancer. , 2001, Sleep.

[17]  D. Cella,et al.  Cancer-related fatigue: prevalence of proposed diagnostic criteria in a United States sample of cancer survivors. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  C. Cleeland,et al.  Serum interleukin‐6 predicts the development of multiple symptoms at nadir of allogeneic hematopoietic stem cell transplantation , 2008, Cancer.

[19]  J. Born,et al.  Acute effects of recombinant human interleukin-6 on endocrine and central nervous sleep functions in healthy men. , 1998, The Journal of clinical endocrinology and metabolism.

[20]  C. Nemeroff,et al.  Neurobehavioral Effects of Interferon-α in Cancer Patients: Phenomenology and Paroxetine Responsiveness of Symptom Dimensions , 2002, Neuropsychopharmacology.

[21]  T. Pollmächer,et al.  Cytokine-associated emotional and cognitive disturbances in humans. , 2001, Archives of general psychiatry.

[22]  Tristen K. Inagaki,et al.  Inflammation and social experience: An inflammatory challenge induces feelings of social disconnection in addition to depressed mood , 2010, Brain, Behavior, and Immunity.

[23]  P. Fayers,et al.  Psychological distress and fatigue predicted recurrence and survival in primary breast cancer patients , 2007, Breast Cancer Research and Treatment.

[24]  C. Morin,et al.  Prevalence, natural course, and risk factors of insomnia comorbid with cancer over a 2-month period. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  F. Penedo,et al.  Interleukin-6, cortisol, and depressive symptoms in ovarian cancer patients. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  J. Ockene,et al.  Depression and cardiovascular sequelae in postmenopausal women. The Women's Health Initiative (WHI) , 2004 .

[27]  Daniel J Buysse,et al.  Quantification of subjective sleep quality in healthy elderly men and women using the Pittsburgh Sleep Quality Index (PSQI) , 1991, Sleep.

[28]  Jennifer L Martin,et al.  To assess, to control, to exclude: Effects of biobehavioral factors on circulating inflammatory markers , 2009, Brain, Behavior, and Immunity.

[29]  Ingrid J Orre,et al.  Levels of circulating interleukin-1 receptor antagonist and C-reactive protein in long-term survivors of testicular cancer with chronic cancer-related fatigue , 2009, Brain, Behavior, and Immunity.

[30]  P. Jacobsen,et al.  Identifying clinically meaningful fatigue with the Fatigue Symptom Inventory. , 2008, Journal of pain and symptom management.

[31]  D. Papanicolaou,et al.  Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. , 1997, The Journal of clinical endocrinology and metabolism.

[32]  Patricia A. Ganz,et al.  Fatigue and Proinflammatory Cytokine Activity in Breast Cancer Survivors , 2002, Psychosomatic medicine.

[33]  L. Hawkley,et al.  Psychosocial and Behavioral Predictors of Inflammation in Middle-Aged and Older Adults: The Chicago Health, Aging, and Social Relations Study , 2006, Psychosomatic medicine.

[34]  P. Flynn,et al.  Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  D. Butterfield,et al.  Adriamycin-induced, TNF-α-mediated central nervous system toxicity , 2006, Neurobiology of Disease.

[36]  M. Caligiuri,et al.  Assessment of tumor necrosis factor alpha blockade as an intervention to improve tolerability of dose-intensive chemotherapy in cancer patients. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  Baldwin M. Way,et al.  Neural sensitivity to social rejection is associated with inflammatory responses to social stress , 2010, Proceedings of the National Academy of Sciences.

[38]  Julie L Otte,et al.  Prevalence, severity, and correlates of sleep-wake disturbances in long-term breast cancer survivors. , 2010, Journal of pain and symptom management.

[39]  R. Dantzer,et al.  From inflammation to sickness and depression: when the immune system subjugates the brain , 2008, Nature Reviews Neuroscience.

[40]  V. Meyer-Rochow,et al.  C-reactive protein Levels and Sleep Disturbances: Observations Based on The Northern Finland 1966 Birth Cohort Study , 2007, Psychosomatic medicine.

[41]  P. Jacobsen,et al.  Course of fatigue in women receiving chemotherapy and/or radiotherapy for early stage breast cancer. , 2004, Journal of pain and symptom management.

[42]  S. Ancoli-Israel,et al.  The relationship between fatigue and quality of life and inflammation during anthracycline-based chemotherapy in breast cancer , 2005, Biological Psychology.

[43]  P. Buckley,et al.  Neuroendocrine-Immune Mechanisms of Behavioral Comorbidities in Patients With Cancer , 2009 .

[44]  M. Irwin,et al.  Effects of sleep and sleep loss on immunity and cytokines , 2002, Brain, Behavior, and Immunity.

[45]  J. Suls,et al.  Associations of Depression With C-Reactive Protein, IL-1, and IL-6: A Meta-Analysis , 2009, Psychosomatic medicine.

[46]  P. Ganz,et al.  Fatigue in breast cancer survivors: occurrence, correlates, and impact on quality of life. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[47]  Heather L. Urry,et al.  Social relationships, sleep quality, and interleukin-6 in aging women. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[48]  G. Tilz,et al.  Soluble receptors for tumour necrosis factor in clinical laboratory diagnosis , 1995, European journal of haematology.

[49]  C. Cleeland,et al.  Inflammatory cytokines are associated with the development of symptom burden in patients with NSCLC undergoing concurrent chemoradiation therapy , 2010, Brain, Behavior, and Immunity.

[50]  H. Jim,et al.  Fatigue after treatment for early stage breast cancer , 2007, Cancer.

[51]  P. Stone,et al.  A comparison of the characteristics of disease-free breast cancer survivors with or without cancer-related fatigue syndrome , 2009, European journal of cancer.

[52]  J. Manson,et al.  A prospective study of soluble tumor necrosis factor-alpha receptor II (sTNF-RII) and risk of coronary heart disease among women with type 2 diabetes. , 2005, Diabetes care.

[53]  E. Bruera,et al.  Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy. , 2004, Cytokine.

[54]  G. Lyman,et al.  Characteristics and correlates of fatigue after adjuvant chemotherapy for breast cancer. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  M. Andrykowski,et al.  Psychometric evaluation of the Pittsburgh Sleep Quality Index. , 1998, Journal of psychosomatic research.

[56]  M. Massie Prevalence of depression in patients with cancer. , 2004, Journal of the National Cancer Institute. Monographs.

[57]  T. Patterson,et al.  Poor Sleep Is Associated with Higher Plasma Proinflammatory Cytokine Interleukin‐6 and Procoagulant Marker Fibrin D‐Dimer in Older Caregivers of People with Alzheimer's Disease , 2006, Journal of the American Geriatrics Society.

[58]  S. Ancoli-Israel,et al.  Prevalence, demographics, and psychological associations of sleep disruption in patients with cancer: University of Rochester Cancer Center-Community Clinical Oncology Program. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[59]  P. Jacobsen,et al.  Use of a case definition approach to identify cancer-related fatigue in women undergoing adjuvant therapy for breast cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[60]  C. Rock,et al.  The relative importance of specific risk factors for insomnia in women treated for early‐stage breast cancer , 2008, Psycho-oncology.

[61]  S. Ancoli-Israel,et al.  Predictors of inflammation in response to anthracycline-based chemotherapy for breast cancer , 2008, Brain, Behavior, and Immunity.