Relationships among Inflammatory Biomarkers and Self-Reported Treatment-Related Symptoms in Patients Treated with Chemotherapy for Gynecologic Cancer: A Controlled Comparison

Previous research suggests that inflammation triggers cancer-treatment-related symptoms (i.e., fatigue, depression, and disruptions in sleep and physical activity), but evidence is mixed. This study examined relationships between inflammatory biomarkers and symptoms in patients with gynecologic cancer compared to age-matched women with no cancer history (i.e., controls). Patients (n = 121) completed assessments before chemotherapy cycles 1, 3, and 6, and 6 and 12 months later. Controls (n = 105) completed assessments at similar timepoints. Changes in inflammation and symptomatology were evaluated using random-effects mixed models, and cross-sectional differences between patients and controls in inflammatory biomarkers and symptoms were evaluated using least squares means. Associations among inflammatory biomarkers and symptoms were evaluated using random-effects fluctuation mixed models. The results indicated that compared to controls, patients typically have higher inflammatory biomarkers (i.e., TNF-alpha, TNFR1, TNFR2, CRP, IL-1ra) and worse fatigue, depression, and sleep (ps < 0.05). Patients reported lower levels of baseline physical activity (p = 0.02) that became more similar to controls over time. Significant associations were observed between CRP, depression, and physical activity (ps < 0.05), but not between inflammation and other symptoms. The results suggest that inflammation may not play a significant role in fatigue or sleep disturbance among gynecologic cancer patients but may contribute to depression and physical inactivity.

[1]  A. Ruiz-Casado,et al.  C-Reactive Protein Is Associated with Physical Fitness in Breast Cancer Survivors , 2022, Journal of clinical medicine.

[2]  H. Jim,et al.  Cumulative burden of symptomatology in patients with gynecologic malignancies undergoing chemotherapy. , 2022, Health psychology : official journal of the Division of Health Psychology, American Psychological Association.

[3]  M. Irwin,et al.  Acute and Chronic Effects of Adjuvant Therapy on Inflammatory Markers in Breast Cancer Patients , 2022, JNCI cancer spectrum.

[4]  W. Malarkey,et al.  Depression and anxiety in colorectal cancer patients: Ties to pain, fatigue, and inflammation , 2022, Psycho-oncology.

[5]  M. Irwin,et al.  Younger women are more susceptible to inflammation: A longitudinal examination of the role of aging in inflammation and depressive symptoms. , 2022, Journal of affective disorders.

[6]  T. Atkinson,et al.  Cancer‐related inflammation and depressive symptoms: Systematic review and meta‐analysis , 2022, Cancer.

[7]  J. Skarbinski,et al.  A New Approach to Understanding Cancer-Related Fatigue: Leveraging the 3P Model to Facilitate Risk Prediction and Clinical Care , 2022, Cancers.

[8]  M. Irwin,et al.  Moderators of inflammation-related depression: a prospective study of breast cancer survivors , 2021, Translational Psychiatry.

[9]  Daniel M. Rotroff,et al.  Metagenomics and chemotherapy‐induced nausea: A roadmap for future research , 2021, Cancer.

[10]  J. Levine,et al.  Distinct sleep disturbance profiles among patients with gynecologic cancer receiving chemotherapy. , 2021, Gynecologic oncology.

[11]  M. Irwin,et al.  Vulnerability to inflammation-related depressive symptoms: Moderation by stress in women with breast cancer , 2021, Brain, Behavior, and Immunity.

[12]  D. Matei,et al.  Ovarian Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. , 2021, Journal of the National Comprehensive Cancer Network : JNCCN.

[13]  M. Fishman,et al.  Systemic inflammation and symptomatology in patients with prostate cancer treated with androgen deprivation therapy: Preliminary findings , 2020, Cancer.

[14]  Sheri J. Hartman,et al.  American Cancer Society Guideline for Diet and Physical Activity for cancer prevention. , 2020, CA: a cancer journal for clinicians.

[15]  H. Uno,et al.  Patterns and predictors of cancer‐related fatigue in ovarian and endometrial cancers: 1‐year longitudinal study , 2020, Cancer.

[16]  M. Irwin Sleep and inflammation: partners in sickness and in health , 2019, Nature Reviews Immunology.

[17]  So-Hyun Park,et al.  Adherence to American Cancer Society Guidelines on Nutrition and Physical Activity in Female Cancer Survivors: Results From a Randomized Controlled Trial (Yale Fitness Intervention Trial) , 2019, Cancer nursing.

[18]  E. Riboli,et al.  Aging, inflammation and cancer. , 2018, Seminars in immunology.

[19]  C. Sabiston,et al.  Changes in physical activity behavior and C-reactive protein in breast cancer patients , 2018, Annals of behavioral medicine : a publication of the Society of Behavioral Medicine.

[20]  S. Jeon,et al.  Inflammation-induced depression: Its pathophysiology and therapeutic implications , 2017, Journal of Neuroimmunology.

[21]  T. Chao,et al.  The Relationship Between Inflammatory Biomarkers and Symptom Distress in Lung Cancer Patients Undergoing Chemotherapy , 2017, Cancer nursing.

[22]  J. Lasselin,et al.  Role of Inflammation in Human Fatigue: Relevance of Multidimensional Assessments and Potential Neuronal Mechanisms , 2017, Front. Immunol..

[23]  K. Conneely,et al.  Fatigue is associated with inflammation in patients with head and neck cancer before and after intensity-modulated radiation therapy , 2016, Brain, Behavior, and Immunity.

[24]  J. Kiecolt-Glaser,et al.  Inflammation: depression fans the flames and feasts on the heat. , 2015, The American journal of psychiatry.

[25]  J. Bower,et al.  Cancer-related fatigue—mechanisms, risk factors, and treatments , 2014, Nature Reviews Clinical Oncology.

[26]  C. Franceschi,et al.  Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. , 2014, The journals of gerontology. Series A, Biological sciences and medical sciences.

[27]  M. Irwin,et al.  Cytokine genetic variations and fatigue among patients with breast cancer. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  R. Wenham,et al.  Lagged relationships among sleep disturbance, fatigue, and depressed mood during chemotherapy. , 2013, Health psychology : official journal of the Division of Health Psychology, American Psychological Association.

[29]  H. Jim,et al.  Prolonged impact of chemotherapy on fatigue in breast cancer survivors , 2012, Cancer.

[30]  C. Cleeland,et al.  Serum sTNF-R1, IL-6, and the development of fatigue in patients with gastrointestinal cancer undergoing chemoradiation therapy , 2012, Brain, Behavior, and Immunity.

[31]  H. Jim,et al.  Cognitive functioning after cancer treatment , 2012, Cancer.

[32]  C. Heckler,et al.  Differential expression of cytokines in breast cancer patients receiving different chemotherapies: implications for cognitive impairment research , 2012, Supportive Care in Cancer.

[33]  P. Butow,et al.  Physical activity in women with ovarian cancer and its association with decreased distress and improved quality of life , 2011, Psycho-oncology.

[34]  Duncan J Macfarlane,et al.  Validity of the international physical activity questionnaire short form (IPAQ-SF): A systematic review , 2011, The international journal of behavioral nutrition and physical activity.

[35]  M. Irwin,et al.  Inflammation and behavioral symptoms after breast cancer treatment: do fatigue, depression, and sleep disturbance share a common underlying mechanism? , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  H. Jim,et al.  Fatigue, Depression, Sleep, and Activity During Chemotherapy: Daily and Intraday Variation and Relationships Among Symptom Changes , 2011, Annals of behavioral medicine : a publication of the Society of Behavioral Medicine.

[37]  E. Lee,et al.  Health-Related Quality of Life in Survivors With Breast Cancer 1 Year After Diagnosis Compared With the General Population: A Prospective Cohort Study , 2011, Annals of surgery.

[38]  P. Jacobsen,et al.  Prevalence, predictors, and characteristics of off‐treatment fatigue in breast cancer survivors , 2010, Cancer.

[39]  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.

[40]  A. Buzdar,et al.  Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer , 2010, Cancer.

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

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

[43]  D. F. Drake,et al.  Activation of Central Nervous System Inflammatory Pathways by Interferon-Alpha: Relationship to Monoamines and Depression , 2009, Biological Psychiatry.

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

[45]  K. Courneya,et al.  Physical Activity in Ovarian Cancer Survivors: Associations With Fatigue, Sleep, and Psychosocial Functioning , 2009, International Journal of Gynecologic Cancer.

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

[47]  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.

[48]  S. Ancoli-Israel,et al.  Neuroendocrine-immune mechanisms of behavioral comorbidities in patients with cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  M. Schwarz,et al.  The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression , 2007, Molecular Psychiatry.

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

[51]  J. Bower,et al.  Cancer-related fatigue: Links with inflammation in cancer patients and survivors , 2007, Brain, Behavior, and Immunity.

[52]  K. Courneya,et al.  Associations between physical activity and quality of life in ovarian cancer survivors. , 2007, Gynecologic oncology.

[53]  L. Natarajan,et al.  The association between fatigue and inflammatory marker levels in cancer patients: A quantitative review , 2007, Brain, Behavior, and Immunity.

[54]  C. Koopman,et al.  A longitudinal study of depression, pain, and stress as predictors of sleep disturbance among women with metastatic breast cancer , 2007, Biological Psychology.

[55]  Sangeeta Agrawal,et al.  Values of sleep/wake, activity/rest, circadian rhythms, and fatigue prior to adjuvant breast cancer chemotherapy. , 2007, Journal of pain and symptom management.

[56]  S. Gabram,et al.  Psychologic stress, reduced NK cell activity, and cytokine dysregulation in women experiencing diagnostic breast biopsy , 2007, Psychoneuroendocrinology.

[57]  W. Kung,et al.  Paclitaxel (Taxol) upregulates expression of functional interleukin-6 in human ovarian cancer cells through multiple signaling pathways , 2006, Oncogene.

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

[59]  N. Hanna,et al.  Screening studies for fatigue and laboratory correlates in cancer patients undergoing treatment. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[60]  D. Meltzer,et al.  Use of a Self-Report-Generated Charlson Comorbidity Index for Predicting Mortality , 2005, Medical care.

[61]  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.

[62]  M. L. Pucak,et al.  Unkind cytokines: Current evidence for the potential role of cytokines in immune-mediated depression , 2005, International review of psychiatry.

[63]  H. Brenner,et al.  Quality of life in patients with colorectal cancer 1 year after diagnosis compared with the general population: a population-based study. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[64]  N. Tarrier,et al.  Social support, anxiety and depression after chemotherapy for ovarian cancer: a prospective study. , 2004, British journal of health psychology.

[65]  E. Thiel,et al.  Physical performance, depression, immune status and fatigue in patients with hematological malignancies after treatment. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[66]  J. Denham,et al.  Fatigue during breast radiotherapy and its relationship to biological factors. , 2004, International journal of radiation oncology, biology, physics.

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

[68]  H. Logan,et al.  Effects of acute stress, relaxation, and a neurogenic inflammatory stimulus on interleukin-6 in humans , 2004, Brain, Behavior, and Immunity.

[69]  P. Ganz,et al.  T-cell homeostasis in breast cancer survivors with persistent fatigue. , 2003, Journal of the National Cancer Institute.

[70]  R. Dantzer,et al.  Cytokine-induced sickness behavior , 2003, Brain, Behavior, and Immunity.

[71]  N. Tsavaris,et al.  Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes , 2002, British Journal of Cancer.

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

[73]  S. Wadler,et al.  Interferon‐mediated fatigue , 2001, Cancer.

[74]  R. Dantzer,et al.  Timing and Specificity of the Cognitive Changes Induced by Interleukin-2 and Interferon-&agr; Treatments in Cancer Patients , 2001, Psychosomatic medicine.

[75]  R. Dantzer,et al.  Early depressive symptoms in cancer patients receiving interleukin 2 and/or interferon alfa-2b therapy. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[76]  J. Ting,et al.  Paclitaxel up-regulates interleukin-8 synthesis in human lung carcinoma through an NF-κB- and AP-1-dependent mechanism , 2000, Cancer Immunology, Immunotherapy.

[77]  U. Matulonis,et al.  Cytokines IL-1beta, IL-2, IL-6, IL-8, MCP-1, GM-CSF and TNFalpha in patients with epithelial ovarian cancer and their relationship to treatment with paclitaxel. , 2000, International journal of gynecological cancer : official journal of the International Gynecological Cancer Society.

[78]  A. Świergiel,et al.  Endotoxin- and Interleukin-1–Induced Hypophagia Are Not Affected by Adrenergic, Dopaminergic, Histaminergic, or Muscarinic Antagonists , 1999, Pharmacology Biochemistry and Behavior.

[79]  D. Mullins,et al.  Paclitaxel enhances macrophage IL-12 production in tumor-bearing hosts through nitric oxide. , 1999, Journal of immunology.

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

[81]  J. Ting,et al.  Effects of paclitaxel on cytokine synthesis by unprimed human monocytes, T lymphocytes, and breast cancer cells , 1998, Cancer Immunology, Immunotherapy.

[82]  R. Yirmiya Endotoxin produces a depressive-like episode in rats , 1996, Brain Research.

[83]  R. Dantzer,et al.  Synergy between tumor necrosis factor α and interleukin-1 in the induction of sickness behavior in mice , 1994, Psychoneuroendocrinology.

[84]  D. Greenberg,et al.  Treatment-related fatigue and serum interleukin-1 levels in patients during external beam irradiation for prostate cancer. , 1993, Journal of pain and symptom management.

[85]  C. Bogdan,et al.  Taxol, a microtubule‐stabilizing antineoplastic agent, induces expression of tumor necrosis factor α and interleukin‐1 in macrophages , 1992, Journal of leukocyte biology.

[86]  M. Watson,et al.  The Factor Structure and Factor Stability of the Hospital Anxiety and Depression Scale in Patients with Cancer , 1991, British Journal of Psychiatry.

[87]  Daniel J Buysse,et al.  The Pittsburgh sleep quality index: A new instrument for psychiatric practice and research , 1989, Psychiatry Research.

[88]  R. Snaith,et al.  The Hospital Anxiety And Depression Scale , 2003, Health and quality of life outcomes.

[89]  Hymie Anisman,et al.  Cascading effects of stressors and inflammatory immune system activation: implications for major depressive disorder. , 2009, Journal of psychiatry & neuroscience : JPN.

[90]  C. Gélinas,et al.  Factors related to persistent fatigue following completion of breast cancer treatment. , 2004, Oncology nursing forum.

[91]  A. Dunn,et al.  Effects of Cytokines on Cerebral Neurotransmission , 1999 .

[92]  C. Mackenzie,et al.  A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. , 1987, Journal of chronic diseases.