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Neuroendocrine-Immune Mechanisms of Behavioral Comorbidities in Patients With Cancer

Andrew H. Miller, Sonia Ancoli-Israel, Julienne E. Bower, Lucile Capuron, Michael R. Irwin

From the Emory University School of Medicine, Atlanta, GA; University of California San Diego, San Diego; University of California Los Angeles, Los Angeles, CA; and the Université Bordeaux, Bordeaux, France

Corresponding author: Andrew H. Miller, MD, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Winship Cancer Institute, 1365-C Clifton Rd, 5th Floor, Atlanta, GA 30322; e-mail: amill02{at}emory.edu

Patients with cancer experience a host of behavioral alterations that include depression, fatigue, sleep disturbances, and cognitive dysfunction. These behavioral comorbidities are apparent throughout the process of diagnosis and treatment for cancer and can persist well into the survivorship period. There is a rich literature describing potential consequences of behavioral comorbidities in patients with cancer including impaired quality of life, reduced treatment adherence, and increased disease-related morbidity and mortality. Medical complications of cancer and its treatment such as anemia, thyroid dysfunction, and the neurotoxicity of cancer chemotherapeutic agents account in part for these behavioral changes. Nevertheless, recent advances in the neurosciences and immunology/oncology have revealed novel insights into additional pathophysiologic mechanisms that may significantly contribute to the development of cancer-related behavioral changes. Special attention has been focused on immunologic processes, specifically activation of innate immune inflammatory responses and their regulation by neuroendocrine pathways, which, in turn, influence CNS functions including neurotransmitter metabolism, neuropeptide function, sleep-wake cycles, regional brain activity, and, ultimately, behavior. Further understanding of these immunologic influences on the brain provides a novel conceptual framework for integrating the wide spectrum of behavioral alterations that occur in cancer patients and may reveal a more focused array of translational targets for therapeutic interventions and future research. Such developments warrant complementary advances in identification of cancer patients at risk as well as those currently suffering, including an increased emphasis on the status of behavior as a "sixth vital sign" to be assessed in all cancer patients throughout their disease encounter.

Supported in part by the National Cancer Institute (NCI), Cancer Control and Population Sciences, Basic and Biobehavioral Research, Biologic Mechanisms of Psychosocial Effects in Disease; Grant Nos. NCI CA85264, NCI CA112035, and CBCRP 11IB-0034, and M01-RR00865 (S.A.-I.); Grant No. NCI CA090407 (J.E.B.); National Institute of Mental Health Grant Nos. MH069124 and M01-RR00039 (A.H.M.); National Institutes of Health Grant Nos. AG026364, HL079955, T32-MH19925, and CA 0014152 (M.R.I.); and the Cousins Center for Psychoneuroimmunology.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.