1 Neuroendocrine-Immune Mechanisms of Behavioral Comorbidities in Patients With Cancer J Clin Oncol 26:

2 Behavioral complications –Depression –Fatigue –Sleep disturbances –Cognitive dysfunction Mounting research on behavioral comorbidities –Prevalence –Consequences –Underlying mechanisms –Related translational implications In this reivew –New research at the interface of immunology/oncology and neurobiology/ neuroendocrinology –Role of inflammation in behavioral pathology –Conceptual framework to integrate the spectrum of behavioral comorbidities –Determining which patients are at greatest risk under what treatment conditions

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4 Activation of innate immune responses (inflammation) → behavioral alterations in both medically ill and medically healthy individuals Studies in laboratory animals and humans –Administration of innate immune cytokines → a syndrome of “sickness behavior” Secondary effects to the capacity of peripheral cytokine signals → to access the brain and activate inflammatory responses within the brain → interaction with patho-physiologic pathways in behavioral disorders

5 Metabolism of relevant neurotransmitters such as serotonin, nor-epinephrine, and dopamine –IFN-alpha,IL-6 –p38 MAPK signaling pathways, TNF-alpha, IL-1 –mRNA and protein of the neuro-peptide CRH Innate immune cytokines effects on regional brain activity –IFN-alpha → increased regional blood flow in the dorsal part of the anterior cingulate cortex Administration of innate immune cytokines to laboratory animals → disruption of long-term potentiation in the hippocampus → disruption of memory consolidation Ongoing research about an emerging relationship between innate immune cytokines and disrupted sleep-wake cycles

6 Psychological stress → a wide variety of behavioral disorders Stress → activation of inflammatory cytokines and signaling pathways both in the periphery and in the brain → activation of microglia in the brain → increased sensitivity to immunologic stimuli (ie, lipopolysaccharide [LPS]) in rat IL-1 in the brain → reduced the expression of BDNF BNDF –Neuronal growth and development –Learning –Synaptic plasticity –Behavioral disorders Effects of stress on brain inflammatory pathways –Activation of the sympathetic nervous system –Release of catecholamines

7 Neuroendocrine system, specifically the HPA axis and glucocorticoids altered release of glucocorticoid hormones (including changes in the circadian cortisol rhythm) or disruption of glucocorticoid receptor function → disruption of glucocorticoid receptor signaling → reduced sensitivity of immune cells to the anti-inflammatory effects of glucocorticoids Altered HPA axis function –Flattening of diurnal cortisol production –Inability to shutdown cortisol production (nonsuppression) after administration of the synthetic glucocorticoid dexamethasone Abnormal DST responses associated with increased production of IL-1 by peripheral-blood mononuclear cells in healthy patients with major depression

8 Activation of innate immune responses –Surgery –Chemotherapy –Radiation Stressor –Receiving a diagnosis of cancer –Battling with chronic uncertainties regarding treatment, recurrence, and mortality Inflammation-induced behavioral alterations –Depression –Fatigue –Sleep disturbance –Cognitive function

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11 Depression Major depression, a syndrome characterized by depressed mood and/or anhedonia and accompanied by alterations in appetite, sleep, activity levels, and cognitive function –Median point prevalence (15% to 29%) –Quality of life, increased health care utilization, poor treatment adherence, and, in some cases, increased rates of cancer recurrence and mortality Role of the immune system in depression in cancer patients in two studies –Increased plasma concentrations of IL-6 –Inconsistent results in correlations between inflammatory biomarkers and depressive symptoms Neuroendocrine changes in cancer patients with major depression –Reduced sensitivity to glucocorticoids as manifested by DST nonsuppression –Showing a flattening of the diurnal cortisol curve No study to date has linked HPA axis and/or glucocorticoid receptor function and increased inflammatory markers in depressed cancer patients.

12 Fatigue Prevalence estimates of fatigue during treatment range from 25% to 99% 34% of disease-free breast cancer survivors reported significant fatigue 5 to 10 years after diagnosis Inflammatory processes as a role in post-treatment fatigue –Breast cancer survivors with persistent fatigue : IL-1 receptor antagonist (IL-1ra), soluble TNF receptor p75, neopterin] –In a larger cohort of breast cancer patients, with fatigued survivors : IL-1ra and soluble IL-6 receptor, production of innate immune cytokines by monocytes after in vitro stimulation with LPS Enhanced cytokine production in fatigued cancer survivors in part from altered HPA axis function –Lower levels of morning serum cortisol –Flattened diurnal cortisol slopes –Blunted cortisol response to acute psychosocial stress

13 Sleep disturbance Over 50% of cancer patients –Reduced sleep efficiency –Prolonged latency to fall asleep –Increased awake time during the night Problems with sleep even before treatment Nearly 20% of breast cancer survivors report greater than 6 months of chronic insomnia. Insomnia as a powerful predictor of cancer-related fatigue Disturbances in sleep-wake activity as well as circadian rhythms to predict increases in mortality in patients with metastatic disease Relationship between innate immune cytokines such as IL-6 and sleep Increased inflammation → sleep disturbance by desynchronization of circadian rhythms, including the release of cortisol

14 Cognitive dysfunction Cognitive dysfunction during cancer treatment on quality of life and social/occupational function –Alterations in memory –Concentration –Executive function –Psychomotor skills Approximately 25% to 33% of patients undergoing systemic chemotherapy exhibit impaired performance on tests of cognitive functions. Chemotherapy is also associated with significant changes in brain white matter as well as alterations in regional brain activity that correlate with cognitive dysfunction. Radiation therapy is often accompanied by neurologic complications. Inflammatory factors in cognitive dysfunction –Negative correlation has been found between plasma IL-6 and executive function in patients with AML or MDS –IFN- therapy is generally associated with reduced psychomotor speed and concentration difficulties, IL-2 therapy is more frequently associated with alterations in working memory and executive function.

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16 Identification of Behavioral Risk Identification of risk for developing behavioral change –High levels of perceived stress (as a function of the cancer diagnosis or other life circumstances) –Undergoing treatment Surgery Chemotherapy Radiation therapy –Disruption of sleep-wake cycles –Genetic factors : functional polymorphisms in the IL-6 gene and the serotonin transporter gene Development of standardized assessments of inflammatory biomarkers –IL-6 (as assessed by highsensitivity [hs] enzyme-linked immunoabsorbent assay) –CRP (as measured by hs assay techniques)

17 Therapeutic Ramifications

18 Cognitive-behavioral, supportive, or insight-oriented psychotherapies –Reduction of stress and restoring of regular circadian cycles –Limited impact of stress on the immune response –Direct effects on neuroendocrine-immune interactions Cognitive-behavioral strategies : improvement in fatigue in 54% –Relaxation training –Enhancement of coping skills –Graded exercise –Establishment of appropriate sleep-wake habits and social rhythms (eg, standardized bed and wake-up times, avoidance of daytime napping, and correction of maladaptive beliefs about sleep) Aerobic exercise can lead to reductions in inflammatory markers. Irwin et al found that multiple types of behavioral treatments induced robust improvements in subjective measures of sleep quality, sleep onset, and sleep maintenance in adults with primary insomnia. No study has included assessments of the impact of these interventions on cortisol rhythms, inflammatory mediators, or behavioral changes.

19 Cytokine antagonists, anti-inflammatory agents, and drugs that disrupt cytokine signaling pathways (eg, NFB and p38 MAPK) are logical treatment considerations. Several recent trials have demonstrated that TNF-  blockade with etanercept is safe in patients with advanced cancer, and it was suggested in at least one study that tolerability of chemotherapy (including reduced fatigue) was improved. In at least two double-blind placebo-controlled trials in cancer patients undergoing treatment, paroxetine (a serotonin reuptake inhibitor) was found to reduce depression while having limited effect on fatigue. Phosphodiesterase type IV inhibitors may have the advantage of additionally inhibiting inflammatory pathways. Regarding sleep and neuroendocrine rhythms, combine chronobiotics (eg, melatonin- receptor agonists, light therapy, or sleep regulation)

20 Conceptual framework designed to integrate a host of behavioral comorbidities Further studies examining neuroendocrine-immune interactions –Contribution of cancer and its treatment to behavioral changes –Contributions of behavioral comorbidities to cancer development, progression and recurrence Increasing understanding of the pathophysiology and treatment of behavioral comorbidities in cancer patients → standardized behavioral assessments as routine care Instantiating behavior as the sixth vital sign will go a long way in emphasizing the need for further research and the importance of both recognizing and treating the behavioral consequences of cancer and its treatment.