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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Clin Oncol. Author manuscript; available in PMC Oct 28, 2009.
Published in final edited form as:
PMCID: PMC2770012
NIHMSID: NIHMS147295

Neuroendocrine-Immune Mechanisms of Behavioral Comorbidities in Patients With Cancer

Abstract

Patients with cancer experience a host of behavioral alterations that include depression, fatigue, sleep disturbances and cognitive dysfunction. These behavioral co-morbidities 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 co-morbidities 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, impact central nervous system functions including neurotransmitter metabolism, neuropeptide function, sleep-wake cycles, regional brain activity and ultimately behavior. Further understanding of these immunological 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.

Introduction

Receiving a diagnosis of cancer and managing the subsequent psychological and physiological assaults presents a formidable challenge. While tremendous advancements have been made in the development of more effective and less traumatic cancer therapies, patients continue to struggle with a myriad of behavioral complications including depression, fatigue, sleep disturbances and cognitive dysfunction. Mounting research has begun to shed increasing light on these behavioral co-morbidities, not only in terms of their prevalence and consequences, but also, most importantly, in terms of potential common underlying mechanisms and related translational implications. Such increasing knowledge will provide a better understanding of treatment strategies and ultimately guidelines for clinical management. Moreover, this knowledge will serve as the basis for implementing more standardized assessments of behavior in the routine care of cancer patients and instantiate behavior as the “sixth vital sign”.

In this review, new research at the interface of immunology/oncology and neurobiology/neuroendocrinology will be described as it relates to the major behavioral challenges faced by cancer patients. More specifically, data will be presented indicating that increased inflammatory responses, in part related to impaired regulation by the neuroendocrine system, interact with pathophysiologic pathways known to be involved in the regulation of behavior and thus may mediate the development of behavioral symptoms in cancer patients. (Figure 1) Of note, this increasing appreciation of the role of inflammation in behavioral pathology is complementary to an increasing awareness of inflammation as a common mechanism in multiple diseases including cardiovascular disease, diabetes and cancer.1 Moreover, this novel conceptual framework may ultimately serve to integrate the spectrum of behavioral co-morbidities experienced by cancer patients and provide an organizing principle for determining which patients are at greatest risk under what treatment conditions. Relevant translational implications of this research as well as directions for future study are also explored.

Figure 1
Neuroendocrine-Immune Mechanisms and Mediators of Behavioral Co-Morbidities in Patients with Cancer

Inflammation and Behavior

Increasing data indicates that activation of innate immune responses (inflammation) may contribute to the development of behavioral alterations in both medically ill and medically healthy individuals. Studies in laboratory animals and humans provide compelling evidence that administration of innate immune cytokines can induce a syndrome of “sickness behavior” that has many overlapping features with the behavioral co-morbidities commonly experienced by cancer patients, including depression, fatigue, impaired sleep, and cognitive dysfunction.2,3 These behavioral effects of cytokines appear to be secondary to the capacity of peripheral cytokine signals to access the brain and activate inflammatory responses within the brain, which then interact with pathophysiologic pathways known to be involved in behavioral disorders.47 Indeed, cytokine-induced behavioral changes have been associated with alterations in the metabolism of relevant neurotransmitters such as serotonin, norepinephrine and dopamine, all of which play a major role in the regulation of multiple behaviors and are the primary targets for currently available psychopharmacologic treatments of depression and anxiety as well as fatigue.8,9 For example, innate immune cytokines, including interferon (IFN)-alpha and interleukin (IL)-6, have been shown to deplete the amino acid, tryptophan, the primary precursor of serotonin, via induction of the enzyme, indolamine 2,3 dioxygenase (IDO).1013 In addition, through activation of p38 mitogen activated protein kinase (MAPK) signaling pathways, tumor necrosis factor (TNF)-alpha and IL-1 have been found to increase the function and expression of the synaptic reuptake pumps for serotonin and norepinephrine. Taken together, these data suggest that innate immune cytokines can lead to a “double hit” on the synaptic availability of relevant neurotransmitters,14 influencing both their synthesis and reuptake, and thereby potentially contributing to the development of behavioral changes.8

Innate immune cytokines also have been found to increase mRNA and protein of the neuropeptide, corticotropin releasing hormone (CRH).15,16 CRH is a key regulator of the hypothalamic-pituitary-adrenal (HPA) axis and has been found to be increased in the cerebrospinal fluid of patients with a number of behavioral disorders including major depression.17 In addition, administration of CRH to laboratory animals has been found to lead to alterations in behavior including depressive and anxiety-like behaviors, impaired sleep, anorexia and reduced activity.17

Another mechanism by which innate immune cytokines may contribute to alterations in behavior is through their effects on regional brain activity. These effects have been investigated in the context of administration of IFN-alpha for cancer and infectious diseases. For example, administration of IFN-alpha has been associated with increased regional blood flow in the dorsal part of the anterior cingulate cortex (dACC) as revealed by functional magnetic resonance imaging during a task of visuo-spatial attention.18 The dACC is believed to play an important role in detecting physical and social threat, and subsequently recruiting attention and coping resources to minimize danger.19 Of note, increased dACC activity has been demonstrated in individuals at risk for mood and anxiety disorders, including subjects with high-trait anxiety, neuroticism and obsessive compulsive disorder.18 Studies using [18F]-fluorodeoxyglucose (FDG) and positron emission tomography (PET) have shown that IFN-alpha administration also results in significant changes in prefrontal cortex and basal ganglia activity, which have been correlated with the development of depression and fatigue, respectively.20,21 IFN-alpha-induced alterations in neurocognitive functions relevant to the basal ganglia (i.e. psychomotor slowing) also have been associated with the development of depressive symptoms in cancer patients.22

In addition to effects on the function of brain regions that subserve various cognitive processes and behavior, administration of innate immune cytokines to laboratory animals has been shown to disrupt long-term potentiation in the hippocampus and thereby disrupt memory consolidation.23,24 Moreover, the release of IL-6 from activated macrophages has been shown to mediate the inhibitory effects of cranial x-ray irradiation on the growth and development of neuronal progenitor cells in the hippocampus.25

Finally, ongoing research has revealed an emerging relationship between innate immune cytokines and disrupted sleep-wake cycles (Figure 1).26,27. Sleep loss induces cellular and genomic markers of inflammation28 and leads to increases in circulating levels of innate immune cytokines and markers of systemic inflammation such as C-reactive protein (CRP).29,30 Conversely, elevations of innate immune cytokines such as IL-6, prior to sleep onset correlate with prolonged sleep latency,3133 and IL-6 administration decreases delta wave sleep.34

Psychological Stress and Inflammation

Given the well-known role of psychological stress in the development of a wide variety of behavioral disorders,35 it is intriguing to note that stress can activate inflammatory cytokines and their signaling pathways [e.g. nuclear factor kappa B (NFkB)] both in the periphery and in the brain.3639 In addition, data in rats indicate that stress can activate microglia in the brain and increase their sensitivity to immunologic stimuli [i.e. lipopolysaccharide (LPS)].38 Of note, stress-induced IL-1 in the brain has been shown to significantly reduce the expression of brain derived neurotrophic factor (BDNF), which is believed to play a pivotal role in neuronal growth and development, learning, synaptic plasticity and ultimately behavioral disorders.40,41

The effects of stress on brain inflammatory pathways are believed to be mediated by activation of the sympathetic nervous system and the release of catecholamines which bind to alpha and beta adrenergic receptors on relevant cells.36,39 Interestingly, recent data suggest that the parasympathetic nervous system via the release of acetylcholine and subsequent activation of the alpha 7 subunit of the nicotinic acetylcholine receptor can inhibit inflammatory signaling pathways (e.g. NFkB),42 suggesting that sympathetic and parasympathetic pathways have an opposing influence on inflammatory responses during stress.

Neuroendocrine Regulation of Inflammatory Responses

The neuroendocrine system, specifically the hypothalamic pituitary adrenal (HPA) axis and glucocorticoids, plays a primary role in the negative regulation of inflammatory responses. Indeed, glucocorticoids, such as cortisol, are the most potent anti-inflammatory hormones in the body.43 These effects are largely mediated by protein-protein interactions between the glucocorticoid receptor and relevant inflammatory signaling molecules including NF-kB.44 Thus, disruption of glucocorticoid signaling either through altered release of glucocorticoid hormones (including changes in the circadian cortisol rhythm) or disruption of glucocorticoid receptor function may contribute to increased inflammatory responses. Of relevance to the potential role of cytokines in this process, cytokine signaling pathways including p38 MAPK have been shown to disrupt glucocorticoid receptor signaling,45,46 and thereby may contribute to reduced sensitivity of immune cells to the anti-inflammatory effects of glucocorticoids. Disruption of glucocorticoid receptor function may also contribute to altered HPA axis function, including flattening of diurnal cortisol production and the inability to shut down cortisol production (non-suppression) following administration of the synthetic glucocorticoid, dexamethasone [as manifested by an abnormal dexamethasone suppression test (DST)]. Of note, abnormal DST responses have been associated with increased production of IL-1 by peripheral blood mononuclear cells (PBMCs) in healthy subjects with major depression.47 Intense and/or chronic stress has also been associated with alterations in HPA axis function including decreased cortisol production, flattening of the cortisol diurnal rhythm and reduced glucocorticoid receptor function as manifested by altered responses to dexamethasone.48 Taken together, these data suggest that both cytokines and stress can conspire to alter HPA axis and glucocorticoid receptor function, leading to a reduced ability of endogenous glucocorticoids to contain inflammatory responses.

Evidence for the Role of Inflammation and its Altered Regulation by the Neuroendocrine System in Behavioral Co-Morbidities in Patients with Cancer

There are a number of factors that increase the likelihood that cancer patients will exhibit activation of inflammatory pathways (Figure 1). Surgery, chemotherapy and radiation are all associated with significant tissue damage and destruction, which in turn is related to activation of innate immune responses. In addition, chemotherapeutic agents and gamma-irradiation are capable of directly inducing NF-kB and its downstream proinflammatory gene products.1 Moreover, receiving a diagnosis of cancer and battling with chronic uncertainties regarding treatment, recurrence, and mortality is one of the greatest stressors imaginable. Given the impact of stress on inflammatory responses, the confluence of the physical and psychological challenges inherent to having and being treated for cancer place the cancer patient at high risk for the development of inflammation-induced behavioral alterations. The most common of these behavioral changes will be reviewed below in the context of evidence that inflammation and its regulation by the neuroendocrine system may be involved.

Depression

Of all the behavioral co-morbidities that plague cancer patients, major depression, a syndrome characterized by depressed mood and/or anhedonia and accompanied by alterations in appetite, sleep, activity levels, and cognitive function, has been one of the most studied and best-characterized. Major depression in patients with cancer occurs at a high rate with a median point prevalence (15–29%) that is approximately 3–5 times greater than the general population.49,50 Aside from a profound impact on quality of life, major depression in patients with cancer is associated with increased healthcare utilization, poor treatment adherence and in some cases increased rates of cancer recurrence and mortality.4952

Relevant to the role of the immune system in depression in cancer patients, increased plasma concentrations of IL-6, have been found in two separate studies in cancer patients diagnosed with major depression (Table 1).53,54 Nevertheless, results have been inconsistent, especially in studies looking at correlations between inflammatory biomarkers and depressive symptoms (as measured by standardized depression rating scales). Of note, however, there is a surprising paucity of studies on depressed cancer patients compared to the rich literature examining patients with other medical illnesses, including cardiovascular disease, as well as healthy depressed subjects, where a large number of studies have revealed a clear relationship between inflammatory markers and both a diagnosis of major depression and depressive symptom severity.6

Table 1
Biomarkers of Inflammation in Cancer Patients with Behavioral Co-Morbidities

Cancer patients with major depression also have been shown to exhibit neuroendocrine changes that might predispose to activation of inflammatory responses including two studies demonstrating reduced sensitivity to glucocorticoids as manifested by DST nonsuppression53,55 (Table 2) and one study showing a flattening of the diurnal cortisol curve.53 No study to date has linked HPA axis and/or glucocorticoid receptor function and increased inflammatory markers in depressed cancer subjects.

Table 2
Neuroendocrine Alterations in Cancer Patients with Behavioral Co-Morbidities

Fatigue

Fatigue is one of the most common and distressing side effects of cancer treatment.56 Prevalence estimates of fatigue during treatment range from 25–99% depending on the sample and method of assessment.56,57 Although fatigue typically declines after cancer treatment, there is growing evidence that fatigue may persist for months or years in a significant subpopulation of patients.58,59 Indeed, a recent study found that 34% of disease-free breast cancer survivors reported significant fatigue 5–10 years after diagnosis,60 similar to estimates obtained in a heterogeneous sample of 5-year cancer survivors.59

A number of studies have shown an association between inflammatory markers and fatigue in cancer patients before treatment onset61,62 and during treatment with radiation63,64 and chemotherapy,65 although negative findings have been reported (Table 1).27,6668 There is also evidence that inflammatory processes play a role in post-treatment fatigue. For example, breast cancer survivors with persistent fatigue were found to exhibit significant elevations in several markers of immune activation [i.e., IL-1 receptor antagonist (IL-1ra), soluble TNF receptor p75, neopterin] compared to non-fatigued survivors.69 These findings were recently replicated in a larger cohort of breast cancer patients, with fatigued survivors again showing elevations in circulating IL-1ra and soluble IL-6 receptor as well as increased production of innate immune cytokines by monocytes following in vitro stimulation with LPS.70 Two studies conducted with patients with hematological malignancies who had completed treatment found no association between fatigue and inflammatory markers.71,72 However, in both of these reports, there was considerable variability in diagnosis, disease stage, length of time since treatment, and duration of fatigue symptomatology. Moreover, a recent meta-analysis of the available literature has supported a relationship between inflammatory biomarkers and fatigue in cancer survivors.73 Among patients with advanced cancer (active disease), there is mixed evidence for an association between fatigue and inflammatory measures.74,75

Evidence suggests that enhanced cytokine production in fatigued cancer survivors may stem in part from altered HPA axis function including altered diurnal cortisol secretion and a decreased cortisol response to stress (Table 2). For example, lower levels of morning serum cortisol,69 flattened diurnal cortisol slopes,76 and a blunted cortisol response to acute psychosocial stress77 have been found in breast cancer survivors with persistent fatigue. Interestingly in a recent study of fatigued breast cancer patients, increased stress-induced inflammatory responses (as manifested by increased IL-6 responses to LPS stimulation of whole blood) were associated with decreased stress-induced salivary cortisol responses.78 Increased inflammatory cytokines have also been associated with dampened cortisol rhythm in patients with metastatic colorectal cancer.79 Taken together, these data suggest that alterations in cortisol secretion over the circadian cycle and in response to stress may play a role in exaggerated inflammatory responses which in turn may be associated with behavioral changes including fatigue.

Sleep Disturbance

Over 50% of cancer patients report problems with sleep, with polysomnographic data confirming reduced sleep efficiency, prolonged latency to fall asleep, and increased awake time during the night.80,81 Even before treatment, patients with cancer have reported significant sleep impairment,82 and among cancer survivors, sleep problems persist well beyond treatment. Indeed, nearly 20% of breast cancer survivors report greater than 6 months of chronic insomnia.80,83 Sleep disturbances come at a considerable price. For example, insomnia is a powerful predictor of cancer-related fatigue,58,84,85 and disturbances in sleep-wake activity as well as circadian rhythms have been found to predict increases in mortality in patients with metastatic disease.86,87

Interestingly, despite data indicating a relationship between innate immune cytokines such as IL-6 and sleep, the relationship between inflammatory markers and sleep in cancer patients has not been examined. Given the strong relationship between fatigue and inflammatory markers, it appears likely that similar relationships may exist with sleep. Clearly, studies are needed in this area.

An important potential mechanism whereby sleep disturbances may contribute to increased inflammation is through desynchronization of circadian rhythms, including the release of cortisol (Figure 1).88 Twenty-four hour circadian cortisol secretion is regulated in the hypothalamus in conjunction with the circadian pacemaker located within the suprachiasmatic nucleus. Forced changes in circadian sleep-wake patterns as well as the induction of sleep debt (as occurs in the context of chronic sleep impairment) have been associated with flattening of cortisol rhythms, especially as manifested by increased cortisol secretory activity in the evening, a normally quiescent period of cortisol release.89,90 In addition, sleep restriction has been associated with reduced ACTH responses to stress in rats.91 Although not adequately studied, there is at least one report in cancer patients that disruption of circadian cycles as manifested by frequent nocturnal awakenings was associated with flattening of circadian cortisol rhythms, which in turn, was associated reduced long term survival.86,87 Disruption of circadian rhythms may be initiated during cancer treatment as a result of a vicious cycle of fatigue and daytime inactivity (with resultant impairment in night-time sleep) and/or the impact of immune activation secondary to cancer treatment and/or psychological stress on sleep-wake cycles. Further studies examining sleep-wake cycles, activation of inflammatory responses and circadian cortisol rhythms are clearly warranted to further clarify these relationships and identify points of therapeutic intervention.

Cognitive Function

Cognitive dysfunction during cancer treatment significantly impacts quality of life and social/occupational function, and represents a major concern in patient management.92 Complaints of cognitive impairment, including alterations in memory, concentration, executive function and psychomotor skills, are frequent in patients with cancer. Aside from cancers that directly affect the central nervous system (CNS), cancers originating in peripheral tissues have also been associated with the occurrence of neuropsychological changes. These cognitive changes are often secondary to cancer treatments, including most notably chemotherapy and radiation. About 25–33% of patients undergoing systemic chemotherapy exhibit impaired performance on tests of cognitive functions.9396 Cognitive dysfunction related to chemotherapy appears to be dose-dependent; with high-doses being associated with greater impairment.95,97 Although cognitive dysfunction during chemotherapy generally resolves after treatment, several studies have reported residual long-term effects.98100 Data indicate that chemotherapy is also associated with alterations in regional brain activity that correlate with cognitive dysfunction.101,102 For example, a [18F]-FDG PET study on patients treated with chemotherapy for breast cancer demonstrated significant decreases in metabolic activity in the dorsolateral prefrontal cortex that correlated with cognitive impairment.103 When directed at the brain, not surprisingly, radiation therapy is often accompanied by neurological complications that may be severe and persist years after treatment.104 Interestingly, however, moderate/transient cognitive alterations have been reported after radiation of sites other than the brain. For example, a study conducted in 48 women undergoing postoperative radiation therapy after breast-conserving surgery indicated significant increases in the cognitive fatigue subscale of the Fatigue Assessment Questionnaire 4 and 5 weeks after initiation of radiation therapy in comparison to baseline.66

Findings suggest that inflammatory factors may play a role in the pathophysiology of cognitive dysfunction in cancer patients.23 For example, a significant negative correlation has been found between plasma IL-6 and executive function in patients with acute myelogenous leukemia or myelodysplastic syndrome (Table 1).61 Probably the most striking example of the effects of cytokines on cognition in cancer patients is the neuropsychological sequelae of cytokine-based immunotherapies such as IFN-alpha and IL-2. A study conducted in patients treated with high-dose IFN-alpha for malignant melanoma indicate that complaints of moderate to severe cognitive symptoms are frequent, especially loss of concentration (30% of patients), psychomotor retardation (40%), memory disturbances (15%) and word-finding problems (15%).105 Cognitive dysfunction in patients undergoing cytokine therapy largely depends on the parameters of treatment (dose, duration and route of administration) and the cytokine administered.106 Thus, whereas IFN-alpha 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.22 Cognitive alterations secondary to high-dose cytokine therapy treatment typically reverse after treatment; however, residual cognitive impairment has been reported.107,108

Translational Implications

Identification of Behavioral Risk

Based on the proposed conceptual framework (Figure 1), individuals with high levels of perceived stress (as a function of the cancer diagnosis or other life circumstances) who are undergoing treatments associated with activation of inflammatory responses (e.g. surgery, chemotherapy, radiation therapy) may be most at risk for developing behavioral change. In addition, increased risk may be associated with significant disruption of sleep-wake cycles. The relative risk for the development of behavioral co-morbidities is also likely influenced by genetic factors. Functional polymorphisms in the IL-6 gene and the serotonin transporter gene may be especially relevant, given the association of IL-6 with several behavioral pathologies in cancer patients and the demonstrated role of serotonin transporter polymorphisms in the relationship between stress and behavior alterations.109,110 Future studies identifying psychological and genetic profiles of risk for behavioral change during cancer and its treatment are clearly warranted. Finally, as part of ongoing research into the role of inflammation in behavioral co-morbidities and the identification of risk, consideration should be given to the development of standardized assessments of inflammatory biomarkers in cancer patients. Based on studies to date, alterations in IL-6 (as assessed by high sensitivity enzyme-linked immunoabsorbent assay) and the downstream, liver-derived, acute phase reactant, CRP [as measured by high sensitivity (hs) assay techniques], appear to be the most reliable regarding both behavioral pathology and medical illness.6,111115 Indeed, as shown in Table 1, a number of studies in cancer patients have revealed associations between IL-6 and CRP and depression, fatigue, and cognitive dysfunction. Furthermore, hsCRP can be run in certified commercial/hospital laboratories, thereby reducing variability across research sites. Moreover, in the case of hsCRP, cut-off values have been established that have both predictive validity and categorization of risk in relation to disease outcome in cardiovascular disorders.113 Given the fluctuating status of cancer patients during treatment, it is also suggested that longitudinal assessments of both behavior and relevant inflammatory biomarkers be obtained to increase the likelihood of identifying relevant associations between these variables that might otherwise be confounded by the vicissitudes of the cancer treatment experience. Examination of inflammatory biomarkers in cancer survivors versus healthy age- and sex-matched controls is yet another strategy to reduce the impact of treatment on the relationship between inflammation and behavioral change.

Therapeutic Ramifications

Given the prevailing knowledge regarding the potential integrated mechanisms involved in behavioral co-morbidities in cancer patients, there are multiple opportunities for translational studies targeting pathways that contribute to the wide range of symptoms (Table 3).

Table 3
Neuroendocrine-Immune Interactions and the Development of Behavioral Co-morbidities in Cancer Patients: Translational Targets

Psychotherapeutic/Behavioral interventions

Cognitive-behavioral, supportive or insight-oriented psychotherapies that reduce stress and restore regular circadian cycles may be especially relevant, given the potential role of stress-induced inflammation and altered regulation of inflammatory responses by the neuroendocrine system. Relevant cognitive-behavioral strategies include relaxation training, enhancement of coping skills, graded exercise, and establishment of appropriate sleep-wake habits and social rhythms (e.g. standardized bed and wake-up times, avoidance of daytime napping, and correction of maladaptive beliefs about sleep).116127 Such interventions may limit the impact of stress on the immune response and may have direct effects on neuroendocrine-immune interactions. Indeed, psychological interventions such as cognitive-behavioral stress management and mindfulness-based stress reduction have been shown to alleviate psychological distress in breast cancer patients, while increasing lymphocyte proliferative responses and normalizing diurnal cortisol secretion.122127 There is also evidence that aerobic exercise can lead to reductions in inflammatory markers in cancer survivors,128 and the possibility that changes in inflammation may mediate the beneficial effects of exercise (and possibly other behavioral therapies) on cancer-related behavioral co-morbidities is an important avenue for future research.129 Interestingly in this regard, a recent cognitive-behavioral therapy program focusing on coping, sleep, physical activity and social support was found to lead to significant improvement in fatigue in 54% of cancer survivors compared to 4% of patients assigned to a control condition.116 Regarding the impact of altered sleep-wake cycles on neuroendocrine and immune function in cancer patients, Irwin and colleagues found that multiple types of behavioral treatments (e.g., cognitive behavioral therapies, relaxation, behavioral only) induced robust improvements in subjective measures of sleep quality, sleep onset, and sleep maintenance in adults with primary insomnia130 extending the findings of prior studies.131,132 However, much less is known about the efficacy of these approaches for insomnia in cancer patients.83,133 Indeed, only one controlled study has examined the efficacy of a behavioral intervention for insomnia in cancer patients,134 with other studies limited by lack of a control group and/or small sample sizes.135,136 Moreover, no study has included assessments of the impact of these interventions on cortisol rhythms, inflammatory mediators, or behavioral changes.

Biologic Interventions

Although further studies are required to characterize the relationship between inflammatory markers and behavior in cancer patients; cytokine antagonists, anti-inflammatory agents and drugs that disrupt cytokine signaling pathways (e.g. NFkB and p38 MAPK) are logical treatment considerations that target the most upstream elements in the cytokine-to-CNS-to-behavior cascade. Of note, given the role of NF-kB and p38 pathways in cancer development and progression, exciting opportunities exist for behavioral scientists to work with oncologists to examine the full spectrum of activity of relevant antagonists of inflammatory pathways. For example, several recent trials have demonstrated that TNF-alpha blockade with etanercept is safe in patients with advanced cancer, and there was suggestion in at least one study that tolerability of chemotherapy (including reduced fatigue) was improved.137139

Moving into the CNS, inflammation-induced alterations in neurotransmitter systems may be best addressed by pharmacologic agents that target specific monoamine systems for specific symptom domains (e.g. serotonin active drugs for mood/anxiety symptoms, dopamine active drugs for fatigue and psychomotor slowing). For example, 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.105,140 On the other hand, preliminary evidence suggests that dopaminergic agents such as the psychostimulant, methylphenidate, may treat fatigue and improve neuropsychological functioning in patients undergoing cancer treatments141 and patients with tumor-related organic brain dysfunction.142,143

CRH, which as noted above is stimulated by innate inflammatory cytokines, is another rational CNS target, and although CRH antagonists are not currently available, there is preliminary indication that these agents may have efficacy in treating depression in otherwise healthy individuals.144 Drugs that enhance glucocorticoid-mediated negative feedback on CRH pathways, through facilitation of glucocorticoid receptor function, may control CRH over-expression. Such drugs (including phosphodiesterase type IV inhibitors), may have the advantage of additionally inhibiting inflammatory pathways.145 Novel treatments supporting neuronal integrity/plasticity (neuroprotective agents) including drugs that stimulate the activity or signaling of relevant growth factors (e.g. BDNF) may be especially important for future development.146,147

Regarding sleep and neuroendocrine rhythms, therapies that combine chronobiotics (e.g., melatonin receptor agonists, light therapy, or sleep regulation) might synchronize the circadian rhythms of cancer patients to their environment, in the same manner as these strategies are used to treat transient rhythm disturbances caused by jet lag or shift work. Such treatment may help restore neuroendocrine rhythmicity, reduce inflammation, and potentially improve therapeutic efficacy of cancer treatments.148,149

Summary

The research described herein provides a conceptual framework designed to integrate a host of behavioral co-morbidities which may share common pathophysiologic features that lend themselves to identification of risk and targeted interventions with broad therapeutic relevance. Further studies examining neuroendocrine-immune interactions as they relate to altered sleep-wake cycles and behavioral co-morbidities in patients with a wide variety of cancers will likely lead to novel insights to the contribution of cancer and its treatment to behavioral changes and, possibly, the contributions of behavioral co-morbidities to cancer development, progression and recurrence. Finally, given the increasing understanding of the pathophysiology and treatment of behavioral co-morbidities in cancer patients, it is especially important that standardized behavioral assessments become part of the routine care of cancer patients. As such, instantiating behavior as the sixth vital sign will go a long way to emphasizing the need for further research and the importance of both recognizing and treating the behavioral consequences of cancer and its treatment.

Acknowledgements

The authors would like to thank Dr. Paige McDonald for her valuable input and support regarding this manuscript. This project was funded in part by the National Cancer Institute (NCI), Cancer Control and Population Sciences, Basic and Biobehavioral Research, Biological Mechanisms of Psychosocial Effects in Disease; NCI CA85264, NCI CA112035, and CBCRP 11IB-0034, M01-RR00865 grants to SA-I; NCI CA090407 grant to JEB; National Institute of Mental Health grant MH069124 to AHM; and National Institutes of Health grants AG026364, HL079955, T32-MH19925, CA 0014152 to MRI and the Cousins Center for Psychoneuroimmunology.

Contributor Information

Andrew H. Miller, Emory University School of Medicine, Atlanta, GA.

Sonia Ancoli-Israel, University of California San Diego, San Diego, CA.

Julienne E. Bower, University of California Los Angeles, Los Angeles, CA.

Lucile Capuron, Université Bordeaux, Bordeaux, France.

Michael R. Irwin, University of California Los Angeles, Los Angeles, CA.

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