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Cancer Nursing:
doi: 10.1097/NCC.0b013e318233a811
Articles: Online Only

Common Biological Pathways Underlying the Psychoneurological Symptom Cluster in Cancer Patients

Kim, Hee-Ju PhD, RN, OCN; Barsevick, Andrea M. PhD, RN, AOCN, FAAN; Fang, Carolyn Y. PhD; Miaskowski, Christine PhD, RN, FAAN

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Author Information

Author Affiliations: College of Nursing, Catholic University of Korea, Seoul,Republic of Korea (Dr Kim); Fox Chase Cancer Center, Philadelphia, Pennsylvania (Drs Barsevick and Fang); Department of Physiological Nursing,University of California, San Francisco (Dr Miaskowski).

The authors have no funding or conflicts of interest to disclose.

Correspondence: Hee-Ju Kim, PhD, RN, OCN, College of Nursing, Catholic University of Korea, 505 Banpo-Dong, Seocho-Gu, Seoul 137-701, Republic of Korea (heeju0906@gmail.com).

Accepted for publication August 19, 2011.

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Abstract

Background: A symptom cluster is a group of symptoms that occur together and are interrelated. The clinical implication of symptom cluster research is to use the clustering patterns of symptoms to understand the mechanisms for these symptoms and develop management strategies targeted at multiple symptoms.

Objective: The purposes of this review were to summarize the evidence for a psychoneurological symptom cluster in cancer patients, to provide information regarding the underlying biological mechanisms for each of the psychoneurological symptoms within the cluster, and to propose possible common biological pathways that may underlie this cluster.

Methods: A systematic review of the literature was conducted.

Results: Empirical evidence exists to support a cluster of psychoneurological symptoms (ie, depressive symptoms, cognitive disturbance, fatigue, sleep disturbance, pain). At a molecular level, common biological pathways (ie, proinflammatory cytokines, hypothalamic-pituitary-adrenal axis, and monoamine neurotransmission system) may underlie the development of symptoms within this cluster. Activation of proinflammatory cytokines is proposed as a first stage of mechanistic pathway. However, other biological factors, such as lowered estrogen or hemoglobin levels, may influence psychoneurological cluster.

Conclusion: Additional studies are needed to confirm the roles of cytokines as well as other biological factors in the development of the psychoneurological cluster and to determine the biomarkers to identify the subgroups of cancer patients who are at greatest risk for this cluster.

Implications for Practice: This information can be used by researchers and clinicians to guide the selection of symptom management strategies that are ideally targeted to the biological mechanisms that underlie this symptom cluster.

The study of symptom clusters in oncology is an emerging area in symptom management research, investigating the co-occurring tendency of multiple symptoms.1,2 One reason why patients may present with a cluster of symptoms, rather than a single symptom, is that symptoms that co-occur may share a common biological mechanism.3,4 The discovery of common mechanistic pathways may lead to the development of novel strategies to manage multiple symptoms. The purpose of this review was to summarize the evidence for (1) a psychoneurological symptom cluster in cancer patients, (2) the underlying biological mechanisms for each psychoneurological symptom within the cluster, and (3) the shared biological mechanisms across these symptoms. This review concludes with a proposal for a common biological pathway that may underlie a psychoneurological symptom cluster.

The literature for this review was selected by searching PubMed and CINAHL databases. Although the psychology databases were not specifically searched, the 2 databases cover literature from psychology. The initial search was conducted using multiple combinations of key words for the period from 1990 to the present: symptom clusters, cancer, depression/depressed mood, cognitive/cognition, fatigue, insomnia, sleep disturbance, pain, pathophysiology, and/or mechanisms. First, articles explicitly related to biological mechanisms of symptoms were reviewed. Then, specific mechanisms identified from the first review were used as additional key words (eg, proinflammatory cytokines) for further data searches. Articles included in the reference lists of the retrieved materials were also reviewed. No other inclusion or exclusion criteria were used. All articles were reviewed, and articles that represent a similar idea were synthesized. Recent articles that were more closely associated with a particular idea were cited within the text.

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Evidence for a Psychoneurological Symptom Cluster in Cancer Patients

For the purpose of this review, a psychoneurological cluster is defined as a set of emotional and/or behavioral symptoms that may be related to psychological and/or neurological dysfunction and that have a tendency to co-occur in cancer patients. In this review, these symptoms include depressive symptoms, cognitive disturbance, fatigue, sleep disturbance, and pain. In the first 3 research papers on symptom clusters in oncology,1,5,6 the symptom cluster was prespecified. In the study by Dodd et al,1 the cluster of fatigue, pain, and sleep insufficiency had a negative impact on cancer patients’ functional status. Using the same symptom cluster, Given et al6 confirmed this finding. In the third study,5 pain had negative impact on fatigue directly as well as indirectly through its impact on sleep disturbance. Findings from this series of symptom cluster studies, as well as studies of multiple symptoms, suggest that moderate to strong correlations exist between pain, fatigue, and sleep disturbance and that these symptoms co-occur in a fairly high percentage of cancer patients.7–10

More recent studies have identified symptom clusters empirically using statistical methods, such as factor or cluster analysis (eg, Bender et al,11 Kim et al12; see Table 1 for exemplar). These studies found that pain, fatigue, and sleep disturbance form a cluster with other psychoneurological symptoms. For example, in a study with a heterogeneous sample of cancer patients,13 psychoneurological symptoms (eg, pain, fatigue, disturbed sleep, emotional distress, drowsiness, difficulty remembering) formed a cluster. In addition, Bender et al11 reported that fatigue, cognitive impairment, and mood problems formed a cluster with some other psychoneurological symptoms in 3 different samples of patients with breast cancer. In the third study, Chen and Tseng15 found a similar psychoneurological symptom cluster (ie, pain, fatigue, sleep disturbance, lack of appetite, drowsiness) in a heterogeneous sample of oncology patients. A fourth study identified symptom clusters in breast or prostate cancer patients at the middle, end, and 1 month after the completion of radiation therapy.22 Across the 3 time points, symptoms of difficulty concentrating, feeling sad, and worrying were found within the mood-cognitive cluster.22 Finally, in a study of symptoms in breast cancer patients undergoing chemotherapy (CTX) or radiation treatment (RTX), a psychoneurological symptom cluster (ie, depressed mood, cognitive disturbance, fatigue, insomnia, pain) was found at 3 time points across the cancer treatment trajectory.12 More recent studies found that only a few psychoneurological symptoms (eg, sleep problems, depressed mood, anxiety, and/or cognitive disturbance) have a tendency to form a cluster.16,17,24,26,27

Table 1
Table 1
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However, several studies did not find a psychoneurological symptom cluster.17,19,21 For example, the symptom clusters that were identified in cancer patients with brain metastases included the following: cluster 1 (fatigue, drowsiness, shortness of breath, pain), cluster 2 (anxiety, depression), and cluster 3 (poor appetite, nausea, poor sense of well-being).19 These differences in symptom clusters across studies may be due to differences in sample characteristics, the symptoms that were assessed, and the methods used to create symptom clusters. However, across these studies, the evidence suggests that a psychoneurological symptom cluster exists in diverse samples of oncology patients. This symptom cluster most often includes depressive symptoms, cognitive disturbance, fatigue, sleep disturbance, and pain.

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Biological Mechanisms That Underlie Individual Psychoneurological Symptoms

In an effort to elucidate whether symptoms in a cluster share a common biological pathway, the biological mechanisms underlying each of the 5 psychoneurological symptoms (ie, depressive symptoms, cognitive disturbance, fatigue, sleep disturbance, pain) are reviewed. These 5 symptoms were chosen because of previous evidence for this symptom cluster11,12 and their high occurrence rates in cancer patients. Although the underlying biological mechanism for each symptom is not completely understood, the most current mechanistic hypotheses are summarized below.

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DEPRESSIVE SYMPTOMS

As summarized in Table 2, the 3 biological mechanisms that are hypothesized to underlie the development of depressive symptoms are as follows: (1) alterations in the serotonin (5-HT) system, in particular decreased 5-HT neurotransmission; (2) dysregulation of noradrenergic neurotransmission; and (3) hyperactivation of hypothalamic-pituitary-adrenal (HPA) axis. These 3 mechanisms are widely known and accepted in practice and theory. Most recently, changes in proinflammatory cytokines were proposed to be involved in the development of depressive symptoms possibly through interactions with the other 3 mechanisms.57

Table 2
Table 2
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The cytokine hypothesis is supported by findings of higher levels of interleukin 6 (IL-6) and/or tumor necrosis factor α (TNF-α) in some depressed patients,45,58,59 as well as the higher prevalence rates of depression in patients with inflammatory diseases60 or those who undergo cytokine treatments.48,61 The recent emergence of the cytokine hypothesis has left many unanswered questions, such as whether relatively small amount of cytokines can induce depressive symptoms, or whether cytokines play a role in depressive symptoms in patients without medical problems.57 However, researchers generally agree that cytokines can induce depressive symptoms at least in a subset of patients, particularly those who are medically ill.62 The majority of the evidence for all of the proposed mechanisms comes from studies of major depression in healthy persons or those with other chronic illnesses. Therefore, additional research is warranted to determine if these mechanisms play a role in depressive symptoms in patients with cancer.

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COGNITIVE DISTURBANCE

A subset of cancer patients experience acute or chronic impairment in various domains of cognitive function (eg, attention, executive function, information processing, motor function, spatial skill, and verbal/visual memory).63 The proposed mechanisms for cognitive disturbance in cancer patients include (1) brain damage, (2) hormonal changes, (3) proinflammatory cytokine activation, (4) anemia, and (5) biomolecular changes induced by medication (Table 3).

Table 3
Table 3
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Direct or indirect brain damage can induce cognitive disturbance. Cancer treatments (eg, RTX or CTX), particularly those given into the central nervous system, can damage neurons or their surrounding tissues82,83 (Table 3, for the neurotoxic effects of cancer treatments). These neurotoxic effects in animals appear to be mediated, in part, by oxidative stress.82

Changes in levels of reproductive hormones due to cancer treatment have been associated with cognitive disturbance (for reference, see Table 3). For example, female patients treated with CTX experience menopausal symptoms, including cognitive disturbance.84 The impact of hormones on cognitive function is thought to occur through changes in the modulation of neurotransmitters (eg, acetylcholine, 5-HT), direct effects of hormones on neuronal circuitry, changes in cerebral blood flow, and/or alteration in lipoproteins.85

Increases in proinflammatory cytokines may be associated with cognitive disturbance in cancer patients, because patients on cytokine treatment report impairments in cognitive function (eg, decreases in reaction time, memory, and ability to plan tasks).74 Cytokines can induce neurological damage in specific regions of the brain (eg, frontal lobe) and/or alterations in neurotransmitter function.74,86

Anemia can induce cognitive disturbance through hypoxic damage to the brain. Anemia can occur due to the cancer itself (eg, leukemia), bone marrow suppression by cancer treatment, malnutrition associated with gastrointestinal symptoms, and/or erythropoiesis suppression by activated inflammatory cytokines.87 Opioid-induced cognitive impairment is a significant clinical problem.88 Opioid metabolites or alterations in anticholinergic activity associated with opioids may cause cognitive disturbance.81,89 Finally, some patients may be genetically more susceptible to cognitive disturbance induced by cancer or its treatment.86

In summary, cancer patients can experience cognitive disturbance from a variety of causes during their illness phases, and some patients may be at a greater risk for cognitive disturbance due to cumulative effects of multiple mechanisms. Specific mechanism relevant to a particular patient should be considered in symptom management.

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FATIGUE

The dysregulation of a number of biochemical pathways induced by cancer and its treatments that are potential mechanisms for fatigue include (1) 5-HT system dysregulation, (2) HPA axis dysregulation, (3) circadian rhythm disruption, (4) proinflammatory cytokine activation, (5) vagal afferent nerve activation, and (6) adenosine triphosphate (ATP) dysregulation (Table 4). Although hyperactivation of the 5-HT system has been associated with fatigue, most of the evidence is from noncancer populations or animal models. Increased levels of 5-HT were found in fatigued individuals with chronic fatigue syndrome90,111 and in animals fatigued from exercise.112 However, recent data suggest that an increase in the central ratio of 5-HT to dopamine, rather than the absolute level of 5-HT, is more important in the development of fatigue.113

Table 4
Table 4
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Disruption (ie, activation or inactivation) in HPA axis function is another potential mechanism for fatigue, which is supported by atypical cortisol responses in fatigued cancer patients relative to nonfatigued patients, and positive or negative associations between fatigue intensity and cortisol level (Table 4). More recently, disruption in the circadian rhythms of hormones and/or in rest activity (ie, daily sleep and activity patterns measured by actigraphy), rather than the hormone level itself, is thought to be more directly related to the development of fatigue.99,100

Release of cytokines was associated with fatigue in patients with cancer102 and chronic fatigue symptoms.104 In addition, cytokine treatment has been shown to induce fatigue in cancer patients.46 Proinflammatory cytokines (eg, IL-1, IL-6, TNF-α) induced by cancer or its treatment may be responsible for the development of fatigue in some cancer patients.103 This hypothesis has led to the examination of the effect of anticytokine treatment on fatigue. In a small clinical trial, anticytokine treatment during cancer CTX showed a favorable toxicity profile, including less fatigue.105

The subjective feeling of “weakness” is in part associated with peripheral muscle fatigue. Vagal afferent nerve stimulation may explain muscle fatigue in some cancer patients, although more conclusive evidence is required. Preclinical studies show that the vagal nerve reflex contributes to decreased motor activity associated with sickness behaviors in animals.106,107 It is possible that peripheral proinflammatory cytokines induced from cancer or its treatment can activate vagal afferent nerves in cancer patients.114,115 Because ATP is required in skeletal muscle metabolism during motor activity, disruption in ATP regeneration can cause muscle fatigue. This hypothesis is further supported by the therapeutic effects of ATP or the coenzyme for ATP generation on fatigue in clinical trials.109,110 Finally, fatigue in some cancer patients may be secondary to anemia and/or cachexia.

Some evidence suggests that cancer and its treatments can induce dysregulation in the biochemical pathways listed above.108 However, the exact mechanistic pathways through which cancer and its treatment cause such dysregulation remain to be determined. In addition, the evidence for these mechanisms is largely based on studies of exercise-induced fatigue and chronic fatigue syndrome. Therefore, the extent to which these mechanisms explain cancer-related fatigue remains to be determined.

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SLEEP DISTURBANCE

The possible biological mechanisms for sleep disturbance include alterations in proinflammatory cytokines, HPA axis disruption, and alterations in neurotransmitter systems (eg, 5-HT) (Table 5). Many studies have suggested that proinflammatory cytokines (eg, IL-6, TNF-α) play a role in sleep disturbance because exogenous cytokines can induce sleep disturbance,116 and patients with sleep problems have circadian alterations in cytokine secretion.118

Table 5
Table 5
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Other studies support the involvement of HPA axis disruption in the development of sleep disturbance (Table 5). Hyperactivity in the HPA axis can induce sleep fragmentation, decreased slow-wave sleep, increased numbers of awakenings, and shortened sleep time.122 Hypothalamic-pituitary-adrenal axis hyperactivity in cancer patients can occur as a result of psychological stress associated with a cancer diagnosis and its treatment132 and from increases in levels of proinflammatory cytokines released in response to cancer or its treatment.51

Many neurotransmitters (eg, adenosine, acetylcholine, γ-aminobutyric acid, norepinephrine, hypocretin, histamine, 5-HT) are involved in regulation of the sleep-wake cycle.133 In particular, 5-HT has received attention from sleep researchers. However, the exact processes by which 5-HT alters sleep-wake mechanisms appear to be extremely complex. The role of 5-HT in the sleep-wake cycle architecture appears to depend on the type of receptor it binds to, the location within the brain, and interaction with other neurotransmitters.134,135 The evidence for sleep disturbance mechanism is mostly from the general population and thus explains the general mechanism, not specific for cancer patients. When, how, and how seriously such mechanisms can cause sleep problems in cancer patients need to be further clarified.

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PAIN

Pain perception depends on an intact sensory system that consists of peripheral sensory receptors, called nociceptors; peripheral nerve fibers (A delta and C fibers) connected to the spinal cord; and nerve tracts within the spinal cord (eg, spinothalamic tract) that ascend to various regions in the brain where pain information is processed. A tumor can induce noxious chemical (eg, H+, ATP, prostaglandins, TNF-α, endothelins, IL-1, IL-6, and growth factors) or mechanical (distension, compression, ischemia) stimuli that activate nociceptors.136

Cancer-related pain can be classified as somatic, visceral, or neuropathic. Cancer-induced bone pain is the most common type of somatic pain.137 Mechanisms for cancer-induced bone pain include activation of sensory neurons by cancer cells or by inflammatory mediators, tumor-induced hypertrophy of osteoclasts, mechanical stress on bone, and/or a hyperexcited pain system138 (Table 6). Visceral pain is induced by the distension of hollow organs and ischemic/inflammatory changes in tissues.137 Visceral pain is often felt on a body wall and is poorly localized, probably because of few sensory visceral afferents and viscerosomatic and viscerovisceral convergence in dorsal horn neurons.150,151 Unlike somatic pain, the dorsal column pathway and vagal afferent pathway play an important role in transmitting visceral pain sensation to the brain.150,152

Table 6
Table 6
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Neuropathic pain is an unpleasant abnormal sensation that is often accompanied by hyperalgesia (ie, increased pain sensation to painful stimuli) and allodynia (ie, pain sensation to normally nonpainful stimuli). It occurs from damage to the peripheral or central nervous system. Neural tissue damage in cancer patients is induced by the cancer itself (eg, infiltration or nerve compression) and from cancer treatments (ie, surgery, RTX, CTX).137 One of the main mechanisms for neuropathic pain is the ectopic discharge of injured or uninjured nerve fibers (Table 6).153,154 An ectopic discharge is an abnormal activation of a neuron. The ectopic discharge not only in injured nerve fiber but also in adjacent uninjured nerve fiber contributes to neuropathic pain development, possibly because uninjured fibers expose to the altered endoneurial environment from the degeneration of injured axon.154 In addition, proinflammatory cytokines may be involved in neuropathic pain generation. For example, levels of IL-2 and TNF-α were higher in patients with painful neuropathy than in both healthy controls and patients with painless neuropathy.155 Furthermore, anti-inflammatory medications can decrease neuropathic pain.156

Cancer-related pain is often accompanied by hyperalgesia and allodynia that occurs as a result of peripheral and central sensitization.157 In peripheral sensitization, peripheral sensory nerve fibers become highly sensitized by inflammatory processes (eg, swelling) as well as inflammatory mediators (eg, prostaglandins, cytokines, nitric oxide, bradykinin, histamine, ATP, acetylcholine).158,159 Central sensitization is a hyperexcitation of dorsal horn neurons in the spinal cord. Central sensitization occurs through the activation of various neuromodulation systems in the spinal cord, such as wide dynamic range neurons,160 the N-methyl D-aspartate receptor system,161 the 5-HT3 receptor system,162,163 neurotrophic factors,161 neuropeptides such as substance P and neurokinin A,159 prostaglandins,164 and proinflammatory cytokines.165,166 Findings from animal studies suggest that cancer can cause peripheral and central sensitization.157 Opioids can induce hyperalgesia. Some cancer patients on the opioids analgesia may be at risk for the development of hyperalgesia.167,168

In summary, pain mechanisms and locations are various, depending on the type of pain and/or the etiology of pain. For instance, some cancer patients can experience general ache associated with hyperalgesia or allodynia, whereas others can experience pain on surgery site. Considering these specific mechanisms is essential to manage pain effectively.

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Common Biological Pathways for the Psychoneurological Symptom Cluster

From the literature reviewed above, it appears that the mechanisms for each of psychoneurological symptoms share common neuromolecular pathways, in particular, proinflammatory cytokines, the HPA axis system, and the 5-HT system (Table 7). Several studies have investigated potential associations between proinflammatory cytokines and 5 symptoms within the psychoneurological cluster. In general, these studies have found that activation of proinflammatory cytokines was associated with each of the psychoneurological symptoms. In addition, the alterations in the HPA axis functioning were linked to depressed mood, fatigue, and sleep disturbance. Alterations in the monoamine neurotransmitter system, including 5-HT, were found to be associated with depressed mood, cognitive disturbance, fatigue, and sleep disturbance. However, the supporting evidence of each of these pathways in relationship to a specific symptom is mostly derived from noncancer populations or animals. Therefore, additional evidence is needed to demonstrate how cancer or its treatment can cause alterations in these pathways and to support how alterations in these pathways induce multiple psychoneurological symptoms simultaneously in cancer patients. Also, further evidence is necessary to demonstrate how these different pathways are related to each other in generating multiple symptoms. Here, we provide evidence that further supports the role of these pathways in the psychoneurological symptom cluster in cancer patients using studies of sickness behaviors, pharmaceuticals, and interactions among proinflammatory cytokines, the HPA axis system, and the 5-HT system.

Table 7
Table 7
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SICKNESS BEHAVIORS: SUPPORT FOR PROINFLAMMATORY CYTOKINES

Similarities in the symptom profile of sickness behavior and the psychoneurological symptom cluster in cancer patients support the hypothesis that proinflammatory cytokines may be one of the possible common biological pathways that underlie this symptom cluster.3,169 It also provides a new perspective on symptoms in cancer patients (ie, looking at multiple symptoms as a single entity).170

Release of proinflammatory cytokines, such as IL-1, IL-6, TNF-α, and interferons, results in a pattern of psychoneurological symptoms, including depressed mood, anhedonia, fatigue, cognitive disturbance, anorexia, decreased activity, sleep disturbances, and increased sensitivity to pain.170,171 Collectively, these symptoms are called “sickness behavior” as they commonly represent behavioral and physiological changes that are observed in individuals with an infection. Empiric data indicate that humans and animals who receive cytokine-producing substances or exogenous cytokines tend to exhibit these behavioral changes.46,61,101,172,173

Endogenous proinflammatory cytokines are released peripherally in response to infection, neoplastically transformed cells, and/or cells damaged by CTX and RTX.170 In fact, studies have reported increased levels of cytokines in cancer patients,174,175 the production of cytokines from tumor tissue,176 and the production of cytokines in response to RTX or CTX in vivo and in vitro.177–179 Cytokine signals are then transmitted to specific brain regions180 (a) by passing through regions where a blood-brain barrier (eg, circumventricular area) is lacking,181 (b) by active transport in brain endothelium,180 (c) by secretion from brain endothelial cells,182 and/or (d) by activation of afferent nerve fibers, such as the vagus nerve, which transmit cytokine signals to brain nuclei.183 The exact signaling pathways through which cytokines produce symptoms in the brain remain unknown.

Treatment strategies based on sickness behavior were proposed both for the symptom cluster in cancer3,170 and for single symptoms.184 For example, Burks184 suggested the use of a drug that antagonizes the cytokine mechanisms (eg, nonsteroidal anti-inflammatory drugs, selective cyclooxygenase 2 inhibitors) to decrease cancer-related fatigue. Lee et al3 proposed to investigate the inhibitor of nuclear factor κB as a treatment target that may link between the expression of proinflammatory cytokines and the production of cancer-related symptoms. Miller170 recommended investigations of cytokine antagonists and drugs that target corticotrophin-releasing factors and inflammatory mediators (ie, prostaglandins) as treatments for multiple cancer symptoms. Because the role of the cytokine system in cancer and its treatment is complex and not completely understood, the development of safe and effective treatments will need to proceed with caution.

At this point in time, studies of sickness behavior suggest a number of directions for oncologic symptom research, in order to clarify the roles of proinflammatory cytokines and other biological components in symptom experience. For instance, it may be necessary to identify the specific subgroups of patients with psychoneurological symptoms who would benefit most from anticytokine agents. Whereas some patients have all of the symptoms of sickness behavior, others have none, and still others have different combinations of symptoms.185,186 In addition, symptoms in cancer patients have different patterns across their illness and treatment trajectory.187,188 These findings suggest that more complex biochemical pathways may be involved in the development of symptom clusters in cancer patients.

A clearer understanding of the nature of the biological mechanisms that underlie the symptoms associated with sickness behavior will facilitate the development of new treatments in oncology patients. Most studies of sickness behavior were conducted in animal models. Therefore, these findings may not be translated directly to humans. In addition, behavioral and biological changes in sickness behaviors in animals (ie, fever, activity level, nociception, sleep disturbance) are very dynamic, depending on the dose and/or the time lapse since the infusion of a cytokine substitute or exogenous cytokine.189–191 For instance, hyperalgesia with motor hyperexcitability in the early phase and hypoalgesia with low motor activity in the late phase were observed in animal sickness behavior.190 Thus, a need exists to examine, in terms of symptom profile, which phase of animal sickness behavior corresponds to which symptoms in specific cancer patient populations (eg, patients with a certain type of cancer, patients in a certain stage of the disease, or patients undergoing treatments). It is also necessary to examine whether biological mechanisms that underlie a specific phase of sickness behavior coincide with biological changes that are observed in a certain group of cancer patients. Sickness behavior in animals is usually studied after a 1-time (single) exposure to high levels of cytokines. In contrast, cancer patients are often chronically exposed to relatively small amount of cytokines. Therefore, longitudinal studies are needed that correlate symptoms of sickness behavior in humans with acute and chronic changes in cytokine levels that are induced by cancer and its treatment.3,57

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Drug studies: support for monoamine neurotransmitter system

Converging empiric evidence obtained from various studies of psychotropic medications further supports the monoamine neurotransmitter system as a potential common underlying pathway for a psychoneurological symptom cluster. These medications appear to alleviate a variety of psychoneurological symptoms through modulation of the monoamine neurotransmitter system in which 5-HT, norepinephrine, and dopamine interact with each other.192 Below, we provide examples of 2 classes of medications (ie, antidepressants, psychostimulants) that support the role of the monoamine neurotransmitter system in the development of these symptoms.

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Antidepressants: Depressive Symptoms, Fatigue, Pain, Sickness Behavior

The effects of antidepressants on psychoneurological symptoms other than depressive symptoms were examined in a number of studies. The classes of antidepressants include tricyclic and tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and others. Each class has slightly different pharmacologic mechanisms of action, even though all of them modulate serotonin, norepinephrine, and/or dopamine to varying degrees. Several studies suggest that a certain class of antidepressants, if not all, can treat fatigue. For example, drugs that modulate the noradrenergic system or the dopamine system (eg, venlafaxine, bupropion) were reported in small open-label studies to alleviate fatigue.193,194 However, randomized clinical trials that examined the effects of SSRI (a drug that modulates serotonin neurotransmission, such as paroxetine) found that it was not effective in decreasing cancer-related fatigue.195,196 These contradictory findings suggest a direction for future research to address different classes of antidepressants that could be effective in reducing cancer-related fatigue.

Antidepressants, such as tricyclic antidepressants, are effective for treating cancer pain.197 The actions of tricyclic antidepressants include (a) increasing the availability of norepinephrine in synapses; (b) increasing the availability of 5-HT in synapses; (c) blocking postsynaptic α-adrenergic, muscarinic cholinergic, and H1-histaminergic receptors; (d) interacting with opioid receptors; and (e) stabilizing membranes.198 Some of these drug actions may be related to the mechanistic pathways of pain. Another class of antidepressant, mirtazapine (an adrenergic and serotonergic receptor antagonist), was reported to be effective for treating multiple symptoms (ie, pain, depressive symptom, insomnia), particularly in patients with advanced-stage cancer.199,200

Lastly, although the results are inconclusive, findings from animal studies of sickness behavior suggest that antidepressants may decrease symptoms induced by proinflammatory cytokines.47,201–204 However, in human, the administration of SSRI (paroxetine) can decrease depressive symptoms and neurotoxicity induced by IFN-α.46,205 Even if symptoms in sickness behavior are all induced by proinflammatory cytokines, the mood and cognitive symptoms associated with sickness behaviors may have different final biological pathways from the neurovegetative symptoms (eg, fatigue, anorexia).206 Some sickness behavior symptoms (ie, depressed mood, anxious mood, memory disturbances, distractibility, psychomotor retardation, pain) were found to be more responsive to SSRI than others (ie, fatigue, anorexia).46 In the same way, some sickness behavior symptoms (eg mood, cognitive symptoms) were associated with average decreases in plasma tryptophan levels (serotonin precursor) and increases in plasma cortisol and adrenocorticotrophic hormone. However, neurovegetative symptoms (eg, fatigue, anorexia, pain) were not associated with these biological markers.207,208 These findings suggest that proinflammatory cytokines may only be an initiating factor in a sequential process (or cascade) that generates the psychoneurological symptom cluster. Each psychoneurological symptom could follow a divergent pathway (eg, dysregulations in different types of monoamines) at some point in the process.

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Psychostimulants: Somnolence, Pain, Cognitive Function, Depressive Symptoms, Fatigue

Psychostimulants are used to treat attention deficit and hyperactivity disorders.209 Findings from several studies suggest that this class of drugs may be useful to treat psychoneurological symptoms, such as pain, cognitive function, depressive symptoms, and fatigue. Methylphenidate, the most frequently studied psychostimulant, was found to increase dopamine concentration in synapses by inhibiting dopamine reuptake210,211 and to affect other neuotransmitters, such as norepinephrine and serotonin by binding to their receptors.210,211 These drug actions may be directly or indirectly related to the mechanisms of symptoms on which the drug has an effect.

For cancer patients, especially those with end-stage disease, psychostimulants (eg, methylphenidate, pemoline) were found to reduce opiate-induced somnolence,212–214 to potentiate the analgesic effects of pain medications,27,215,216 and to alleviate cognitive impairment.217,218 The effectiveness of methylphenidate for depressive symptoms in cancer patients was reported in case studies,219,220 in a phase II trial,209,221 and in a 1-group posttest design.222 Findings from several clinical studies suggest that psychostimulants, particularly in the case of long-term use, may be effective in managing fatigue in cancer patients,209,223–225 in HIV patients,226 in patients with Parkinson’s disease,227 and in patients with sarcoidosis.228 Recent data suggest that the effect of psychostimulants may be limited to only a subgroup of cancer patients (eg, advanced disease with severe fatigue).229 Additional studies are needed to confirm the effect of psychostimulants on psychoneurological symptoms in cancer patients because the number of studies is small; many studies had methodological constraints (eg, small samples, absence of a control group); and several studies reported the lack of a therapeutic effect.230–232

In summary, antidepressants and psychostimulants appear to have efficacy in the management of multiple psychoneurological symptoms, although more conclusive evidence from rigorously designed studies is required. The efficacy of a drug on multiple psychoneurological symptoms suggests that common neurotransmitter pathways, in particular monoamine neurotransmitters, may underlie the development of these symptoms. Diverse imbalances in monoamine neurotransmissions may contribute to the development of different types of symptoms in cancer patients. For instance, 5-HT dysregulation may induce depressive symptoms, whereas noradrenaline dysregulation may induce fatigue.

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INTERACTIONS BETWEEN CYTOKINES, HPA, AND MONOAMINE NEUROTRANSMITTER SYSTEMS

Proinflammatory cytokines, the monoamine system, and the HPA axis system interact with each other.51,233 Such interactions may have an important regulatory role in the development of psychoneurological symptoms in cancer patients. Proinflammatory cytokines can reduce the synthesis of serotonin by enhancing the activity of indolamine-2.3-dioxygenase, an enzyme that degrades and converts the serotonin precursor to another substance (ie, kynurenine).234–237 By converting serotonin precursor to another substance, inflammatory cytokines can decrease serotonergic neurotransmission. Interferon α treatment–induced sickness behavior responds to antidepressants, which mostly modulate the serotonin system. This finding further supports the interaction between cytokines and the monoamine system.46,205

Associations between cytokines and the HPA axis have been reported.102 Glucocorticoids can directly and indirectly inhibit proinflammatory cytokine production.238 Conversely, proinflammatory cytokines can activate the HPA axis, possibly through modulation of 5-HT and norepinephrine pathways.51,239,240 Serotonin and its diverse receptors are involved in the regulation of the HPA axis.241 Stress-induced HPA axis activation is in part mediated through the 5-HT receptor system.241,242

Although inflammatory cytokines, the monoamine neurotransmitters, and the HPA axis interact with each other; the exact directional relationships among the 3 that would contribute to the development of symptoms remain to be determined. The present review proposes that proinflammatory cytokines induced from cancer or its treatment may be the first step in the generation of the psychoneurological symptom cluster in cancer patients. Proinflammatory cytokines may produce different types of symptoms by differently modulating the HPA axis system as well as the production of monoamines (Figure). The occurrence as well as the intensity and types of symptoms within the psychoneurological symptom cluster may be influenced by the location within the brain where the alterations in cytokines, HPA axis, and/or monoamine neurotransmitters occur. Another factor that can influence an individual’s response could be the receptor types to which such molecular elements bind. Genetic variations may also explain interindividual differences in the symptom cluster experience, by influencing the modulation of cytokines, monoamines, and the HPA system. Based on the overall evidence summarized in this review, all of these factors warrant investigation to determine their roles in the psychoneurological symptom cluster.

Figure. Proposed com...
Figure. Proposed com...
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Discussion and Conclusions

The evidence is mounting that supports the tendency for a number of psychoneurological symptoms to cluster in cancer patients (Table 1). However, symptoms that make up a psychoneurological cluster vary somewhat across studies possibly because of differences in study designs. As for the psychoneurological cluster, this review chose to focus on depressed mood, cognitive disturbance, fatigue, sleep disturbance, and pain because these symptoms were the most common symptoms identified through empiric studies.

The present review describes 3 common biological pathways that may underlie the development of this psychoneurological cluster in oncology patients. In this article, as illustrated in the Figure, the role of proinflammatory cytokines is hypothesized as the initial activating factor in the generation of this symptom cluster. A recent study further supports this hypothesis in that the release of systemic proinflammatory cytokines after allogeneic hematopoietic stem cell transplantation coincided with the worsening of treatment-related psychoneurological symptoms (ie, pain, fatigue, drowsiness, sleep disturbance).243

However, the possibility that other biological factors (eg, hormonal factors) are involved cannot be ruled out. For example, expanding knowledge of the role of estrogen in the brain suggests that female breast cancer patients may experience multiple psychoneurological symptoms induced by hormonal changes due to cancer treatments. Estrogen is involved in various psychoneurological symptoms including mood, locomotor activity, pain sensitivity, and cognition.244,245 Also, hot flashes in breast cancer patients are an ultimate product of estrogen withdrawal, and changes in 5-HT are thought to be involved in its final pathological mechanism.246 Therefore, another possible scenario is that the psychoneurological cluster observed in women during and after treatment for breast cancer may be due to reduced ovarian function and lowered levels of estrogen.

In some groups of cancer patients, lower hemoglobin levels may be the initial factor that induces psychoneurological symptoms. In fact, in a study of patients undergoing CTX, a cluster of symptoms (ie, fatigue, loss of appetite, sleep disturbance, interference with function) was alleviated following treatment of the anemia with darbepoetin α.247

In addition to biological factors, psychosocial factors, such as stress, may produce the psychoneurological symptom cluster through disruption of HPA axis pathways. In a small longitudinal study (n = 11 with stage II breast cancer receiving CTX; 11 healthy women), alterations in biomarkers of the HPA axis were linked with the development of fatigue, sleep disturbance, and depressive symptoms.248 Additional evidence suggests that stress may activate the HPA axis by increasing 5-HT levels in the brain.242

Taken together, the evidence suggests that various biological and psychological factors can initiate psychoneurological symptoms in cancer patients. Proinflammatory cytokines may induce psychoneurological symptoms in at least subgroups of cancer patients. An examination of subgroups of patients with a unique psychoneurological cluster experience and their biological associates will expand our understanding of the biological mechanisms that underlie this cluster and will facilitate the development of effective interventions that can treat multiple symptoms simultaneously in specific subgroups of cancer patients.

The proposed pathways described in this article suggest a number of directions for future studies. For example, studies are necessary to confirm the role of cytokines as well as other possible biological factors in the generation of the psychoneurological symptom cluster.

To confirm the role of cytokines, the next generation of research needs to clarify the cutoff levels at which cytokines result in symptoms and determine which cytokines are useful biomarkers that can be used to identify patients who are at higher risk for more severe symptoms. Future studies need to include a wide range of cancer diagnoses and/or to adopt longitudinal prospective studies or randomized clinical trials with cytokine or anticytokine treatment. The development of proper animal models and translation of preclinical study findings into clinical findings are important issues to consider in the design of future studies.3 This type of research may lead to the development of interventions that can be tested in clinical studies. Although this review focuses on the biological aspects of the symptom experience, psychological, sociocultural, and behavioral aspects cannot be overlooked.249 Future studies can be guided by theoretical frameworks that include the complex relationships among multiple mechanisms that may underlie the development of one or more symptom clusters.

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Keywords:

Biological mechanism; Cancer; Sickness behavior; Symptom cluster; Symptom management

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