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Psychosomatics 49:283-291, July-August 2008
doi: 10.1176/appi.psy.49.4.283
© 2008 Academy of Psychosomatic Medicine
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Review

Cancer Fatigue: A Neurobiological Review for Psychiatrists

Mitchell R. Levy, M.D.

Received November 6, 2006; revised April 13, 2007; accepted April 24, 2007. From the Dept. of Psychiatry, Univ. of Washington, Seattle, WA. Send correspondence and reprint requests to Mitchell Levy, M.D., Dept. of Psychiatry, Univ. of Washington, 4225 Roosevelt Way, Suite 306, Seattle, WA 98105. e-mail: mrlevy{at}u.washington.edu
© 2008 The Academy of Psychosomatic Medicine


  ABSTRACT

 
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BACKGROUND: Fatigue, both during and subsequent to treatment, is a ubiquitous and debilitating phenomenon for patients undergoing treatment for cancer of all types. OBJECTIVE: This review will focus on understanding the complex neurobiological mechanisms underlying the phenomenon of cancer-related fatigue (CRF) and their relevance for various treatment routes. METHOD: The review will describe the prevalence of CRF, differential diagnosis, consideration of neurobiological mechanisms, and routes for intervention. DISCUSSION: The review will provide suggestions for future study and research, and a future article will describe behavioral and educational strategies psychiatrists may use in alleviating cancer fatigue.

Key Words: Cancer • Fatigue • Cytokines • Interferon • Neuropsychiatry

  DEFINITION AND EPIDEMIOLOGY

 
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Cancer fatigue is defined as: "a subjective inability to maintain effort, of a markedly different quality and severity from ordinary fatigue, adversely impacting function and unrelieved by rest or sleep."1 With the mounting armamentarium available to treat cancer (and consequent survival rates), psychiatrists are increasingly called upon for help with management of conditions related to oncological treatment. Although most psychiatric practitioners may feel comfortable with the diagnosis of depression and anxiety disorders related to cancer treatment, they may be less conversant with fatigue, an important contributor to patient disability both during and subsequent to treatment. Passik et al.,2 in a recent survey, reported that 43% of cancer patients had little awareness that there were interventions to assess and treat their fatigue. This review will provide an overview of issues related to intra- and posttreatment fatigue, analysis of proposed neuropsychoimmunological pathways involved in pathological cancer fatigue, and routes for intervention.

Patients treated for cancers of nearly all types report fatigue as a consistent and disabling issue in treatment. Wide ranges in patient age, medical comorbidity, cancer type, and treatment pose challenges in screening for fatigue. Although acknowledging these difficulties, Prue et al.,3 in a comprehensive recent review, suggest that rates of fatigue as high as 90% have been reported for those undergoing treatment for various types of cancer. Within the relatively homogenous and well-studied population of patients being treated for breast cancer, most patients’ fatigue levels will markedly increase during the course of cancer treatment.4 For patients undergoing treatment for breast cancer, exposure to radiotherapy versus chemotherapy has been variably linked with fatigue symptoms.3,5,6 More clearly correlated with complaints of fatigue during breast cancer treatment are symptoms of both depression and anxiety.7,8 Further exacerbating factors for cancer-related fatigue (CRF) include pain, sleep disruption, and anemia.9–11

With very few exceptions,12–14 studies also describe patients’ reporting high levels of fatigue after treatment for cancer. As with patients actively undergoing treatment, challenges to quantifying rates and severity of fatigue relate to heterogeneity of cancer types, patient variation, and differences in cancer treatment. Reviewing those studies with standardized ratings methods for CRF after treatment, Prue et al.3 summarized evidence of fatigue rates in the range of 17%–38%. These elevated rates of fatigue may be sustained several years after treatment.15 Among breast cancer patients, rates of fatigue have been described as alternately increased16 and decreased, specifically after radiotherapy.7,17–19 Chemotherapies, and particularly, the intensive myeloablative regimens utilized in stem-cell treatments for breast cancer, are more consistently associated with elevated posttreatment CRF.20–22 As in patients undergoing treatment, levels of CRF are increased by pain and impaired sleep.23,24 Longer-term fatigue may lead to adverse impacts on patients’ quality of life and a delayed return to work.25–27


  MEASUREMENT AND SCREENING

 
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The measurement of fatigue faces the challenge of correlating subjective reports by patients and caregivers with objective assessment of decrease in mental and physical performance.28 Within populations of ill individuals, researchers have struggled to define or classify a subjectively-reported process—whether to measure the completion of a prolonged effort or an increased "subjective cost" to that work performed.29 Whereas reports of nonpathological fatigue correlate with impairment in cognitive performance and higher-level executive functioning, it is less clear that this relationship holds for medical patients.30,31

In the assessment of CRF, researchers have used instruments either gauging fatigue as a single or multidimensional concern.32–34 Typical scales ask patients for their subjective feeling and fatigue level, its impact on their daily life, and aspects of mental versus physical components of fatigue. Such instruments are subject to the biases of recall and subjective reporting and may or may not correlate with objectively-assessed difficulties in functioning.38 More recent surveys on CRF have attempted to assess fatigue by use of comprehensive rating scales and in comparison to control populations.35 See Table 1 for a summary of various cancer fatigue rating scales.


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TABLE 1. Instruments Commonly Used in Assessment of Cancer-Related Fatigue



Researchers have described CRF as a multidimensional construct having physical, cognitive, and emotional aspects. Proposed ICD–10 criteria have been put forth to aid with diagnosis and to help differentiate CRF from similar disorders, such as major depression (see Table 2).36,37 A preliminary study by Young and White38 supported the validity of these suggested criteria and highlighted the degree to which cognitive distortions about activity and levels of psychological distress may correlate with elevated rates of CRF.


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TABLE 2. Draft ICD–10 Criteria for Cancer-Related Fatigue (CRF)



Differential Diagnosis: Fatigue or Depression?
Differential diagnosis of CRF with other overlapping psychiatric disorders, particularly major depression, presents a challenge. Many symptoms consistent with global medical illness overlap prominently with those of depression (see Table 3). Prevalence rates for depression in cancer patients are also quite high, with ranges from 1.5% to 53% reported.39,40 Median point-prevalence rates for depression in cancer patients range from 22% to 29%;41 and both symptom clusters may exist in some patients.


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TABLE 3. Symptoms of Global Medical Illness Overlapping With Those of Depression



Researchers have stressed either "inclusive" or "exclusive" approaches for diagnosing depression in oncology patients. Inclusive methods allow for diagnosis of depression with the presence of symptoms of medical illness included in totaling criteria for major depressive disorder.42 Exclusive approaches suggest substituting complaints such as hopelessness or social withdrawal in place of neurovegetative symptoms potentially due to illness.43 The use of brief structured interviews44 or patient self-reports in screening for depression45 has been advocated, as well. Some instruments have focused on the specific population of depressed, medically compromised inpatients.46–49

As Guo et al.50 point out, the challenge for clinicians in the oncology setting is the frequent overlap of cancer-related weight loss, poor concentration, fatigue, and sleep disruption with those of depression. Their group suggests a modified version of the Hamilton Rating Scale for Depression (Ham–D), highlighting items such as: late insomnia, agitation, psychic anxiety, diurnal sleep variation, depressed mood, and sexual symptoms as useful to screen out depression.50 Reuter et al.51 emphasize the cognitive/affective component to diagnosing depression, with their group finding "loss of interest" and depressed mood as diagnostic elements. In contrast to some studies, they also found complaints of fatigue to aggregate with depression.51 Finally, many screening instruments and studies may be less sensitive for diagnosing depression among different ethnic, racial, and cultural groups.52

Clearly, patients may present as experiencing significant CRF and also fulfilling criteria for major depression.53 Depression has been associated with elevated levels of CRF in a breast cancer cohort by Reuter et al.54 and in hematopoietic stem-cell transplant by Prieto et al.55 The relationship between depression and CRF may be bidirectional and may also imply a shared mechanism.56 Cytokines implicated in neurovegetative symptoms and fatigue have been associated with high rates of depression, most notoriously in treatments involving interferon-{alpha}1B (IFN-{alpha}).57 Elevated levels of immune activation, particularly, soluble interleukin-2 (IL-2) receptor and IL-6, may be risks for depressive states induced by interferon treatment.58 Conversely, such mood changes related to interferon administration are then sensitive to antidepressant medications targeting changes to CNS functioning. Depression prophylaxis for patients undergoing interferon treatment has been shown to be effective.59 Given adverse impacts of depression on illness and self-care,60 Raison et al.61 argue for identification and treatment of even subsyndromal depression, given the relative safety of modern antidepressants.

There is some debate as to whether antidepressants may relieve aspects of fatigue and "sickness syndrome" independent of improvement in mood.62 The timing of depression may often antecede fatigue in those patients exposed to IFN-{alpha}. Also, the differential responsiveness of depression versus fatigue to antidepressant treatment suggests some degree of diverging etiologies. Depressive symptoms often respond to treatment with pharmacotherapy with little change in symptoms of fatigue.63,64 Therefore, CRF is not explained entirely by the presence of psychiatric disturbance alone.65 However, certain coping styles and psychological distress have been associated with CRF. Catastrophizing, defined as persistent negative thoughts about self and the future, has been connected with higher levels of fatigue in some,66 but not all studies.5,20 This was found to be particularly so for women undergoing radiotherapy for breast cancer.67


  PROPOSED ETIOLOGY

 
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Neuroendocrine: Are Cytokines the Culprit?
Alterations of normal homeostatic body function for prolonged periods have been termed "allostasis." States such as CRF may represent imbalances in inflammatory and inhibitory mechanisms induced by cancer treatment.68 The role of cytokines, low-molecular-weight proteins mediating cellular communications, has been repeatedly implicated in aspects of CRF. Released in the peripheral circulation by tumor-cell lysis or through host inflammatory responses, cytokines are involved with immunologic mediation of cellular proliferation, immune-cell differentiation, and gene activation.69 Although likely pleiotropic in actions, cytokines are typically viewed as either predominantly mediating pro-inflammatory responses: interleukin (IL)-1, IL-6, and Tumor Necrosis Factor-{alpha} (TNF-{alpha}); or promoting anti-inflammatory actions: IL-4, IL-10, and IL-13.70

Most particularly relevant to induction of fatigue, the inflammatory cytokines are associated with so-called "sickness behavior"71—loss of energy and motivation, sleep and appetite changes, and decrease in exploratory and mating behaviors.72 A similar spectrum of behaviors is also associated with induction of agents that subsequently induce pro-inflammatory cytokines, such as bacterial endotoxin or lipopolysaccharide.62 In some studies, elevated levels of CRF have been reported in association with increased serum measurements of pro-inflammatory cytokines.73–76 This relationship has not been found consistently in all studies, however.77–79

The influence of relatively large inflammatory cytokines on the CNS may occur via several mechanisms. Their effects on the CNS may occur either through the crossing of the otherwise limiting blood–brain barrier (BBB) directly via carrier-mediated transport,80 or, alternatively, crossing at circumventricular organs, entering in regions where the BBB is absent or weak. Cytokines may then subsequently communicate with neural structures.81 Inflammatory cytokines may also induce second-messenger signaling (such as endothelial-cell adhesion molecules, chemokines, nitric oxide, and prostaglandins) in binding to vascular endothelium cells and further degrading BBB integrity.82 CNS microglia may secrete cytokines, which further impair the integrity of the BBB and allow for the passage of leukocytes into the CNS, releasing inflammatory mediators.83 Also, cytokines have been demonstrated to alter neurotransmission in the CNS via the afferent vagus nerve root.84 Finally, it has recently been found that cytokines are released by glial cells within the CNS, which may be induced to express inflammatory mediators under conditions of stress.85 (Such interactions are likely bidirectional, with CNS communication with peripheral immune cells and inflammatory mediators).86

Several models have been generated to explain the mechanism of cytokine effects and related symptoms. Cytokines may function via corticotrophin-releasing hormone (CRH) and stimulation of the hypothalamic–pituitary axis (HPA).87,88 Studies have demonstrated the induction of CRH from the hypothalamus generated by cytokines IL-1 and IL-6.89,90 CRH effects include the induction of adrenocorticotropin hormone (ACTH) and glucocorticoid hormones from the adrenal medulla. Supporting this hypothesis, CRH alterations have been linked to aspects of "sickness behavior" in animal studies.91 As additional evidence for HPA dysregulation, Bower et al.92 related disruption of intrinsic cortisol diurnal rhythms to increased levels of CRF.

Typically, glucocorticoid hormones are involved with suppression of inflammatory immune-system activity. The action of cytokines may engender resistance in tissues to the anti-inflammatory actions of glucocorticoid hormones and subsequently perpetuate an inflammatory response.93 Alternatively, the mechanism of action for fatigue behaviors may relate to cytokine effects on CNS monoamine function. These neurotransmitters include, specifically, norepinephrine, serotonin, and dopamine.94 Functioning of the monoamine serotonin system has been shown to be altered by cytokine activity: IFN-{alpha} has been associated with reduction in serum L-tryptophan, a serotonin precursor. This may occur via changes in the metabolic enzyme idolamine 2,3-dioxygenase, responsible for the breakdown of tryptophan to kynurenine.95–97 Alterations in neurotransmitter functioning may occur at other points in their functional cycle. Recently, using a mouse model, Zhu et al.98 demonstrated that IL-1β and TNF-{alpha} affected serotonin transporter activity (SERT) in the dorsal raphe area of the brainstem.98,99

Neurophysiologic: Disrupted Pathways
The understanding of neural circuitry involved with pathologic states in psychiatry such as depression and obsessive–compulsive disorder, has been tremendously enhanced by functional neuroimaging studies. These techniques have yet to be used in the understanding of CRF. However, some suggestive studies, primarily of other medical conditions, have attempted to correlate states of fatigue with changes in brain state. Filippi et al.,100 using functional MRI (fMRI), studied fatigue states occurring secondary to multiple sclerosis. Their work linked fatigue with regions of decreased frontal and basal ganglia perfusion. Furthermore, although cognition in fatigue states may be maintained, more strongly diffuse cerebral activation as a compensatory strategy has been seen in fMRI in other conditions, such as traumatic brain injury and chronic fatigue syndrome.

Deluca101 has proposed an impairment of coordination between cerebral-cortical and subcortical systems as underlying clinical fatigue. Areas of the basal ganglia project fibers to both prefrontal cortex (striatocortical) and thalamus (striatothalamocortical). Diverse insults, related to immune, neuroendocrine, and cytokine activity may affect sensitive basal ganglia regions. Support for the idea of cytokines’ impact on regional cerebral blood flow was recently demonstrated via changes noted in single-photon computed tomography (SPECT) imaging after the administration of exogenous interferon.102 Alterations in functioning through both basal ganglia and thalamic pathways may then suppress prefrontal cortical activity. This may represent a "final common pathway" for cancer and other chronic fatigue states.103

Psychopharmacological Treatment: Interrupting the Cascade
Neuroprotective agents to ameliorate the impacts of cancer treatments, including CRF, are under increasing investigation. Working downward through the inflammatory cascade, several possible levels exist for intervention (see Figure 1). At the point of cytokine release and activation, treatments may potentially include compounds that inhibit cytokine actions. In addition to fatigue, enhanced pain facilitation is a demonstrated component of "sickness behavior." Research exploring the role of activated CNS glial cells in states of exaggerated or prolonged pain has suggested the possibility of interrupting the inflammatory cytokine process.85,104 Cytokine IL-1 receptor-antagonists and soluble TNF-receptor infusion have been explored for reducing peripheral nerve pain.105,106 Similarly, other mediators, such as the n-3 fatty acids provided in supplementation and prostaglandin inhibitors, may assist in reducing the inflammatory cytokine response.107–109 Mediated through the level of the glucocorticoid receptor, the agent rolipram has demonstrated anti-inflammatory benefit through inhibition of TNF-{alpha}.110 Last, at the level of the brain, CRH-antagonists111and monoamine modulators may lessen an exaggerated CNS response to inflammation.


Figure 1
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FIGURE 1.  The Inflammatory Cascade


Treatments at the level of neurophysiological response represent the next level for intervention. Interruption of the symptoms related to sickness behavior may relieve CRF with treatments currently available. For example, anemia, related in part to cytokine-mediated impairments in erythropoiesis, has been associated with increased levels of CRF.112–114 Treatment of anemia either with transfusion or recombinant erythropoietin has been associated with reductions in CRF.115,116 In addition to its role in improving hematologic indices, erythropoietin may also provide benefits in reducing adverse cytokine actions and neural damage from cancer treatments.117 Recombinant erythropoietin or nonhematopoietic variants may protect against neurotoxic and oxidative damage that generates fatigue states.118

The National Comprehensive Cancer Network (NCCN) and other groups have highlighted the need to address and treat contributors to fatigue, such as insomnia, depression, and pain. These guidelines are generated from information grounded on current expert opinion, case studies, and predominantly open clinical-trial data. Selective serotonin-reuptake inhibitors are typically recommended as first-line agents to address coexisting depression and anxiety.119 The use of more activating antidepressants, such as bupropion or duloxetine, to address components of both depression and CRF may be therapeutic, as well.120,121 Reviews have also suggested benefits to addressing depression with sedating tricyclic antidepressants when insomnia, commonly present in fatigue states, is a concern.122 Provocatively, antidepressant agents modulating serotonin and norepinephrine have shown effects reducing pro-inflammatory cytokine activity both in-vitro and in animal models.123–125 For example, in-vitro antidepressants of different classes have initiated reductions in IFN-{gamma} levels and increases in anti-inflammatory IL-10.126 It is less clear to what extent these effects are related to monoamine changes or how conclusively and consistently such effects are demonstrated.127

After addressing comorbid medical issues and instituting behavioral approaches (which will be discussed in a forthcoming paper by this author), NCCN guidelines also suggest the role of pharmacological adjuncts specifically to relieve CRF. More limited evidence, based primarily on open trials, is available to support the role of stimulants, although they are commonly used clinically.128,129 Methylphenidate has been suggested at dosages divided daily up to 1 mg/kg; results based on controlled trials have been equivocal about efficacy for CRF.130 Used with success for treating fatigue secondary to multiple sclerosis, the stimulant modafinil, modulating the neurotransmitter hypocretin, has been suggested for use in CRF.131,132 Corticosteroid adjuncts have been shown beneficial in cancer-related weight loss and wasting syndromes and are often used broadly as a class of agents for cachexia.133,134 Specifically, megestrol, an exogenous synthetic progesterone, has shown some benefit in alleviating fatigue in cancer patients.135 Steroid hormones may function by supplanting reductions in HPA functioning or blocking inflammatory cytokine activity.136


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Additional research is warranted to address the underlying neurocircuitry involved in CRF. Studies utilizing finer-resolution functional neuroimaging tools or newer modalities, such as magnetic resonance spectroscopy, could delineate areas of interest and changes with fatigue resolution. Some questions for further research include the following: How can factors related to the inflammatory mediators and their contribution to CRF be quantified and understood? Analogously to interventions for inflammatory pain disorders, at what level should interventions be targeted, and at what stage of treatment, to interdict the fatigue process? What role should stimulants play in treating CRF? Last, what interventions during cancer treatments might later help protect at-risk patients and prevent fatigue? What premorbid or treatment-associated factors may sensitize patients to CRF? There is much work yet to be done in improving the quality of the lives that cancer researchers have so admirably lengthened.


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