Fatigue in Cancer Patients and Survivors: Mechanisms and Treatment

Julienne E. Bower, PhD

Dr. Bower is assistant professor in the Department of Psychiatry and Biobehavioral Sciences at David Geffen School of Medicine at the University of California, Los Angeles, and research scientist in the Cousins Center for Psychoneuroimmunology at the UCLA Neuropsychiatric Institute.

Disclosure: Dr. Bower reports no affiliation with or financial interest in any commercial organization that might pose a conflict of interest.

Funding/support: This work was supported by a Career Development Award from the National Cancer Institute (grant no. K07 CA09047) awarded to Dr. Bower.

Please direct all correspondence to: Julienne E. Bower, PhD, Cousins Center for Psychoneuroimmunology, 300 UCLA Medical Plaza, Rm 3306, Los Angeles, CA 90095-7076; Tel: 310-794-9383; Fax: 310-794-9247; E-mail: [email protected].

Abstract

Fatigue is one of the most common and distressing side effects of cancer and its treatment, occurring in approximately 60% to 96% of cancer patients. Cancer-related fatigue is more pervasive, debilitating, and longer lasting than normal fatigue and is not relieved by adequate sleep or rest. The mechanisms underlying fatigue in cancer patients and survivors are not known, although correlates of fatigue have been identified. Emerging evidence suggests that pro-inflammatory cytokines are involved in cancer-related fatigue. Psychological factors are also strongly correlated with fatigue, particularly depressed mood. However, cancer-related fatigue cannot be explained entirely by depression. Exercise and psychoeducational interventions are effective in reducing fatigue and improving quality of life during and after cancer treatment.

Introduction

With advances in detection and treatment, survival times for many cancers have increased significantly in recent years. In 1971, there were approximately 3 million cancer survivors in the United States; by 2001, this number had increased to 9.8 million.¹ As survival times increase, addressing the impact of cancer and its treatment on long-term outcomes has become increasingly important. In particular, better understanding and management of cancer-related symptoms is critical for reducing suffering and improving quality of life in cancer survivors.

Fatigue is one of the most common and distressing side effects of cancer and its treatment. An emerging literature has examined the prevalence and correlates of cancer-related fatigue and the efficacy of treatments designed to reduce fatigue in cancer patients and survivors. This article will review the literature on cancer-related fatigue, focusing on potential psychological and biological mechanisms and the association between fatigue and depression. In addition, research on treatments for fatigue will be considered.

Prevalence of Fatigue

Studies have shown that approximately 60% to 96% of cancer patients experience fatigue at some point during the course of cancer treatment.² Fatigue has been documented across a range of different types of cancer and cancer treatments, including radiation therapy, chemotherapy, bone marrow transplant, and biological response modifiers. The intensity and duration of fatigue experienced by cancer patients during treatment is significantly greater than that experienced by healthy controls.³ Perhaps more important, fatigue causes significantly more disruption in the lives of cancer patients than healthy controls.⁴ In a nationwide survey of cancer patients, over 50% reported that fatigue affected their ability to work, their physical and emotional well-being, their social activity, and their ability to enjoy life in the moment.⁵

Although fatigue typically declines after completion of cancer treatment, there is growing evidence to suggest that fatigue may persist for months or even years in a substantial minority of patients. Bower and colleagues⁶ found that approximately 30% of breast cancer survivors reported significant fatigue an average of 3 years after cancer diagnosis. A similar high incidence of fatigue (26%) was found in a large cohort of Hodgkin’s disease survivors assessed at an average of 12 years after treatment.⁷ Consistent with research conducted with cancer patients during treatment, fatigue has a detrimental impact on all aspects of quality of life in cancer survivors.^6,8

Definition and Mechanisms

Fatigue is a nonspecific, multidimensional construct that is generally thought to involve subjective feelings of tiredness, weakness, and/or lack of energy. Cancer-related fatigue differs from “normal” fatigue due to lack of sleep or overexertion in several ways. First, fatigue in cancer patients is more pervasive, more debilitating, and longer-lasting. Second, it involves physical, mental, and emotional fatigue. Third, cancer-related fatigue is not relieved by adequate sleep or rest. These components are captured in a description of fatigue⁹ provided by an oncologist and cancer survivor:

During cancer therapy, I always felt the exhaustion of prolonged exercise but without any positive attributes. . . . My limbs felt heavy. The quality of my sleep was changed. The mere act of sleeping itself seemed like work sometimes. . . . My brain felt tired and so did my spirits. I seemed to have lost my zest for life.

In 1998, a multidisciplinary group of medical practitioners, researchers, and patient advocates developed diagnostic criteria to define a syndrome of cancer-related fatigue.¹⁰ The key criteria were significant fatigue, diminished energy, or increased need to rest, disproportionate to any recent change in activity level that is present every day or nearly every day during the same 2-week period in the last month. Examples of other symptoms include weakness or heaviness, diminished concentration or attention, decreased motivation or interest in usual activities, unrefreshing or nonrestorative sleep, and postexertional malaise. These symptoms must cause clinically significant distress or impairment, result from cancer or cancer treatment, and cannot be primarily caused by a comorbid psychiatric disorder.

Despite its prevalence, the mechanisms that underlie the onset and persistence of cancer-related fatigue have not been determined. Investigators have proposed that fatigue may be caused by the disease itself, by treatments for the disease, by physical symptoms or conditions resulting from the disease or its treatment, by psychological responses to cancer, and by comorbid medical conditions (Table 1).¹¹ Interestingly, disease and treatment-related factors are not consistently associated with fatigue. For example, research conducted with breast cancer patients has shown no relationship between fatigue and initial disease stage, type of surgery, length of chemotherapy treatment, or use of tamoxifen.^8,12,13 There is mixed evidence for an association between receipt of adjuvant chemotherapy and fatigue in breast cancer patients; several studies have not found significant differences between patients treated with surgery, radiation therapy, and/or chemotherapy,⁶ while others have documented higher levels of fatigue among former chemotherapy patients compared to those treated with radiation therapy alone.¹⁴

Biological Correlates of Fatigue

Several studies have examined biological correlates of fatigue, with mixed results. There is some evidence that low hemoglobin is associated with increased fatigue¹⁵ and, among anemic patients, increases in hemoglobin following treatment with darbepoetin-a are associated with improvements in fatigue and quality of life.¹⁶ However, the association between fatigue and hemoglobin is typically modest and has not been documented in all studies.¹⁷ Moreover, low hemoglobin does not explain all of the variance in fatigue even in the positive reports.^15,18 Low serum albumin has also been correlated with cancer-related fatigue in a study conducted with patients undergoing treatment for leukemia and non-Hodgkin’s lymphoma.¹⁹

Another potential biological mechanism for cancer-related fatigue may come from changes in the immune system induced by cancer or cancer treatment, including release of pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Basic research²⁰ on neuro-immune signaling in animal models has shown that inflammatory stimuli can signal the central nervous system to generate fatigue, as well as changes in sleep, appetite, mood, and social/sexual behavior. Conversely, antagonists or synthesis blockers of cytokines abolish these effects. In cancer patients, pharmacologic doses of cytokines (eg, immunotherapy with IL-2) lead to fatigue, decreased activity, sleep disturbance, depressed mood, and pain.²¹ Similarly, it appears that acute induction of cytokines in healthy individuals has behavioral effects, leading to fatigue, depressed mood, anxiety, and cognitive and sleep disturbance.^22,23

Investigators have begun to examine the role of pro-inflammatory cytokines and the cytokine network in cancer-related fatigue. In an early study conducted with prostate cancer patients,²⁴ fatigue and serum levels of IL-1β both increased during radiation therapy. A positive correlation between inflammatory markers and fatigue has been documented in more recent research conducted with breast and lung cancer patients undergoing chemotherapy.²⁵ However, fatigue was not correlated with changes in pro-inflammatory cytokines in breast cancer patients undergoing radiation therapy.¹⁷

It may be difficult to detect an association between fatigue and pro-inflammatory cytokines during cancer treatment when the immune system is rapidly responding to tissue damage and other treatment-related changes. Thus, evaluation of cancer survivors may yield a clearer picture of the relation between cytokines and fatigue. Bower and colleagues²⁶ compared breast cancer survivors with persistent fatigue to a control group of nonfatigued survivors. Both groups had completed treatment at least 2.5 years previously and were disease-free, with no immune-related medical conditions. Fatigued survivors showed significant elevations in several markers of pro-inflammatory cytokine activity compared to nonfatigued controls, including IL-1 receptor antagonist, soluble TNF receptor type II, and neopterin. These molecules can be measured more reliably in serum than the pro-inflammatory cytokines that induce their production, and may provide a better measure of cytokine activity. Elevations in inflammatory markers were coupled with elevations in CD4⁺ T-lymphocytes, suggesting a chronic inflammatory process involving the T-cell compartment.²⁷ Fatigued survivors also reported behavioral changes consistent with pro-inflammatory cytokine activity, including depressed mood, sleep disturbance, decreased activity, and cognitive disturbance.²⁶

There are several mechanisms through which chronic inflammation might develop or persist in cancer patients, including alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Adrenal cortex-derived steroids have potent effects on pro-inflammatory cytokine production and activity,²⁸ and disturbances in HPA-axis function have been observed in other conditions characterized by inflammation and fatigue.²⁹ There may be a dysregulation in HPA axis responsiveness among breast cancer survivors with persistent fatigue. Fatigued survivors show lower levels of morning serum cortisol,²⁶ flattened diurnal cortisol slopes,³⁰ and a blunted cortisol response to acute psychosocial stress compared to nonfatigued controls.³¹

Fatigue and Depression

Fatigue often co-occurs with physical and psychological symptoms in cancer patients, including menopausal symptoms, pain, and sleep disturbance.^6,12 Perhaps the strongest and most consistent correlate of cancer-related fatigue is depression. In a recent review of 30 studies conducted with cancer patients, the correlation between fatigue and depression ranged from 0.18–0.80, with an average correlation of 0.54.³²

One potential explanation for the high correlation between symptoms of fatigue and depression is methodological, as instruments assessing depression typically include symptoms of fatigue. However, removing fatigue-related items from depression inventories does not appreciably reduce the association between depression and fatigue.^6,32 In addition, fatigue is also highly correlated with measures of depressed mood that do not include neurovegetative symptoms.

A second possibility is that fatigue may lead to symptoms of depression due to its interference with normal activities. The disruption caused by fatigue may be particularly problematic for cancer survivors, who have completed cancer treatment and are ready to resume their normal lives. Indeed, breast cancer survivors reported that fatigue caused greater interference with mood than a control group of women with no cancer history.⁴

A third possibility is that fatigue occurs secondary to mood disturbance in cancer patients. Fatigue is a prominent symptom of depression, which is elevated in cancer patients relative to the general population.³³ However, several lines of evidence suggest that cancer-related fatigue cannot be explained entirely by presence of depression. First, cancer patients with persistent fatigue do not necessarily report depressed mood. For example, Bower and colleagues⁶ found that approximately 50% of fatigued breast cancer survivors scored below the clinical cut-off of 16 on the Center for Epidemiologic Studies Depression Scale. Second, prospective studies have shown that fatigue and depressive symptoms follow different trajectories over the course of cancer treatment. Visser and colleagues³⁴ found that while fatigue either increased or remained stable after onset of radiation therapy, depression decreased. Nine months later, fatigue had decreased whereas levels of depression remained stable. Third, pretreatment depression appears to be a poor predictor of fatigue severity after treatment. In a study of patients undergoing radiation therapy, pretreatment depressed mood explained only 4% of the variance in post-treatment fatigue.³⁴ Further, the presence of a psychiatric disorder before cancer diagnosis was not associated with fatigue severity after chemotherapy in a sample of breast cancer survivors, although psychiatric history is known to be a risk factor for depression after cancer diagnosis.⁸

Finally, it is possible that fatigue and depression may be driven by a common underlying biological disturbance. As described above, pro-inflammatory cytokines have been associated with both fatigue and depressed mood in cancer patients and healthy individuals; furthermore, there is evidence that individuals with clinical depression have elevated serum levels of pro-inflammatory cytokines and markers of cytokine activity, including cancer patients with depression.³⁵ The research of Bower and colleagues²⁶ with breast cancer survivors indicates that women with persistent fatigue display both depressed mood and elevated markers of pro-inflammatory cytokine activity. However, none of these inflammatory markers were correlated with depressed mood in these patients, nor did controlling for depression alter the association between fatigue and immune alterations.²⁶ These results suggest that pro-inflammatory cytokine activity may be specifically related to energy symptoms rather than depression in this patient group.

Pro-inflammatory cytokines are also known to induce changes in monoamines, and may influence both fatigue and depression through their effects on serotonin pathways.³⁶ To test this hypothesis, Morrow and colleagues³⁷ conducted a randomized controlled trial of paroxetine for fatigue in cancer patients undergoing chemotherapy. Of the 704 eligible patients, 549 (78%) reported fatigue at baseline and were randomized to receive either 20 mg/day of paroxetine or placebo during their second cycle of chemotherapy. Patients were reassessed during their fourth cycle of chemotherapy, approximately 8 weeks later. Results documented significant reductions in depressive symptoms among patients treated with paroxetine compared to controls. However, paroxetine had no effect on fatigue, even among patients who reported more severe fatigue at baseline. It should be noted that paroxetine is sedating in some and may itself increase fatigue.

Another trial³⁸ examined the effect of paroxetine among patients with malignant melanoma undergoing treatment with interferon-α (IFN-α). Depression and fatigue are both common side effects of IFN-α treatment, as are anhedonia, impaired concentration, and sleep disturbance.³⁹ Forty patients with malignant melanoma were randomized to receive either paroxetine or placebo beginning 2 weeks before initiation of IFN-α and continuing over the first 12 weeks of IFN-α therapy. Paroxetine treatment significantly reduced the incidence of major depression over the 12-week study period (11% incidence of depression in the paroxetine group versus 45% incidence in the placebo group). Examination of symptom clusters indicated that depressive (ie, depressed mood, guilt, suicidal thoughts, anhedonia) and cognitive symptoms emerged at week 8 of IFN-α therapy in the placebo group and were blocked by treatment with paroxetine.⁴⁰ However, neurovegetative and somatic symptoms, including fatigue, emerged at week 2 of IFN-α therapy in both groups and were only partially blocked at week 8 by paroxetine treatment. Thus, it appeared that depressed mood and fatigue had a different course during IFN-α treatment, and that paroxetine had a differential effect on these symptoms.

Overall, there is compelling evidence that fatigue is distinguishable from depression in cancer patients and may have distinct biological origins. Moreover, these results suggest that specific cytokine signals may be related to specific symptoms or symptom clusters, rather than depression in general, in cancer patients. Fatigue, mood changes, sleep disturbance, pain, cognitive changes, and other aspects of sickness behavior may be differentially influenced by cytokines and other biological signals.

Treatment of Cancer-Related Fatigue

A growing number of controlled intervention studies have specifically targeted fatigue in cancer patients. Most of this research has focused on exercise and has shown consistently positive results. A recent review⁴¹ found that all of the published exercise trials demonstrated lower levels of fatigue in cancer patients who exercised compared to control or comparison groups. Positive effects were demonstrated across a range of exercise programs, from home-based walking programs to supervised laboratory regimens, and across a range of cancer populations. Aerobic exercise was particularly effective, with fatigue levels approximately 40% to 50% lower in exercising subjects. Although most trials have been conducted with patients undergoing cancer treatment, beneficial effects have also been observed in research conducted with cancer survivors.⁴²

Psychosocial interventions have also shown beneficial effects on fatigue. For example, an educational group intervention designed to provide information about cancer and ways to manage the disease had positive effects on vitality and physical functioning in women undergoing treatment for breast cancer,⁴³ with the beneficial effects of treatment on vitality maintained over a 3-year follow-up.⁴⁴ Similarly, a psychoeducational group intervention emphasizing patient education and coping skills training led to improvements in fatigue, vigor, and depressed mood among patients with malignant melanoma.⁴⁵ Other forms of group therapy (ie, supportive expressive group therapy) and individual therapy have also shown beneficial effects on fatigue.^46,47 Effective treatments for fatigue do not necessarily require in-person interaction; for example, a patient self-administered form of stress management training demonstrated beneficial effects on vitality, physical function, and mental health among breast cancer patients undergoing chemotherapy.⁴⁸

Pharmacologic treatments for cancer-related fatigue include erythropoietin (for chemotherapy-induced anemia) and psychostimulants. As noted above, treatment with erythropoietin leads to increases in hemoglobin and concurrent improvements in fatigue and physical function among cancer patients with anemia.¹⁶ However, as most cancer patients are not anemic, erythropoietin is unlikely to be a viable treatment for most cases of cancer-related fatigue. There is preliminary evidence that psychostimulants may have beneficial effects on fatigue. In two open-label studies^49,50 conducted with advanced cancer patients, methylphenidate led to rapid improvements in fatigue and other symptoms.

Overall, these results provide strong evidence that exercise interventions lead to improvements in cancer-related fatigue, although the mechanisms for these effects have not been determined. There is also compelling evidence that psychosocial interventions may improve energy and other aspects of mental and physical function in cancer patients. Few studies have examined pharmacologic treatments for cancer-related fatigue other than erythropoietin; however, preliminary evidence suggests that psychostimulants may be effective for patients with advanced cancer (Table 2).

Conclusion

The growing literature on cancer-related fatigue highlights the prevalence of this symptom and its importance for quality of life in cancer patients and survivors. Fatigue in cancer patients is likely multifactorial and influenced by physiological changes associated with the disease and/or its treatment, comorbid medical conditions, physical symptoms, and psychological responses to the cancer experience. Fatigue is known to co-occur with sleep disturbance, pain, and particularly depression in cancer patients.

The interrelationship between fatigue and depression is complex: fatigue may be a symptom of depression, may precipitate feelings of depression, or they may both be symptoms of an underlying biological disturbance. The literature indicates that cancer-related fatigue cannot be explained by depression and that treatment with paroxetine has differential effects on depression and fatigue in cancer patients undergoing treatment, suggesting different biological mechanisms.

There is limited research on biological correlates of fatigue, although preliminary evidence suggests that fatigue may be associated with an inflammatory process in cancer patients and survivors. Alterations in HPA axis function observed in fatigued breast cancer survivors may be a cause or consequence of these immune alterations. Investigators are developing targeted treatments for cancer-related fatigue, including exercise, psychosocial interventions, and pharmacotherapy. All of these therapeutic modalities have been associated with improvements in cancer-related fatigue, with the strongest and most consistent results seen in trials utilizing aerobic exercise. PP

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