Invited ReviewCancer-related fatigue: Links with inflammation in cancer patients and survivors
Introduction
There are a growing number of cancer survivors in the United States, and a concomitant rise in attention to quality of life after cancer diagnosis and treatment. In particular, behavioral side effects of cancer treatment have become a focus of research and clinical attention. The most common and distressing side effect of cancer treatment is fatigue (Lawrence et al., 2004). Fatigue occurs across different types of cancer and cancer treatments and may persist for months or years after successful treatment completion. In addition to its importance for patients’ well-being, cancer-related fatigue is of interest as a potential clinical model of sickness behavior that may provide valuable insight into proinflammatory cytokine effects on the brain and behavior. This review will consider the evidence for a link between inflammation and cancer-related fatigue, focusing on research conducted by our group with breast cancer patients and survivors.
Section snippets
Prevalence and description of cancer-related fatigue
Prevalence estimates of fatigue during treatment range from 25% to 99%, depending on the patient population and type of assessment. Most studies find that 30% to 60% of patients report moderate or severe fatigue while undergoing treatment with radiation, chemotherapy, hormone therapy, and biological therapies (Lawrence et al., 2004). A substantial minority of these patients continue to experience problems with fatigue long after treatment completion. In a large cohort study, we found that
Etiology of cancer-related fatigue
Fatigue is a non-specific, multidimensional symptom that is likely influenced by multiple factors that coexist and vary in influence depending on individual characteristics of the patient. Fatigue is not linked to a specific type of cancer or cancer therapy, although patients with advanced cancer and those undergoing chemotherapy typically report more severe fatigue. Psychosocial factors are strongly correlated with fatigue, including depression, anxiety, and coping style (Andrykowski et al.,
Fatigue and inflammation during radiation therapy
To test the hypothesis that activation of inflammatory cytokines is associated with fatigue onset during cancer treatment, we recently conducted a study among early stage breast and prostate cancer patients undergoing radiation therapy (Bower et al., 2005). Radiation provides an interesting model in which to examine links between inflammation and fatigue for several reasons. First, radiation is a mainstay of cancer treatment and is known to elicit symptoms of fatigue. Second, exposure to
Fatigue and inflammation in cancer survivors
As mentioned above, fatigue continues long after successful treatment completion in approximately one-third of cancer survivors (Bower et al., 2000, Cella et al., 2001). Persistent fatigue typically cannot be explained by underlying medical or psychiatric problems or treatment-related biological changes such as anemia. We have conducted several studies to test the hypothesis that post-treatment fatigue in breast cancer survivors is associated with elevated inflammatory processes. This research
Mechanisms for persistent inflammation and fatigue
Treatment with radiation and chemotherapy may elicit acute increases in proinflammatory cytokines, with subsequent effects on fatigue. However, the physiologic basis for the prolonged inflammatory processes observed in our research with fatigued breast cancer survivors is unclear. Alterations in immune regulatory systems provide one plausible mechanism for chronic inflammatory activity. Our research has focused on the hypothalamic–pituitary–adrenal (HPA) axis, given the well known effects of
Risk factors for inflammation and fatigue
The possibility that individual differences may set the stage for enhanced inflammatory responses to cancer diagnosis and treatment has led us to investigate other potential risk factors for chronic inflammation and associated symptoms of fatigue. One of the primary factors that influence cytokine expression levels is genetic variation or gene polymorphisms. Cytokine gene polymorphisms have been linked to cancer susceptibility and severity (Hefler et al., 2005), and to physiological responses
Conclusions and recommendations for future research
These results provide mounting support for the hypothesis that proinflammatory cytokines contribute to cancer-related fatigue. We have documented elevations in soluble markers of inflammation in two separate cohorts of breast cancer survivors that are suggestive of a chronic inflammatory state (Bower et al., 2002, Collado-Hidalgo et al., 2006). Our recent work extends these findings to the acute treatment setting and suggests that activation of proinflammatory cytokines may also play a role in
Acknowledgments
The author thanks all of the individuals who have collaborated on this research, particularly Patricia Ganz, M.D., Steve Cole, Ph.D., Najib Aziz, M.D., Michael R. Irwin, M.D., and John L. Fahey, M.D. This research was supported by the Cousins Center for Psychoneuroimmunology in the Semel Institute for Neuroscience at UCLA, the Jonsson Comprehensive Cancer Center at UCLA, and by career development awards from the National Cancer Institute (K07 CA90407) and the California Breast Cancer Research
References (52)
- et al.
TGFB1 polymorphisms are associated with risk of late normal tissue complications in the breast after radiotherapy for early breast cancer
Radiother. Oncol.
(2005) - et al.
Diurnal cortisol rhythm and fatigue in breast cancer survivors
Psychoneuroendocrinology
(2005) - et al.
Inflammatory responses to psychological stress in fatigued breast cancer survivors: Relationship to glucocorticoids
Brain Behav. Immun.
(2007) - et al.
Relation of the −174 G/C polymorphism of interleukin-6 to interleukin-6 plasma levels and to length of hospitalization after surgical coronary revascularization
Am. J. Cardiol.
(2001) - et al.
Cytokines and psychopathology: lessons from interferon-alpha
Biol. Psychiatry
(2004) - et al.
Physical performance, depression, immune status and fatigue in patients with hematological malignancies after treatment
Ann. Oncol.
(2004) - et al.
Fatigue, serum cytokine levels, and blood cell counts during radiotherapy of patients with breast cancer
Int. J. Radiat. Oncol. Biol. Phys.
(2001) - et al.
Treatment-related fatigue and serum interleukin-1 levels in patients during external beam irradiation for prostate cancer
J. Pain Symptom Manage.
(1993) - et al.
Fatigue in women receiving adjuvant chemotherapy for breast cancer: characteristics, course, and correlates
J. Pain Symptom Manage.
(1999) - et al.
High level of fatigue in lymphoma patients treated with high dose therapy
J. Pain Symptom Manage.
(2000)
The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions
Brain Res. Brain Res. Rev.
Clinical depression and inflammatory risk markers for coronary heart disease
Am. J. Cardiol.
The association between fatigue and inflammatory marker levels in cancer patients: a quantitative review
Brain Behav. Immun.
Effects of radiation on normal tissue: consequences and mechanisms
Lancet Oncol.
Fatigue during breast radiotherapy and its relationship to biological factors
Int. J. Radiat. Oncol. Biol. Phys.
Levels of fatigue compared to levels of cytokines and hemoglobin during pelvic radiotherapy: a pilot study
Biol. Res. Nurs.
Off-treatment fatigue in breast cancer survivors: a controlled comparison
J. Behav. Med.
Use of a case definition approach to identify cancer-related fatigue in women undergoing adjuvant therapy for breast cancer
J. Clin. Oncol.
Genetic predisposition of the interleukin-6 response to inflammation: implications for a variety of major diseases?
Clin. Chem.
Fatigue in breast cancer survivors: occurrence, correlates, and impact on quality of life
J. Clin. Oncol.
Fatigue and proinflammatory cytokine activity in breast cancer survivors
Psychosom. Med.
T-cell homeostasis in breast cancer survivors with persistent fatigue
J. Natl. Cancer Inst.
Altered cortisol response to psychologic stress in breast cancer survivors with persistent fatigue
Psychosom. Med.
Fatigue in long-term breast carcinoma survivors: a longitudinal investigation
Cancer
Interleukin-6 gene −174g>c and −572g>c promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery
Arterioscler. Thromb. Vasc. Biol.
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