Cancer-related fatigue: Links with inflammation in cancer patients and survivors

doi:10.1016/j.bbi.2007.03.013

Brain, Behavior, and Immunity

Volume 21, Issue 7, October 2007, Pages 863-871

https://doi.org/10.1016/j.bbi.2007.03.013 Get rights and content

Abstract

Fatigue is one of the most common and distressing side effects of cancer and its treatment and may persist long after successful treatment completion. Emerging evidence suggests that inflammatory processes may be involved in cancer-related fatigue both during and after treatment. In this review, we consider the evidence for an association between inflammation and fatigue in cancer patients and survivors. Further, we identify potential mechanisms for persistent inflammation, focusing on the HPA axis. Risk factors and treatments for cancer-related fatigue are also discussed.

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)

C.N. Andreassen 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)
J.E. Bower et al.
Diurnal cortisol rhythm and fatigue in breast cancer survivors
Psychoneuroendocrinology
(2005)
J.E. Bower et al.
Inflammatory responses to psychological stress in fatigued breast cancer survivors: Relationship to glucocorticoids
Brain Behav. Immun.
(2007)
F. Burzotta 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)
L. Capuron et al.
Cytokines and psychopathology: lessons from interferon-alpha
Biol. Psychiatry
(2004)
F. Dimeo et al.
Physical performance, depression, immune status and fatigue in patients with hematological malignancies after treatment
Ann. Oncol.
(2004)
H. Geinitz et al.
Fatigue, serum cytokine levels, and blood cell counts during radiotherapy of patients with breast cancer
Int. J. Radiat. Oncol. Biol. Phys.
(2001)
D.B. Greenberg et al.
Treatment-related fatigue and serum interleukin-1 levels in patients during external beam irradiation for prostate cancer
J. Pain Symptom Manage.
(1993)
P.B. Jacobsen et al.
Fatigue in women receiving adjuvant chemotherapy for breast cancer: characteristics, course, and correlates
J. Pain Symptom Manage.
(1999)
H. Knobel et al.
High level of fatigue in lymphoma patients treated with high dose therapy
J. Pain Symptom Manage.
(2000)

B.S. McEwen et al.

The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions

Brain Res. Brain Res. Rev.

(1997)

G.E. Miller et al.

Clinical depression and inflammatory risk markers for coronary heart disease

Am. J. Cardiol.

(2002)

C. Schubert et al.

The association between fatigue and inflammatory marker levels in cancer patients: a quantitative review

Brain Behav. Immun.

(2007)

H.B. Stone et al.

Effects of radiation on normal tissue: consequences and mechanisms

Lancet Oncol.

(2003)

C. Wratten et al.

Fatigue during breast radiotherapy and its relationship to biological factors

Int. J. Radiat. Oncol. Biol. Phys.

(2004)

K. Ahlberg et al.

Levels of fatigue compared to levels of cytokines and hemoglobin during pelvic radiotherapy: a pilot study

Biol. Res. Nurs.

(2004)

M.A. Andrykowski et al.

Off-treatment fatigue in breast cancer survivors: a controlled comparison

J. Behav. Med.

(1998)

M.A. Andrykowski et al.

Use of a case definition approach to identify cancer-related fatigue in women undergoing adjuvant therapy for breast cancer

J. Clin. Oncol.

(2005)

M. Bennermo et al.

Genetic predisposition of the interleukin-6 response to inflammation: implications for a variety of major diseases?

Clin. Chem.

(2004)

J.E. Bower et al.

Fatigue in breast cancer survivors: occurrence, correlates, and impact on quality of life

J. Clin. Oncol.

(2000)

J.E. Bower et al.

Fatigue and proinflammatory cytokine activity in breast cancer survivors

Psychosom. Med.

(2002)

J.E. Bower et al.

T-cell homeostasis in breast cancer survivors with persistent fatigue

J. Natl. Cancer Inst.

(2003)

J.E. Bower et al.

Altered cortisol response to psychologic stress in breast cancer survivors with persistent fatigue

Psychosom. Med.

(2005)

J.E. Bower et al.

Fatigue in long-term breast carcinoma survivors: a longitudinal investigation

Cancer

(2006)

Bower, J.E., Ganz, P.A., Fahey, J.L., Belin, T.R., Tao, M.L., 2005. Mechanisms of fatigue during radiation therapy for...

D.J. Brull et al.

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.

(2001)

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Fatigue is a common side effect of cancer and its treatment and is thought to be driven in part by activation of the proinflammatory cytokine network. However, the cellular and molecular underpinnings of cancer-related fatigue (CRF) have not been determined, nor have immune pathways beyond inflammation been carefully investigated. The goal of this study was to examine the association between CRF and activation of canonical proinflammatory gene regulation pathways and Type I interferon (IFN) signaling pathways in breast cancer patients during and after treatment.
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Invited ReviewCancer-related fatigue: Links with inflammation in cancer patients and survivors

Abstract

Introduction

Section snippets

Prevalence and description of cancer-related fatigue

Etiology of cancer-related fatigue

Fatigue and inflammation during radiation therapy

Fatigue and inflammation in cancer survivors

Mechanisms for persistent inflammation and fatigue

Risk factors for inflammation and fatigue

Conclusions and recommendations for future research

Acknowledgments

Radiother. Oncol.

Psychoneuroendocrinology

Brain Behav. Immun.

Am. J. Cardiol.

Biol. Psychiatry

Ann. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

J. Pain Symptom Manage.

J. Pain Symptom Manage.

J. Pain Symptom Manage.

Brain Res. Brain Res. Rev.

Am. J. Cardiol.

Brain Behav. Immun.

Lancet Oncol.

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.

Invited Review
Cancer-related fatigue: Links with inflammation in cancer patients and survivors