Full-Length ReviewThe association between fatigue and inflammatory marker levels in cancer patients: A quantitative review
Introduction
Fatigue affects between 70 and 100% of patients with cancer undergoing radio- or chemotherapy and may persist for months or years after treatment (World Health Organization, 1994, Mock et al., 2000). Cancer-related fatigue (CaRF) is a very distressing condition, which has serious impact on the quality of life and is strongly associated with depression (Richardson, 1995, Visser and Smets, 1998). It is now seen as more troublesome to cancer patients than cancer-related pain, nausea or vomiting (Blohmer et al., 2005). Biological factors such as hematocrit, hemoglobin, albumin, and thyroid hormone have been inconsistently related to fatigue in cancer patients (Greenberg et al., 1992, Irvine et al., 1994, Geinitz et al., 2001, Bruera et al., 1989, Wang et al., 2002, Dimeo et al., 2004).
During the last decade, the links between illness-related psychological symptoms such as fatigue and ongoing inflammatory processes have received increasing attention in cancer research. Suffering from cancer and being treated for cancer are related to the release of inflammatory markers and the expression of receptors for inflammatory markers both by immune cells and malignant cells (Smyth et al., 2004). There are certain types of hematological cancers in which cytokines such as interleukin-6 (IL-6), interleukin-10 (IL-10), and interleukin-1β (IL-1β) are consistently elevated and cytokine receptor antagonists such as interleukin-1 receptor antagonist (IL-1ra) are consistently lowered (Kurzrock, 2001a). Likewise, the frequency of elevated neopterin varies from about 90% in hemotological neoplasias to about 20% in tumours like breast cancer or malignant melanoma (Murr et al., 2002). Neopterin is a non-specific marker of the cellular immune response and is released by macrophages upon stimulation with interferon-γ (INF-γ) (Fuchs et al., 1993). Regarding the release of cytokines during cancer treatment, studies showed that IL-6, IL-1, tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β) are the major cytokines in the radiation response of non-hemopoietic tissues (Herskind et al., 1998). On the other hand, the antineoplastic agent paclitaxel (Taxol®) can induce the expression of cytokines in various human tissues including tumour cells (IL-6, interleukin-8 [IL-8]) and leukocytes (IL-1β, interleukin-12 [IL-12], TNF-α) in vitro (Collins et al., 2000, White et al., 1997, Bogdan and Ding, 1992, Mullins et al., 1999). In patients with breast cancer, paclitaxel was shown to be associated with an increase in circulating levels of IL-6, IL-8, and IL-10 (Pusztai et al., 2004).
Several lines of evidence suggest that increases in inflammatory marker levels might be responsible for fatigue in cancer patients. First, animal studies have shown that direct application of IL-1 into the brain leads to a variety of symptoms such as loss of appetite, fever, fatigue, depressed activity, and decreased learning and cognitive functioning (Larson and Dunn, 2001, Kelley et al., 2003). These behavioral manifestations are designated as “sickness behavior” (Kent et al., 1992), which can be partially blocked by IL-1ra and may also be triggered by other cytokines such as IL-6 and TNF-α (Swiergiel et al., 1997). Second, the parenteral application of high concentrations of recombinant proinflammatory cytokines such as INF, IL-6, IL-12, IL-1β, TNF-α, and interleukin-2 (IL-2) to enhance immune defenses against cancer often leads to a syndrome referred to as the systemic inflammatory response syndrome. One of the major symptoms of this systemic response is intense fatigue, which in many patients calls for dose reduction or even interruption of therapy (Kelley et al., 2003, Pusztai et al., 2004). Third, chronic fatigue syndrome, which is clinically characterized by fatigue, myalgia and low-grade fever, has been shown to be associated with increased levels of TNF-α, IL-1β, interleukin-4 (IL-4), and IL-6 (Cannon et al., 1999). Finally, inflammatory markers interfere with several other conditions, which are suspected to be associated with CaRF. For instance, IL-1, IL-6, and TNF suppress red blood cell production and, thus, contribute to the development of anemia, which in turn contributes to CaRF (Kurzrock, 2001b).
This converging evidence leads many authors to suggest that fatigue in cancer patients is associated with a persistent activation of the immune system and an increased production of inflammatory markers. Surprisingly, despite increasing interest in this area, to our knowledge there have been no methodical reviews of this literature. In this study, we systematically reviewed the existing literature on this topic and statistically combined the retrieved studies to test whether CaRF is associated with changes in cytokines and neopterin levels.
Section snippets
Retrieval of research results
This study quantitatively reviews published research results dealing with the association between fatigue and inflammatory marker levels in cancer patients. As we were mainly interested in the origin of CaRF under natural conditions, we excluded studies from this quantitative review when they applied immunotherapy, i.e., when cytokine levels were altered through application of recombinant molecules (e.g., cytokines, cytokine decoy receptors). In addition, we only included studies, which
Retrieval results
Screening PubMed using our Mesh Term resulted in a total of 575 publications. Among these, many articles mainly published before 2000, addressed fatigue as a side effect of immunotherapy (e.g., interferon treatment) in cancer patients. Many others, the majority of which applied darbepoetin-alpha, did not measure cytokine levels. These articles were excluded from further analysis. We located 18 articles, mainly published after 2000, which measured inflammatory markers and fatigue when patients
Discussion
Given the high prevalence and burden of fatigue in cancer patients there is no doubt about the necessity of both shedding light on the pathophysiology of CaRF and finding options for its treatment. This quantitative review tested whether fatigue in cancer patients is associated with an increased production of inflammatory markers.
We found 20 studies in the published literature that specifically dealt with the association between fatigue and inflammatory marker levels in cancer patients.
Acknowledgment
This work was supported by Grants from NIH (HL44915 and RR00827).
References (73)
- et al.
Association between asthenia and nutritional status, lean body mass, anemia, psychological status, and tumor mass in patients with advanced breast cancer
J. Pain Symptom Manage
(1989) - et al.
Physical performance, depression, immune status and fatigue in patients with hematological malignancies after treatment
Ann. Oncol.
(2004) Interleukin-1 and interleukin-1 antagonism
Blood
(1991)- et al.
Neopterin as a marker for activated cell-mediated immunity: application in HIV infection
Immunol. Today
(1988) - 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.
High serum levels of TNF-alpha after its administration for isolation perfusion of the limb
Cytokine
(1992) - et al.
Efficacy of l-carnitine administration on fatigue, nutritional status, oxidative stress, and related quality of life in 12 advanced cancer patients undergoing anticancer therapy
Nutrition
(2006) - et al.
Fatigue syndrome due to localized radiation
J. Pain. Symptom Manage.
(1992) - 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.
Sickness behavior as a new target for drug development
Trends Pharmacol. Sci.
(1992)
High level of fatigue in lymphoma patients treated with high dose therapy
J. Pain Symptom Manage
Cytokine deregulation in cancer
Biomed. Pharmacother.
Behavioral effects of cytokines
Brain Behav. Immun.
The relationship between fatigue and quality of life and inflammation during anthracycline-based chemotherapy in breast cancer
Biol. Psychol.
Asthenia: an important symptom in cancer patients
Cancer Treat Rev.
Anti-inflammatory cytokines
Chest
Diurnal rhythms of pro-inflammatory cytokines: regulation by plasma cortisol and therapeutic implications
Cytokine
Effects of repeated administration of granulocyte colony-stimulating factor (G-CSF) on neutrophil counts, plasma cytokine, and cytokine receptor levels
Cytokine
Low levels of circulating inflammatory cytokines—do they affect human brain functions?
Brain Behav. Immun.
Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy
Cytokine
Daily psychosocial stressors and cyclic response patterns in urine cortisol and neopterin in a patient with systemic lupus erythematosus
Psychoneuroendocrinology
Screening studies for fatigue and laboratory correlates in cancer patients undergoing treatment
Ann. Oncol.
The role of cytokines in the behavioral responses to endotoxin and influenza virus infection in mice: effects of acute and chronic administration of the interleukin-1-receptor antagonist (IL-1ra)
Brain Res.
Measuring cytokine levels in blood. Importance of anticoagulants, processing, and storage conditions
J. Immunol. Methods
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.
Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis
Arthritis Rheum.
Time-dependence of urinary neopterin, a marker of cellular immune activity
Clin. Chem.
Cancer-related anemia: biological findings, clinical implications and impact on quality of life
Oncology
Taxol, a microtubule-stabilizing antineoplastic agent, induces expression of tumor necrosis factor alpha and interleukin-1 in macrophages
J. Leukoc. Biol.
Fatigue and proinflammatory cytokine activity in breast cancer survivors
Psychosom. Med.
Acute phase responses and cytokine secretion in chronic fatigue syndrome
J. Clin. Immunol.
Inflammatory biomarkers for persistent fatigue in breast cancer survivors
Clin. Cancer Res.
Paclitaxel up-regulates interleukin-8 synthesis in human lung carcinoma through an NF-kappaB- and AP-1-dependent mechanism
Cancer Immunol. Immunother.
Psychosocial factors and interleukin-6 among women with advanced ovarian cancer
Cancer
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