Full-Length Review
The association between fatigue and inflammatory marker levels in cancer patients: A quantitative review

https://doi.org/10.1016/j.bbi.2006.11.004Get rights and content

Abstract

Increased cytokine and neopterin levels may be responsible for cancer-related fatigue, the most common complaint among cancer patients. We quantitatively reviewed empirical findings on this topic, focusing on studies not using immunotherapy. PubMed, PsychINFO and BIOSIS were searched for articles published until July 2006. Studies remained unweighted or were weighted according to study quality and sample size. The correlation coefficient r was used for statistical analyses. Heterogeneity among the studies was examined using the I2 index. Eighteen studies (1037 participants) of moderately high methodological quality were located and statistically analyzed. Most studies measured more than one inflammatory marker, resulting in a total of 58 correlation estimates. In 31 of these, we had to impute a null correlation because results had been simply reported as nonsignificant and no further statistical information was available. General analyses based on weighting according to sample size showed a significantly positive correlation between fatigue and circulating levels of inflammatory markers (r = 0.11, p < 0.0001). Analyses of individual inflammatory markers revealed significantly positive correlations between fatigue and IL-6 (r = 0.12, p = 0.004), fatigue and IL-1ra (r = 0.24, p = 0.0005), and fatigue and neopterin (r = 0.22, p = 0.0001). Fatigue did not correlate significantly with IL-1β (r = 0.05, p = 0.42) or TNF-α (r = 0.04, p = 0.34). Given its preliminary nature due to the limited available data, this quantitative review showed a positive association between cancer-related fatigue and circulating levels of IL-6, IL-1ra and neopterin. Future studies examining the relationship between cancer related fatigue and inflammation would benefit from multiple rather than single blood sampling and from repeated daily ratings of the multidimensional nature of fatigue.

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)

  • H. Knobel et al.

    High level of fatigue in lymphoma patients treated with high dose therapy

    J. Pain Symptom Manage

    (2000)
  • R. Kurzrock

    Cytokine deregulation in cancer

    Biomed. Pharmacother.

    (2001)
  • S.J. Larson et al.

    Behavioral effects of cytokines

    Brain Behav. Immun.

    (2001)
  • P.J. Mills et al.

    The relationship between fatigue and quality of life and inflammation during anthracycline-based chemotherapy in breast cancer

    Biol. Psychol.

    (2005)
  • R. Morant

    Asthenia: an important symptom in cancer patients

    Cancer Treat Rev.

    (1996)
  • S.M. Opal et al.

    Anti-inflammatory cytokines

    Chest

    (2000)
  • N. Petrovsky et al.

    Diurnal rhythms of pro-inflammatory cytokines: regulation by plasma cortisol and therapeutic implications

    Cytokine

    (1998)
  • T. Pollmächer et al.

    Effects of repeated administration of granulocyte colony-stimulating factor (G-CSF) on neutrophil counts, plasma cytokine, and cytokine receptor levels

    Cytokine

    (1996)
  • T. Pollmächer et al.

    Low levels of circulating inflammatory cytokines—do they affect human brain functions?

    Brain Behav. Immun.

    (2002)
  • L. Pusztai et al.

    Changes in plasma levels of inflammatory cytokines in response to paclitaxel chemotherapy

    Cytokine

    (2004)
  • C. Schubert et al.

    Daily psychosocial stressors and cyclic response patterns in urine cortisol and neopterin in a patient with systemic lupus erythematosus

    Psychoneuroendocrinology

    (2003)
  • A. Shafqat et al.

    Screening studies for fatigue and laboratory correlates in cancer patients undergoing treatment

    Ann. Oncol.

    (2005)
  • A.H. Swiergiel et al.

    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.

    (1997)
  • P.W. Thavasu et al.

    Measuring cytokine levels in blood. Importance of anticoagulants, processing, and storage conditions

    J. Immunol. Methods

    (1992)
  • 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)
  • W.P. Arend et al.

    Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis

    Arthritis Rheum.

    (1990)
  • A. Auzeby et al.

    Time-dependence of urinary neopterin, a marker of cellular immune activity

    Clin. Chem.

    (1988)
  • J.U. Blohmer et al.

    Cancer-related anemia: biological findings, clinical implications and impact on quality of life

    Oncology

    (2005)
  • C. Bogdan et al.

    Taxol, a microtubule-stabilizing antineoplastic agent, induces expression of tumor necrosis factor alpha and interleukin-1 in macrophages

    J. Leukoc. Biol.

    (1992)
  • J.E. Bower et al.

    Fatigue and proinflammatory cytokine activity in breast cancer survivors

    Psychosom. Med.

    (2002)
  • J.G. Cannon et al.

    Acute phase responses and cytokine secretion in chronic fatigue syndrome

    J. Clin. Immunol.

    (1999)
  • A. Collado-Hidalgo et al.

    Inflammatory biomarkers for persistent fatigue in breast cancer survivors

    Clin. Cancer Res.

    (2006)
  • T.S. Collins et al.

    Paclitaxel up-regulates interleukin-8 synthesis in human lung carcinoma through an NF-kappaB- and AP-1-dependent mechanism

    Cancer Immunol. Immunother.

    (2000)
  • E.S. Costanzo et al.

    Psychosocial factors and interleukin-6 among women with advanced ovarian cancer

    Cancer

    (2005)
  • Deeks, J.J., Higgins, J.P.T., Altman, D.G., 2003. Analyzing and presenting results. In: Cochrane Reviewers’ Handbook...
  • Cited by (300)

    • Biomarkers of fatigue in oncology: A systematic review

      2024, Critical Reviews in Oncology/Hematology
    • Cancer-related fatigue and depression: a monocentric, prospective, cross-sectional study in advanced solid tumors

      2022, ESMO Open
      Citation Excerpt :

      In addition, the concomitant evaluation of cytokine level modifications over time, already widely described in literature as possible involved factors for CRF and depression, and of their possible association with PROMs results and patients’ symptoms, might also represent another future perspective already poorly investigated.16,19,20,79,80

    View all citing articles on Scopus
    View full text