Inflammatory cytokines are associated with the development of symptom burden in patients with NSCLC undergoing concurrent chemoradiation therapy

https://doi.org/10.1016/j.bbi.2010.03.009Get rights and content

Abstract

Elevations in cancer treatment-induced circulating inflammatory cytokines may be partially responsible for the development of significant symptom burden (e.g., pain, fatigue, distress, disturbed sleep) during concurrent chemoradiation therapy (CXRT). Sixty-two patients undergoing CXRT for locally advanced non-small cell lung cancer (NSCLC) reported symptoms weekly for 15 weeks via the M. D. Anderson Symptom Inventory (MDASI). Serum inflammatory cytokines were assessed weekly during therapy via enzyme-linked immunosorbent assay. Dynamic changes in cytokines and associated symptom profiles were estimated using mixed-effect models. MDASI symptom severity increased gradually as CXRT dose accumulated and peaked at week 8. Serum concentrations of interleukin (IL)-6, IL-10, and serum soluble receptor 1 for tumor necrosis factor (sTNF-R1) increased significantly by week 8 (all p < .05). During CXRT, controlled for age, sex, race, body mass index, cancer recurrence, previous treatment status, total radiotherapy dose, and CXRT delivery technique, an increase in sTNF-R1 was significantly related to an increase in the mean score for all 15 MDASI symptoms (estimate, 1.74; SE, 0.69; p < .05) and to a larger radiation dose to normal lung volume (estimate, 1.77; SE, 0.71; p < .01); an increase in serum IL-6 was significantly related to increased mean severity for the five most severe symptoms (pain, fatigue, disturbed sleep, lack of appetite, sore throat) (estimate, 0.32; SE, 0.16; p < .05). These results suggest a role for over-expressed pro-inflammatory cytokines in significant worsening of symptoms in NSCLC patients undergoing CXRT, and warrant further study to identify biological targets for ameliorating treatment-related symptom burden.

Introduction

Lung cancer is a highly symptomatic disease that has the second-highest yearly incidence rate among all cancers in the United States (Jemal et al., 2009). Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer. The treatment of choice for loco-regional and advanced NSCLC is concurrent chemoradiation therapy (CXRT) (Jemal et al., 2009, Yamamoto et al., 2006), a modality that is frequently associated with multiple symptoms induced by accumulating doses of radiation and chemotherapy (Wang et al., 2006).

However, with the exception of pain, many non-specific cancer symptoms—such as fatigue, disturbed sleep, poor appetite, and distress—are not intentionally monitored in the clinical setting and may not be treated as specific toxicities of cancer or cancer treatment (Cleeland, 2000, Cox et al., 1995, Patrick et al., 2004). Collectively, these non-specific symptoms and toxicities form a “symptom burden” that can affect patient functioning. Symptom burden may provoke treatment interruptions, such as dose reduction or withdrawal from chemotherapy and/or radiotherapy for patients with NSCLC, which could compromise the effectiveness of intervention (Cleeland, 2007).

Controlling symptoms requires first that they be assessed, preferably throughout the course of treatment. The subjective nature of the symptom experience has necessitated the use of validated multiple-symptom assessment instruments that can capture the patient’s own report of the severity of symptoms (so-called patient-reported outcomes).

Controlling symptoms also requires a better understanding of the mechanism(s) underlying the development of treatment-related symptoms. Recent cancer research has shown that symptoms such as pain, fatigue, and disturbed sleep frequently cluster together and often share the same developmental pattern over the trajectory of disease progression and treatment (Barsevick et al., 2006, Cleeland et al., 2003, Dodd et al., 2001, Fan et al., 2007, Hickok et al., 2005, Wang et al., 2006), This symptom clustering suggests that common biological mechanisms may underlie the development of multiple cancer treatment-related symptoms. Dysregulation of inflammatory cytokines has been suggested as one possible common biological mechanism of multiple-symptom production (Cleeland et al., 2003, Dantzer, 2001, Lee et al., 2004, Miller et al., 2008, Rube et al., 2004, Wang et al., 2008). The over-response of inflammatory cytokines to the insult from aggressive cancer therapy has been studied in radiation pneumonitis and other clinical outcomes, but the possibility that CXRT-induced fluctuations in circulating cytokines may trigger the development of symptoms has only recently been studied in limited cohorts of cancer patients (Bower et al., 2002, Bower et al., 2009, Hart et al., 2005, Meyers et al., 2005, Miller et al., 2008, Wratten et al., 2004).

Investigating the possible role of inflammatory cytokines in producing symptom burden in patients being treated with chemoradiotherapy for NSCLC requires identification of specific cytokines and evidence of their correlation with the emergence of the most severe symptoms during CXRT. We therefore designed a longitudinal descriptive study with patient-reported symptoms as primary outcomes; symptoms were assessed via the M. D. Anderson Symptom Inventory (Cleeland et al., 2000). Our goals were (1) to establish patterns of dynamic changes in both symptoms and serum levels of inflammatory cytokines by examining the effect of CXRT on their development, and (2) to track and identify the critical interaction between serum concentrations of inflammatory cytokines and the development of multiple symptoms in patients with NSCLC undergoing CXRT. We hypothesized that the cumulative dose of CXRT in patients with NSCLC would induce an over-expression of certain inflammatory cytokines during therapy, promoting the development of multiple symptoms that would worsen over time.

Section snippets

Patients

Patients with NSCLC were recruited consecutively from clinic in the Department of Radiation Oncology at The University of Texas M. D. Anderson Cancer Center in Houston, Texas. Eligible patients were scheduled for curative CXRT, were at least 18 years old, and had a pathological diagnosis of unresectable NSCLC. The study was approved by the M. D. Anderson Cancer Center Institutional Review Board. All participants gave written informed consent.

The M. D. Anderson Symptom Inventory

Patient-reported outcomes for symptom severity were

Patient sample

Sixty-two patients were recruited for the study and all patients completed the treatment regimen. Approximately 10% of the eligible patients approached declined to participate. Patients were administered a total radiation dose of 50–70 Gy (mean 64 Gy, SD 7) over an average of 6.5 weeks, at 1.8–2.0 Gy per fraction daily. A standard platinum-taxane based chemotherapy regimen was concurrently administered to all patients during radiotherapy. All patients had good performance status (ECOG PS = 0–1)

Discussion

This longitudinal study demonstrated, in response to accumulating combined radiation and chemotherapy in patients with NSCLC, (1) a significant worsening of symptom burden during CXRT that peaked at week 8; (2) a significant increase in serum IL-6, sTNF-R1, and IL-10 during 8 weeks of CXRT, perhaps as a result of tissue destruction; and (3) association between over-expressed serum concentrations pro-inflammatory cytokines (primarily sTNF-R1 and IL-6) and worsening treatment-related symptoms.

CXRT

Financial support

This work was supported by the National Institutes of Health [Grant Nos. R21 CA109286 to X.S.W. and Z.X.L., R01 CA026582 to C.S.C.].

Previous presentation

This research was presented at the American Society of Clinical Oncology 44th Annual Meeting in Chicago, Illinois, May–June 2008.

Conflicts of interest

None.

Acknowledgments

The authors thank Jeanie F. Woodruff, ELS, for editorial support; Maria Sanchez, RN, for clinical data collection; Hongli Tang for cytokine assay; and Marilyn Morrissey, MPH, for protocol management.

References (37)

  • C.E. Rube et al.

    Increased expression of pro-inflammatory cytokines as a cause of lung toxicity after combined treatment with gemcitabine and thoracic irradiation

    Radiother. Oncol.

    (2004)
  • C.E. Rube et al.

    Modulation of radiation-induced tumour necrosis factor alpha (TNF-α) expression in the lung tissue by pentoxifylline

    Radiother. Oncol.

    (2002)
  • C. Schubert et al.

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

    Brain Behav. Immun.

    (2007)
  • 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)
  • M.H. Barcellos-Hoff

    How do tissues respond to damage at the cellular level? The role of cytokines in irradiated tissues

    Radiat. Res.

    (1998)
  • J.E. Bower et al.

    Fatigue and proinflammatory cytokine activity in breast cancer survivors

    Psychosom. Med.

    (2002)
  • J.E. Bower et al.

    Inflammatory biomarkers and fatigue during radiation therapy for breast and prostate cancer

    Clin. Cancer Res.

    (2009)
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