Elsevier

Cytokine

Volume 23, Issue 6, 21 September 2003, Pages 151-163
Cytokine

Cytokine profiles in patients receiving wide-field + prostate boost radiotherapy (xRT) for adenocarcinoma of the prostate

https://doi.org/10.1016/S1043-4666(03)00185-6Get rights and content

Abstract

As a result of the association between ionizing irradiation and the induction of inflammatory and fibrogenic cytokines, circulating levels of IL-1α, macrophage colony stimulating factor (M-CSF) and TGFβ were measured in a group of 37 patients who presented with well-defined adenocarcinoma of the prostate and were treated with wide-field pelvic (WFP) + prostate boost (PB) radiotherapy (xRT) according to RTOG protocols 94-08 and 94-13. First and foremost, patients with prostate cancer (PC) were found to have a significantly (p<0.05) elevated plasma level of the three cytokines prior to treatment. Moreover, during WFP + PB xRT, these circulating cytokine levels were further elevated, the elevation occurring in the form of cyclic waves; the concurrent waves of elevated IL-1α and M-CSF preceding that of TGFβ. In addition to providing support for the existence of a humoral response to xRT in patients receiving WFP + PB xRT, the data demonstrated a significant correlation between the integral radiation dose (ID) and the temporal expression and magnitude of plasma IL-1α, M-CSF and TGFβ levels in patients that had received 1–5 fractions (1.8–9 Gy) of WFP + PB xRT. Thereafter, the appearance of elevated waves of cytokine expression in the patient's plasma continued independent of additional fractions of WFP + PB xRT.

Introduction

Clinical approaches to controlling malignant disease that involve radiotherapy continue to be limited by the consequences of xRT on the integrity of normal tissue homeostasis. Historically, these side effects, determined by the inherent tolerance levels of respective normal tissues, have been viewed as representing separate, temporally distinguishable events, defined chronologically as being either an acute (mitotic) effect involving the parenchymal cells, or a late effect arising in response to xRT damage sustained by connective or supportive tissue cells. While the mechanism responsible for late effects is largely unknown, and no method for predicting such risks is currently available, considerable interest has been focused on the potential use of circulating cytokine levels as prognostic markers of the side effects of xRT [1], [2].

In response to ionizing radiation, inflammatory and fibrogenic cytokines are expressed by a number of diverse cell types [3], [4], [5], [6]. These observations, along with the results of their rodent studies, prompted Rubin and his colleagues to suggest that both cellular and humoral responses to radiation injury occur in normal tissues, the humoral response involving a ‘cytokine cascade’ paradigm overriding the temporal distinction existing between the early and late consequences of xRT [7]. More recently, elevated proinflammatory and fibrotic cytokines have been observed in the plasma of patients receiving radiotherapy, thereby providing additional support for the existence of a humoral response to xRT. With emphasis on thoracic xRT, the proinflammatory cytokines IL-1α and IL-6 and the profibrotic cytokine TGFβ have been linked to the temporal development of radiation-induced inflammatory pneumonitis and pulmonary fibrosis, respectively [1], [8], [9], [10]. Unfortunately, with the exception of a pilot study [11], there has been no comprehensive temporal study of plasma cytokine expression in a well-defined group of patients receiving a uniform course of pelvic xRT. To this end, the present study was designed and carried out in order to assess the temporal expression of the proinflammatory cytokines IL-1α and macrophage colony stimulating factor (M-CSF) and TGFβ in the plasma of prostate cancer (PC) patients receiving wide-field pelvic (WFP) xRT followed by a prostate boost (PB). Along with the more commonly studied IL-1α and TGFβ, M-CSF was selected as a representative of the proinflammatory cytokines for this study because of its role in the activation of macrophages, a population of fixed and circulating cells associated with host defense. In addition, the macrophage is implicated in the pathogenesis of chronic inflammatory bowel disorders [12], where elevated levels of circulating M-CSF have been observed [13], [14]. Of additional interest, elevated serum levels of M-CSF reportedly accompany vascular damage resulting from a number of inflammatory agents [15]. Under the experimental design, patients were either entered into or treated according to RTOG protocols no. 94-08 or 94-13 which prescribe a course of WFP + PB xRT, administered under well-defined conditions of uniform time–dose schedules and radiation fields. The data described herein demonstrate that WFP + PB xRT is associated with the generation of waves of enhanced plasma cytokine expression, where the waves of the proinflammatory cytokines IL-1α and M-CSF precede the expression of the profibrotic TGFβ. In addition, while correlations between the magnitude of cytokine expression in the patient's plasma and the energy absorbed during xRT (integral xRT dose) were initially significant (p<0.05) up to an accumulated dose of 9.0 Gy, thereafter, the subsequent waves of plasma cytokine expression appeared to develop independently of additional fractions of WFP + PB xRT.

Section snippets

Plasma cytokine concentrations in healthy control and prostate cancer patients

The patient population contributing to this study is summarized in Table 1. The mean age for the 37 members of the PC group was 70.58 ± 8.51, whereas the mean age of the HC group was 61.33 ± 6.02. Based on clinical stage, the distribution of patients entered into the PC group favored the T2 over T1 stage by a ratio approaching 2:1; patients with stage T2 disease presented without positive nodes or any evidence of metastatic disease. Using Pearson-Product-Moment and Student's t analysis, there

Discussion

The data generated during this study have revealed a number of characteristics concerning circulating cytokine levels in patients diagnosed with untreated, primary adenocarcinoma of the prostate (without clinical evidence of metastasis) undergoing conventional, WFP + PB xRT. First and foremost, prostate patients presenting for radiotherapy demonstrated elevated plasma levels of the proinflammatory/fibrotic cytokines IL-1α, M-CSF, and TGFβ. Secondly, in response to WFP + PB xRT, these

Patients

Thirty-seven consenting male patients were entered into this research study. The patients were selected from those receiving xRT for PC involving WFP and PB xRT as defined by RTOG Protocols #94-08 and #94-13. Eligibility for this study was based on the following: histologically confirmed, locally confined adenocarcinoma of the prostate, with or without significant risk for lymph node involvement based on a clinical stage of T1–T2, a grade of T1-2cNoMo, and PSA and Gleasons scores of ≤21 and

Acknowledgements

Supported by Grant No. CA GRB-Z from the NIH, DHHS. The authors would like to thank Ms Karen Christie and Dana Lawson for their assistance with identifying patients and phlebotomy service; Sharon L. Grice for assisting with the manuscript preparation and Dr Hyder Arastu for helpful suggestions in recruiting patients.

References (56)

  • D. Gius et al.

    Intracellular oxidation/reduction status in the regulation of transcription factors NFκB and AP-1

    Toxicol Lett

    (1999)
  • D. Gius et al.

    Intracellular oxidation/reduction status in the regulation of transcription factors NFκB and AP-1

    Toxicol Lett

    (1999)
  • M.W. Epperly et al.

    Intratracheal injection of adenovirus containing the human MnSOD transgene protects athymic nude mice from irradiation-induced organizing alveolitis

    Int J Radiat Oncol Biol Phys

    (1999)
  • E.L. Travis et al.

    Spatial heterogeneity of the volume effect for radiation pneumonitis in mouse lung

    Int J Radiat Oncol Biol Phys

    (1997)
  • D.E. Hallahan et al.

    The role of cytokines in radiation oncology

  • A. Beetz et al.

    Induction of interleukin 6 by ionizing radiation in a human epithelial line: control by corticosteroids

    Int J Radiat Biol

    (1997)
  • G.E. Woolschak et al.

    Modulation of gene expression in Syrian hamster embryo cells following ionizing radiation

    Cancer Res

    (1990)
  • J. Wang et al.

    Radiation-induced alteration of rat mesangial cell transforming growth factor-β and expression of the genes associated with extracellular matrix

    Radiat Res

    (1996)
  • M.S. Anscher et al.

    Transforming growth factor β as a predictor of liver and lung fibrosis after autologous bone marrow transplantation for advanced breast cancer

    N Engl J Med

    (1993)
  • M.S. Anscher et al.

    Normal tissue injury after cancer therapy is a local response exacerbated by an endocrine effect of TGFβ

    Br J Radiol

    (1995)
  • D.S. Gridley et al.

    Pilot study of cytokine profiles in prostate cancer patients undergoing proton or conventional radiotherapy

    Int J Oncol

    (1996)
  • Y.R. Mahida

    The key role of macrophages in the immunopathogenesis of inflammatory bowel disease

    Inflamm Bowel Dis

    (2000)
  • K. Mikiyama et al.

    Serum concentration of macrophage colony stimulating factor (M-CSF) in patients with inflammatory bowel disease

    Gastroenterol Jap

    (1993)
  • F.H. Klebl et al.

    Expression of macrophage-colony stimulating factor in normal and inflammatory bowel disease intestine

    J Pathol

    (2001)
  • A. Suehiro et al.

    Serum macrophage colony-stimulating factor (M-CSF) level is elevated in patients with infarctions related to vascular damage

    Am J Hematol

    (1999)
  • W.H. Kuttch et al.

    Quantitation of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in the effusions and plasma of ovarian epithelial neoplasm

    Am J Obstet Gynecol

    (1992)
  • G. Mantovani et al.

    Tumor-associated lympho-monocytes from neoplastic effusions are immunologically defective in comparison with patient autologous PBMCs but are capable of releasing high amounts of various cytokines

    Int J Oncol

    (1997)
  • K.C. Fearon et al.

    Elevated circulating interleukin-6 is associated with an acute-phase response but reduced fixed hepatic protein synthesis in patients with cancer

    Ann Surg

    (1991)
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