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Cytokine plasma levels: reliable predictors for radiation pneumonitis?

Rübe CE, Palm J, Erren M, Fleckenstein J, König J, Remberger K, Rübe C - PLoS ONE (2008)

Bottom Line: Unexpectedly, cytokine plasma levels measured before and during RT did not correlate with RP incidence.Moreover, IL-6 and TGF-beta1 plasma levels measured during follow-up were significantly associated with the individual tumour responses of these patients.The results of this study did not confirm that cytokine plasma levels, neither their absolute nor any relative values, may identify patients at risk for RP.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiotherapy and Radiooncology, Saarland University, Homburg, Saar, Germany. claudia.ruebe@uniklinik-saarland.de

ABSTRACT

Background: Radiotherapy (RT) is the primary treatment modality for inoperable, locally advanced non-small-cell lung cancer (NSCLC), but even with highly conformal treatment planning, radiation pneumonitis (RP) remains the most serious, dose-limiting complication. Previous clinical reports proposed that cytokine plasma levels measured during RT allow to estimate the individual risk of patients to develop RP. The identification of such cytokine risk profiles would facilitate tailoring radiotherapy to maximize treatment efficacy and to minimize radiation toxicity. However, cytokines are produced not only in normal lung tissue after irradiation, but are also over-expressed in tumour cells of NSCLC specimens. This tumour-derived cytokine production may influence circulating plasma levels in NSCLC patients. The aim of the present study was to investigate the prognostic value of TNF-alpha, IL-1beta, IL-6 and TGF-beta1 plasma levels to predict radiation pneumonitis and to evaluate the impact of tumour-derived cytokine production on circulating plasma levels in patients irradiated for NSCLC.

Methodology/principal findings: In 52 NSCLC patients (stage I-III) cytokine plasma levels were investigated by ELISA before and weekly during RT, during follow-up (1/3/6/9 months after RT), and at the onset of RP. Tumour biopsies were immunohistochemically stained for IL-6 and TGF-beta1, and immunoreactivity was quantified (grade 1-4). RP was evaluated according to LENT-SOMA scale. Tumour response was assessed according to RECIST criteria by chest-CT during follow-up. In our clinical study 21 out of 52 patients developed RP (grade I/II/III/IV: 11/3/6/1 patients). Unexpectedly, cytokine plasma levels measured before and during RT did not correlate with RP incidence. In most patients IL-6 and TGF-beta1 plasma levels were already elevated before RT and correlated significantly with the IL-6 and TGF-beta1 production in corresponding tumour biopsies. Moreover, IL-6 and TGF-beta1 plasma levels measured during follow-up were significantly associated with the individual tumour responses of these patients.

Conclusions/significance: The results of this study did not confirm that cytokine plasma levels, neither their absolute nor any relative values, may identify patients at risk for RP. In contrast, the clear correlations of IL-6 and TGF-beta1 plasma levels with the cytokine production in corresponding tumour biopsies and with the individual tumour responses suggest that the tumour is the major source of circulating cytokines in patients receiving RT for advanced NSCLC.

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Correlations between the IL-6 and TGF-β1 ratios and the incidence of radiation pneumonitis.For every patient, the ratios of the plasma levels at the end of radiotherapy (end-RT) and before RT (pre-RT) are plotted logarithmically (base 10): relative values >imply an increase (supposed high risk for RP), values <1 imply a decrease of the plasma levels at the end of RT (supposed low risk for RP). The ratios were plotted separately for the patients without radiation pneumonitis (grade 0) (n = 31), and with moderate (grade I/II) (n = 14) and severe (grade III/IV) (n = 7) lung toxicity.
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pone-0002898-g003: Correlations between the IL-6 and TGF-β1 ratios and the incidence of radiation pneumonitis.For every patient, the ratios of the plasma levels at the end of radiotherapy (end-RT) and before RT (pre-RT) are plotted logarithmically (base 10): relative values >imply an increase (supposed high risk for RP), values <1 imply a decrease of the plasma levels at the end of RT (supposed low risk for RP). The ratios were plotted separately for the patients without radiation pneumonitis (grade 0) (n = 31), and with moderate (grade I/II) (n = 14) and severe (grade III/IV) (n = 7) lung toxicity.

Mentions: To test the hypothesis that IL-6 and TGF-β1 ratios can be used for the identification of patients at risk as previously proposed in the literature [15], [17], [18], [19], [20], [21], [22], the cytokine plasma levels measured at the end of RT were divided by the corresponding pre-RT values for all patients and correlated with the incidence of RP. In figure 3, these relative values for IL-6 and TGF-β1 are plotted separately on a base 10 logarithmic scale for the patients without RP (grade 0), as well as for patients with moderate (grade I/II) and severe lung toxicity (grade III/IV). Relative values >1 imply an increase (associated with high risk for RP according to the literature), values <1 imply a decrease of the plasma levels at the end of RT compared to the pre-RT levels (associated with low risk for RP) [15], [16], [17], [18], [22]. Figure 3 illustrates that the ratios for IL-6 and TGF-β1 were similarly distributed in all patients irrespective of their suffered lung toxicity. Similar results were obtained for ratios obtained by maximal plasma levels measured during RT divided by the corresponding pre-RT values (data not shown). In summary, we observed no statistically significant correlation between the IL-6 and TGF-β1 ratios and the incidence of RP (end-RT IL-6/pre-RT IL-6: r = 0.08; p = 0.59; end-RT TGF-β1/pre-RT TGF-β1: r = 0.04; p = 0.80).


Cytokine plasma levels: reliable predictors for radiation pneumonitis?

Rübe CE, Palm J, Erren M, Fleckenstein J, König J, Remberger K, Rübe C - PLoS ONE (2008)

Correlations between the IL-6 and TGF-β1 ratios and the incidence of radiation pneumonitis.For every patient, the ratios of the plasma levels at the end of radiotherapy (end-RT) and before RT (pre-RT) are plotted logarithmically (base 10): relative values >imply an increase (supposed high risk for RP), values <1 imply a decrease of the plasma levels at the end of RT (supposed low risk for RP). The ratios were plotted separately for the patients without radiation pneumonitis (grade 0) (n = 31), and with moderate (grade I/II) (n = 14) and severe (grade III/IV) (n = 7) lung toxicity.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2483418&req=5

pone-0002898-g003: Correlations between the IL-6 and TGF-β1 ratios and the incidence of radiation pneumonitis.For every patient, the ratios of the plasma levels at the end of radiotherapy (end-RT) and before RT (pre-RT) are plotted logarithmically (base 10): relative values >imply an increase (supposed high risk for RP), values <1 imply a decrease of the plasma levels at the end of RT (supposed low risk for RP). The ratios were plotted separately for the patients without radiation pneumonitis (grade 0) (n = 31), and with moderate (grade I/II) (n = 14) and severe (grade III/IV) (n = 7) lung toxicity.
Mentions: To test the hypothesis that IL-6 and TGF-β1 ratios can be used for the identification of patients at risk as previously proposed in the literature [15], [17], [18], [19], [20], [21], [22], the cytokine plasma levels measured at the end of RT were divided by the corresponding pre-RT values for all patients and correlated with the incidence of RP. In figure 3, these relative values for IL-6 and TGF-β1 are plotted separately on a base 10 logarithmic scale for the patients without RP (grade 0), as well as for patients with moderate (grade I/II) and severe lung toxicity (grade III/IV). Relative values >1 imply an increase (associated with high risk for RP according to the literature), values <1 imply a decrease of the plasma levels at the end of RT compared to the pre-RT levels (associated with low risk for RP) [15], [16], [17], [18], [22]. Figure 3 illustrates that the ratios for IL-6 and TGF-β1 were similarly distributed in all patients irrespective of their suffered lung toxicity. Similar results were obtained for ratios obtained by maximal plasma levels measured during RT divided by the corresponding pre-RT values (data not shown). In summary, we observed no statistically significant correlation between the IL-6 and TGF-β1 ratios and the incidence of RP (end-RT IL-6/pre-RT IL-6: r = 0.08; p = 0.59; end-RT TGF-β1/pre-RT TGF-β1: r = 0.04; p = 0.80).

Bottom Line: Unexpectedly, cytokine plasma levels measured before and during RT did not correlate with RP incidence.Moreover, IL-6 and TGF-beta1 plasma levels measured during follow-up were significantly associated with the individual tumour responses of these patients.The results of this study did not confirm that cytokine plasma levels, neither their absolute nor any relative values, may identify patients at risk for RP.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiotherapy and Radiooncology, Saarland University, Homburg, Saar, Germany. claudia.ruebe@uniklinik-saarland.de

ABSTRACT

Background: Radiotherapy (RT) is the primary treatment modality for inoperable, locally advanced non-small-cell lung cancer (NSCLC), but even with highly conformal treatment planning, radiation pneumonitis (RP) remains the most serious, dose-limiting complication. Previous clinical reports proposed that cytokine plasma levels measured during RT allow to estimate the individual risk of patients to develop RP. The identification of such cytokine risk profiles would facilitate tailoring radiotherapy to maximize treatment efficacy and to minimize radiation toxicity. However, cytokines are produced not only in normal lung tissue after irradiation, but are also over-expressed in tumour cells of NSCLC specimens. This tumour-derived cytokine production may influence circulating plasma levels in NSCLC patients. The aim of the present study was to investigate the prognostic value of TNF-alpha, IL-1beta, IL-6 and TGF-beta1 plasma levels to predict radiation pneumonitis and to evaluate the impact of tumour-derived cytokine production on circulating plasma levels in patients irradiated for NSCLC.

Methodology/principal findings: In 52 NSCLC patients (stage I-III) cytokine plasma levels were investigated by ELISA before and weekly during RT, during follow-up (1/3/6/9 months after RT), and at the onset of RP. Tumour biopsies were immunohistochemically stained for IL-6 and TGF-beta1, and immunoreactivity was quantified (grade 1-4). RP was evaluated according to LENT-SOMA scale. Tumour response was assessed according to RECIST criteria by chest-CT during follow-up. In our clinical study 21 out of 52 patients developed RP (grade I/II/III/IV: 11/3/6/1 patients). Unexpectedly, cytokine plasma levels measured before and during RT did not correlate with RP incidence. In most patients IL-6 and TGF-beta1 plasma levels were already elevated before RT and correlated significantly with the IL-6 and TGF-beta1 production in corresponding tumour biopsies. Moreover, IL-6 and TGF-beta1 plasma levels measured during follow-up were significantly associated with the individual tumour responses of these patients.

Conclusions/significance: The results of this study did not confirm that cytokine plasma levels, neither their absolute nor any relative values, may identify patients at risk for RP. In contrast, the clear correlations of IL-6 and TGF-beta1 plasma levels with the cytokine production in corresponding tumour biopsies and with the individual tumour responses suggest that the tumour is the major source of circulating cytokines in patients receiving RT for advanced NSCLC.

Show MeSH
Related in: MedlinePlus