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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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Correlation between the pre-RT IL-6 and TGF-β1 plasma levels, respectively, and the IL-6 and TGF-β1 staining intensity of the corresponding tumour biopsies (grade 1–4) (IL-6: no grade 4 samples).For both cytokines, statistically significant correlations were found between the amount of pre-RT plasma levels and the staining intensity of the corresponding tumour biopsies.
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pone-0002898-g005: Correlation between the pre-RT IL-6 and TGF-β1 plasma levels, respectively, and the IL-6 and TGF-β1 staining intensity of the corresponding tumour biopsies (grade 1–4) (IL-6: no grade 4 samples).For both cytokines, statistically significant correlations were found between the amount of pre-RT plasma levels and the staining intensity of the corresponding tumour biopsies.

Mentions: To evaluate the potential impact of tumour-derived cytokine production on circulating plasma levels, the tumour biopsies of the NSCLC patients were immunohistochemically stained for IL-6 and TGF-β1. The 52 analysed tumour specimens revealed a heterogeneous staining pattern for IL-6 and TGF-β1 with variably intense cytoplasmatic and/or nuclear staining of the tumour cells. Examples of the TGF-β1 immunohistochemistry of tumour biopsies are presented in figure 4. Compared to the rather intense staining for TGF-β1 in most of the analyzed tumour biopsies, the IL-6 staining of the tumour specimens was generally weaker. In figure 5 the pre-RT plasma levels for IL-6 and TGF-β1, respectively, were plotted against the staining intensity of the corresponding tumour specimens for every patient. For both cytokines a statistically significant correlation was found between the amount of pre-RT plasma levels and the staining intensity of the corresponding tumour biopsies, suggesting that -irrespective of the subsequent irradiation- the IL-6 and TGF-β1 plasma levels in NSCLC patients were influenced to a great extent by the cytokine release of their tumours (IL-6: r = 0.67, p<0.0001; TGF-β1: r = 0.83, p<0.0001).


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)

Correlation between the pre-RT IL-6 and TGF-β1 plasma levels, respectively, and the IL-6 and TGF-β1 staining intensity of the corresponding tumour biopsies (grade 1–4) (IL-6: no grade 4 samples).For both cytokines, statistically significant correlations were found between the amount of pre-RT plasma levels and the staining intensity of the corresponding tumour biopsies.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002898-g005: Correlation between the pre-RT IL-6 and TGF-β1 plasma levels, respectively, and the IL-6 and TGF-β1 staining intensity of the corresponding tumour biopsies (grade 1–4) (IL-6: no grade 4 samples).For both cytokines, statistically significant correlations were found between the amount of pre-RT plasma levels and the staining intensity of the corresponding tumour biopsies.
Mentions: To evaluate the potential impact of tumour-derived cytokine production on circulating plasma levels, the tumour biopsies of the NSCLC patients were immunohistochemically stained for IL-6 and TGF-β1. The 52 analysed tumour specimens revealed a heterogeneous staining pattern for IL-6 and TGF-β1 with variably intense cytoplasmatic and/or nuclear staining of the tumour cells. Examples of the TGF-β1 immunohistochemistry of tumour biopsies are presented in figure 4. Compared to the rather intense staining for TGF-β1 in most of the analyzed tumour biopsies, the IL-6 staining of the tumour specimens was generally weaker. In figure 5 the pre-RT plasma levels for IL-6 and TGF-β1, respectively, were plotted against the staining intensity of the corresponding tumour specimens for every patient. For both cytokines a statistically significant correlation was found between the amount of pre-RT plasma levels and the staining intensity of the corresponding tumour biopsies, suggesting that -irrespective of the subsequent irradiation- the IL-6 and TGF-β1 plasma levels in NSCLC patients were influenced to a great extent by the cytokine release of their tumours (IL-6: r = 0.67, p<0.0001; TGF-β1: r = 0.83, p<0.0001).

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