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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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Related in: MedlinePlus

Time courses of TNF-α, IL-1β, IL-6 and TGF-β1 plasma levels (mean values) before (0), during (1–6 weeks) and after radiotherapy (1–9 months), depicted separately for patients with (n = 21) and without radiation pneumonitis (n = 31).Error bars represent SEs of the means. Gray-shaded area indicates the normal range of the cytokine plasma levels.
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pone-0002898-g002: Time courses of TNF-α, IL-1β, IL-6 and TGF-β1 plasma levels (mean values) before (0), during (1–6 weeks) and after radiotherapy (1–9 months), depicted separately for patients with (n = 21) and without radiation pneumonitis (n = 31).Error bars represent SEs of the means. Gray-shaded area indicates the normal range of the cytokine plasma levels.

Mentions: In figure 2 the cytokine dynamics are depicted separately for patients with (lung toxicity: grade I–IV) and without RP. The measured TNF-α and IL-1β plasma levels were within normal ranges (as expected for healthy individuals) at nearly all times and no significant differences between patients with or without RP were observed. For IL-6, in contrast, the plasma levels in patients not developing RP were already increased before and during RT. This contrasts to previous studies [20], [21], where higher IL-6 levels were observed in patients suffering RP. After completion of RT during follow-up (1–9 months) both patient groups (with and without RP) exhibited slightly increased IL-6 plasma levels.


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)

Time courses of TNF-α, IL-1β, IL-6 and TGF-β1 plasma levels (mean values) before (0), during (1–6 weeks) and after radiotherapy (1–9 months), depicted separately for patients with (n = 21) and without radiation pneumonitis (n = 31).Error bars represent SEs of the means. Gray-shaded area indicates the normal range of the cytokine plasma levels.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002898-g002: Time courses of TNF-α, IL-1β, IL-6 and TGF-β1 plasma levels (mean values) before (0), during (1–6 weeks) and after radiotherapy (1–9 months), depicted separately for patients with (n = 21) and without radiation pneumonitis (n = 31).Error bars represent SEs of the means. Gray-shaded area indicates the normal range of the cytokine plasma levels.
Mentions: In figure 2 the cytokine dynamics are depicted separately for patients with (lung toxicity: grade I–IV) and without RP. The measured TNF-α and IL-1β plasma levels were within normal ranges (as expected for healthy individuals) at nearly all times and no significant differences between patients with or without RP were observed. For IL-6, in contrast, the plasma levels in patients not developing RP were already increased before and during RT. This contrasts to previous studies [20], [21], where higher IL-6 levels were observed in patients suffering RP. After completion of RT during follow-up (1–9 months) both patient groups (with and without RP) exhibited slightly increased IL-6 plasma levels.

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