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Early Variations of Circulating Interleukin-6 and Interleukin-10 Levels During Thoracic Radiotherapy Are Predictive for Radiation Pneumonitis

From the Department of Pneumology, Hôpital de la Croix Rousse; Departments of Public Health (Department of Public Health—Biostatistics Unit) and Radiation Oncology and Cytokines and Cancer Research Unit Institut National de la Santé et de la Recherche Médicale U.590, Centre Léon Bérard; Department of Pneumology, Hôpital St Joseph; and Department of Pneumology, Hôpital Louis Pradel, Lyon; Department of Pneumology, Hôpital de Villefranche sur Saône, Villefranche sur Saône, France; and Blokhin Cancer Research Center, Moscow, Russia

Address reprint requests to Dominique Arpin, MD, Hôpital de la Croix Rousse, 103 Grande Rue de la Croix Rousse, 69317 Lyon Cedex 04, France; e-mail: dominique.arpin{at}chu-lyon.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To investigate variations of circulating serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF), and interleukin-10 (IL-10) during three-dimensional conformal radiation therapy (3D-CRT) in patients with non–small-cell lung cancer and correlate these variations with the occurrence of radiation pneumonitis.

PATIENTS AND METHODS: Ninety-six patients receiving 3D-CRT for stage I to III disease were evaluated prospectively. Circulating cytokine levels were determined before, every 2 weeks during, and at the end of treatment. Radiation pneumonitis was evaluated prospectively between 6 and 8 weeks after 3D-CRT. The predictive value of clinical, dosimetric, and biologic (cytokine levels) factors was evaluated both in univariate and multivariate analyses.

RESULTS: Forty patients (44%) experienced score 1 or more radiation pneumonitis. No association was found between baseline cytokine levels and the risk of radiation pneumonitis. In the whole population, mean levels of TNF, IL-6, and IL-10 remained stable during radiotherapy. IL-6 levels were significantly higher (P = .047) during 3D-CRT in patients with radiation pneumonitis. In the multivariate analysis, covariations of IL-6 and IL-10 levels during the first 2 weeks of 3D-CRT were evidenced as independently predictive of radiation pneumonitis in this series (P = .011).

CONCLUSION: Early variations of circulating IL-6 and IL-10 levels during 3D-CRT are significantly associated with the risk of radiation pneumonitis. Variations of circulating IL-6 and IL-10 levels during 3D-CRT may serve as independent predictive factors for this complication.

	INTRODUCTION

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Non–small-cell lung cancer (NSCLC) is the most common cancer in developed countries.¹ Approximately 30% of lung cancer patients present at diagnosis without distant metastases, but with locally advanced or medically inoperable disease. For these patients, conventional (60 Gy over 6 weeks) thoracic radiation therapy (RT) has been the treatment of choice in the past, despite a local control of less than 20% and a 5-year survival rate in the range of 5% to 10%.² Increased radiation doses,³ or adjunction of concomitant chemotherapy to RT,⁴ have produced a significant improvement of local control, although this is not always translated into survival gain for the patients because of a parallel increase of locoregional toxicity.⁵

Radiation pneumonitis (RP), which represents the acute expression of radio-induced lung damage, is one of these limiting toxicities. The symptoms of RP, especially dyspnea, are frequently out of proportion with the irradiated lung volume; resolution occurs spontaneously or after corticosteroid treatment in the majority of patients.⁶ However, 8% to 13% of NSCLC patients develop severe toxicity,⁶ and approximately 1.6% die from RP after thoracic radiotherapy.⁷

At the cellular level, RP is characterized by the infiltration of inflammatory cells into the pulmonary interstitium and alveolar spaces.⁸ Although the pathogenesis of RP remains unclear, this process may involve active interactions between cellular and humoral factors including immune and parenchymal cells, chemokines, and adhesion molecules. Research in radiation pulmonary injury has supported the involvement of cytokine factors in the development of RP.⁹ Animal data have shown an early overproduction of both pro-inflammatory (interleukin-1 [IL-1], tumor necrosis factor alpha [TNF]) and pro-fibrogenic (transforming growth factor beta 1 [TGFß1]) cytokines during radiotherapy and have suggested a role of the sustained production of these cytokines in the development of acute and late pulmonary toxicities.⁹ In humans, some clinical reports have shown changes in the plasma concentration of TGFß1^10,11 and IL-6^12,13 during RT and suggested that these variations could identify patients at risk of RP.

The risk of developing RP after thoracic RT has been essentially based on measurements of dosimetric parameters (ie, total dose, dose per fraction, and volume of normal tissue irradiated). In NSCLC patients treated with three-dimensional conformal radiation therapy (3D-CRT), specific dose-volume histogram (DVH) parameters have been previously reported to be risk factors for RP. In particular, the mean lung dose (MLD)^14,15 and the percentage of irradiated lung volume exceeding 20 Gy (V20) and 30 Gy (V30) have been identified as useful parameters to predict the risk of RP.^15-19 However, none of these parameters can predict RP with absolute reliability. A recent review by Rodrigues et al²⁰ has reported a high percentage of false-negative (ie, predicting low risk of RP whereas patient actually developed RP) rates for volume-dose thresholds and MLD among published studies. Therefore, there is a need to develop additional predictive tools that will help identify patients at risk for RP after 3D-CRT; the measurement of changes in cytokine levels during 3D-CRT may be useful in this setting.

In 1996, we initiated a large prospective study in 96 consecutive NSCLC patients treated with 3D-CRT to identify factors that might differentiate patients at high and low risk for RP. Results of this study showing that age 60 years, V20, V30, and MLD were predictive of RP in this population have been recently published.¹⁹ We present here additional data concerning the kinetic profile of pro-inflammatory (IL-6, TNF) and anti-inflammatory (IL-10) cytokines before and during 3D-CRT in these patients, and we analyze the correlations between variations of these cytokine levels before and during 3D-CRT and the risk of developing radiation pneumonitis.

	PATIENTS AND METHODS

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Patient Eligibility
From November 1996 to September 2000, 96 consecutive patients were enrolled onto this prospective study. Patients of older than 18 years of age with localized histologically or cytologically confirmed NSCLC, life expectancy more than 6 months, Karnofsky performance status 80, and good pulmonary function tests (PFTs; ratio of forced expiratory volume at 1 second on vital capacity 50%, ratio of diffusion capacity for carbon monoxide on alveolar volume 50%) were eligible. PFTs were performed immediately before 3D-CRT in the event of surgery or 28 days before 3D-CRT if surgery was not performed. Voluntary, written informed consent was obtained before registration from all patients. The protocol procedures were approved by an independent protocol review committee and an ethical committee.

Treatment Description
The modality of 3D-CRT has been previously discussed.^18,19 Briefly, patients received conventional fractionated RT (2 Gy per fraction, 5 days per week). The total irradiation dose ranged from 46 to 72 Gy, with a median of 66 Gy. Target volumes (ie, gross tumor volume [GTV], clinical target volumes 1 and 2) were defined using the International Commission on Radiation Units and Measurements (ICRU) -50 report.²¹ The structures of interest, such as GTV, clinical target volumes, and normal structures, were contoured on multiple computed tomography pictures. Lungs were automatically contoured, excluding the GTV. Doses were calculated taking into account the tissue density heterogeneity, and DVHs of the lungs (considered as combined-paired organ) were calculated based on computed tomography–defined lung volumes. Total MLD, V20, and V30 were calculated from lung DVHs. The total MLD was calculated as follows: MLD = [(right lung volume x mean lung dose to right lung) + (left lung volume x mean lung dose to left lung)]/(left lung volume + right lung volume). 3D-CRT was performed using previously published DVH thresholds parameters, V20 and V30, corresponding to irradiated lung volume receiving more than 20 and 30 Gy, respectively.^15,16

Evaluation of RP
The occurrence and severity of RP were prospectively determined 6 to 8 weeks and 6 months after the end of 3D-CRT using a scale derived from the Lent-Soma scale defined by the Radiation Therapy Oncology Group (RTOG) and the European Organisation for Research and Treatment of Cancer.²² Management items of the Lent-Soma classification²² were not considered in this study because, in France, corticosteroids are given early in the course of the disease, including for the treatment of score 2 RP, which might have artificially increased the rate of score 3 RP.

Thus RP was scored here from clinical symptoms, radiologic abnormalities, and loss of pulmonary function. This evaluation included three subjective scales (cough, dyspnea, and thoracic pain) and two objective scales (chest x-ray read by an independent committee of experts and PFTs [reduction of vital capacity and/or diffusion capacity for carbon monoxide on alveolar volume]). All single-scale measures ranged in score from 0 to 4. The final scoring was equal to the average of the five scores. For example, if one patient was scored as cough grade 1, dyspnea grade 1, thoracic pain grade 0, chest x-ray grade 2, PFTs grade 1, then the final score was (1 + 1 + 0 + 2 + 1)/5 = 1. RP was defined as the development of pulmonary toxicity of score 1.

Circulating Cytokines Analysis
IL-6, IL-10, and TNF serum levels were determined before 3D-CRT (baseline), then every 2 weeks during 3D-CRT until the sixth week of treatment (ie, four serum samples). As previously described,²³ the sera of the patients were collected and immediately stored at 4°C, then quickly centrifuged at 1,000 x g at 4°C for 10 minutes, and then stored frozen at –80°C after fractionation in 400 µL. IL-6, IL-10, and TNF concentrations in the serum were measured using a specific enzyme immunoassay kit from Immunotech (Marseille, France), with a limit of detection of 3 pg/mL for IL-6 and 5 pg/mL for IL-10 and TNF. Both assays use the quantitative sandwich enzyme immunoassay technique. All serum level determinations were performed in duplicate.

Statistical Analysis
Analyses were performed using SPSS version 11.5 (SPSS Inc, Chicago, IL). Differences between baseline cytokine levels in patients with and without RP were tested using the nonparametric Mann-Whitney’s exact test to allow for abnormal distributions. Analysis of variance for repeated measures was used to study associations between cytokine levels during 3D-CRT and the time factor, occurrence of RP, and time to RP. The univariate analysis of clinical and dosimetric factors predictive of RP was previously discussed.¹⁹ Briefly, standard statistical analysis methods were used to assess correlations between occurrence of RP and potential prognostic features in the univariate analysis; Pearson’s ² test or Fisher’s exact test were used for categoric variables, and Student’s t test for quantitative variables, as appropriate. In the multivariate analysis, a significant relationship with occurrence of RP (P .15) was used as the criterion for including a variable in a stepwise logistic regression procedure. In the stepwise procedure, a .15 significance level for entering and removing explanatory variables (clinical, dosimetric, changes in cytokine levels) was used to determine the independent risk factors for RP. The final model was chosen on the basis of those variables for which P .05. A two-way significance level of 5% was considered to be statistically significant in all analyses.

	RESULTS

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Patient Characteristics
The characteristics of the patients are listed in Table 1. Of the 96 patients enrolled, six patients could not be evaluated for RP at 6 to 8 weeks after 3D-CRT. Two patients died before evaluation because of cancer progression, and four PFTs were not performed. Previous surgery was performed in 49 patients (51%). Sixty-three patients (66%) had previously received one line of chemotherapy. Eleven patients (11%) had received two lines, and none had received more than two lines of chemotherapy before RT. Finally, 24 (25%) of the 96 patients received a cisplatin-based regimen during RT.

View larger version (11K): [in this window] [in a new window]   Fig 1. Cytokine distribution at baseline and during three-dimensional conformal radiation therapy. (A) interleukin (IL)-6; (B) IL-10; (C) tumor necrosis factor alpha (TNF). Central boxes represent 50% of the distribution of the values (inter-quartile range). The upper edge of a box indicates the 75th percentile, and the lower edge represents the 25th percentile. Central horizontal lines represent the median. The small circles represent distant values (ie, beyond 1.5 times the interquartile range).

View larger version (10K): [in this window] [in a new window]   Fig 2. Variations of interleukin-6 (IL-6) at baseline and during three-dimensional conformal radiation therapy (3D-CRT) for patients who did (n = 27) or did not (n = 40) develop radiation pneumonitis (RP) 6 to 8 weeks after 3D-CRT. The solid line with circles represents IL-6 levels (mean values) in patients with RP (score 1). The line with squares represents IL-6 levels (mean values) in patients with no RP (score 0). Error bars represent SEs of the means.

View larger version (10K): [in this window] [in a new window]   Fig 3. Variations of interleukin-10 (IL-10) at baseline and during three-dimensional conformal radiation therapy (3D-CRT) for patients who did (n = 27) or did not (n = 40) develop radiation pneumonitis (RP) 6 to 8 weeks after 3D-CRT. The solid line with circles represents IL-10 levels (mean values) in patients with RP (score 1). The line with squares represents IL-10 levels (mean values) in patients with no RP (score 0). Error bars represent SEs of the means.

	DISCUSSION

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In this article, we report a high incidence (44%) of RP in NSCLC patients treated with 3D-CRT. Although the incidence of RP has been the subject of numerous reports, rates vary significantly between studies. The lack of consensus on uniform criteria for defining RP makes it difficult to compare the incidence and severity of RP across studies and may explain the high variability of RP incidence observed by Mosvas et al in their review.⁶ For instance, some authors have used their own scoring system^16,24 and others have used the Southwest Oncology Group classification^14,25 in which grade 2 toxicity is defined as a need for corticosteroid therapy, whereas the same grade is defined as mild or moderate symptoms without corticosteroid requirement in the RTOG classification.³ In this study, we used a classification derived from the Lent-Soma (Late Effect on Normal Tissues—Subjective, Objective, Management, and Analytic) scale, defined by both the RTOG and the European Organisation for Research and Treatment of Cancer.²² This classification is based not only on subjective (clinical) evaluation of RP but also on objective measurements of loss of pulmonary function and radiologic changes and probably allows a more precise and reproducible evaluation of the incidence and severity of RP than clinical-based scoring systems. In our study, the large majority (82%) of RP patients had score 1 toxicity, whereas 6% had score 2, 1.1% had score 3, and no patient had score 4 toxicity. The high rate of RP observed in our study is thus mainly due to score 1 toxicity. Actually, our results compare favorably with other prospective studies in which a range of 7% to 10% of grade 2 toxicity was observed after 3D-CRT, using various scoring scales.^14,16,25

In many publications regarding predictive factors for pulmonary toxicity, RP is defined essentially using clinical symptoms^11,16,26 or is only considered as relevant if the score of toxicity is grade 2 or higher.¹⁴ These methods consequently do not consider score 1 toxicities, which probably represent the large majority of events observed after 3D-CRT, as demonstrated in our study. Although they are only slight complications with minimal clinical expression, patients with these score 1 toxicities nonetheless experience genuine toxic events in comparison with patients who do not develop any clinically, radiologically, or functionally measurable acute radio-induced reaction. Moreover, as demonstrated in this study, a majority of patients with RP score 1 at 6 to 8 weeks also experienced score 1 toxicity at 6 months. The main objective of our study was to investigate variations of circulating cytokines during 3D-CRT and to correlate these variations with the risk of developing RP, whatever its intensity. From this pathogenic point of view, and as a patient can develop a genuine RP without marked clinical signs, it was decided to consider the whole spectrum of expression of RP, including score 1 toxicity, according to the criteria defined above.

To our knowledge, this is one of the largest prospective studies investigating circulating cytokines before and during 3D-CRT in a population of patients treated for NSCLC in the same institution. No statistically significant correlation was found between baseline levels of cytokines before RT and the risk for developing RP. Concerning pro-inflammatory cytokines, Chen et al¹³ reported no correlation between baseline TNF and the incidence of RP. However, they also reported that baseline IL-6 was increased in patients who did develop grade 1 and 2 RP according to the National Cancer Institute common toxicity criteria. A similar trend was observed in the present study for baseline IL-6 in patients who did and those who did not develop RP (15.7 pg/mL v 7.6 pg/mL, respectively), but the difference did not reach statistical significance (P = .56). However, the scoring methods, the type of enzyme-linked immunosorbent assay test used, and the characteristics of the populations (87% of the 25 patients included had gross disease at the time of irradiation in Chen’s study) were different between the two studies, thus providing a potential explanation for this discrepancy. Elevations of IL-6 and IL-10 circulating levels have also previously been described in patients with NSCLC and were related to tumor cell or stromal cell production. IL-6 levels are significantly more elevated in the bronchoalveolar lavage (BAL) fluid of patients with NSCLC than in patients with nonmalignant disease,²⁷ and elevated IL-10 plasma concentrations have been found in NSCLC patients and were correlated with reduced survival.²⁸ Taken together, these observations suggest that cytokine levels before RT are a nonspecific process that may be influenced by many parameters, including pre-RT treatments, tumor and/or stromal cell production, or host-associated disease.

Although circulating IL-6 and IL-10 levels remained stable in the whole population during 3D-CRT, their circulating levels showed a statistically significant opposite evolution between RP and non-RP patients included in our study. IL-6 levels remained significantly elevated throughout the treatment in RP patients in comparison with non-RP patients, with a significant peak elevation at 2 weeks of treatment. IL-6 is a multifunctional cytokine involved in the regulation of immunologic and inflammatory response.²⁹ In the lung parenchyma, IL-6 is synthesized by a large variety of cells, including alveolar macrophages, type 2 pneumocytes, T lymphocytes, and fibroblasts.^30-32 Recently, IL-6 concentration has been reported to be elevated in the BAL fluid of patients treated with thoracic RT for NSCLC.³³ Of note, this increase was only observed in irradiated areas, strongly suggesting a specific inducing role of ionizing RT in this local overproduction. Elevated circulating IL-6 levels during RT have also been recently correlated with an increased risk of developing RP in a preliminary study¹² that reported higher IL-6 levels in the group of RP patients throughout the treatment. The present observation made from a larger cohort of patients treated by 3D-CRT confirms these results and further suggests that the maximal intensity of overproduction occurs in the first weeks of treatment.

IL-10 is an anti-inflammatory cytokine produced by monocytes and macrophages. One of its main functions is to downregulate inflammation by blocking the production of pro-inflammatory cytokines, such as IL-6, and reducing the function of antigen-presenting cells.^34,35 In our study, IL-10 levels remained low in RP patients throughout the treatment, whereas a consistent elevation of circulating IL-10 was observed at 2 weeks in non-RP patients. The lack of statistical difference between RP and non-RP groups, despite the magnitude of the difference between mean IL-10 levels at 2 weeks in RP and non-RP patients (56.9 pg/mL v 409.0 pg/mL), may be due to the wide dispersion of IL-10 values observed in RP and non-RP patients. This variation of IL-10 production may indeed reflect differences in the IL-10 producing capacity of each individual related to IL-10 gene promoter differences, as recently reported in non-Hodgkin’s lymphomas.³⁶

Because cytokines mutually regulate their production with synergistic or antagonistic biologic effects, the role of each given cytokine must be considered in this complex interactive network. In our study, the opposite evolution of circulating IL-6 and IL-10 levels during the first 2 weeks of 3D-CRT was significantly associated with the risk of subsequent RP and seemed to be an independent predictive factor for early radio-induced toxicity in multivariate analysis. To our knowledge, this is the first observation that early variations of biologic markers during thoracic RT are an independent predictive factor for RP. This indicates that such variations could be an additional predictive tool to be used in association with dosimetric parameters such as MLD, V20, or V30 for a more precise evaluation of the risk of early radio-induced toxicity. Furthermore, these results also suggest that the balance between pro-inflammatory and anti-inflammatory cytokine secretions during the first weeks of irradiation may be involved in the pathogenesis of RP.

RP is a frequent complication of lung RT for which the biologic mechanisms remain unclear. However, several lines of evidence suggest that RP could represent the clinical expression of a bilateral lymphocytic alveolitis, reflecting the inflammatory and immune response of the lung tissue damaged by ionizing radiation, similar to that seen in farmer’s lung disease or pigeon breeders’ disease.^37-39 Indeed, bilateral lymphocytic alveolitis seems to be a common process after strictly unilateral thoracic irradiation. In 1995, Morgan et al, using both BAL and gallium lung scan, observed that 75% of women irradiated for breast cancer had a bilateral lymphocytic alveolitis with CD4⁺ lymphocyte infiltration 1 month after the end of RT.³⁷ These findings were confirmed later by others³⁸ in a larger population of women treated for breast cancer, with 85% of the patients presenting a bilateral lymphocytic alveolitis in BAL after strictly unilateral thoracic irradiation, even if they were asymptomatic. Like other immune and inflammatory processes, this alveolitis may be regulated by direct cell-cell interaction and indirect cell-cell communication by production of cytokines. Interestingly, Yoshida et al⁴⁰ demonstrated in 1995 that the overexpression of IL-6 and IL-6 receptor by in vivo transfection in Wistar rats can experimentally induce profound lymphocytic alveolitis without marked fibrosis, although the overexpression of TGFß1 by the same method is associated with fibrosis with minimal associated alveolitis. These experimental data suggest that IL-6 overproduction is relevant to alveolitis but not to fibrosis. Moreover, recent human data have shown a positive link between IL-6 level in BAL and the number of lymphocytes in BAL fluids in patients with idiopathic nonspecific interstitial pneumonia and with usual interstitial pneumonia.⁴¹ Taken together, these results support the active involvement of IL-6 as one of the causes of lymphocytic alveolitis both in experimental models and in human lung disease. Concerning RP, which is thought to be a lymphocytic alveolitis, the occurrence of a significant peak of IL-6 in the first weeks of treatment in patients with subsequent RP is in accordance with this hypothesis. Because the opposite evolution of IL-6 and IL-10 levels during the first 2 weeks of 3D-CRT were significantly related to the occurrence of RP in our study, this also suggests that a defect in IL-10 anti-inflammatory response is likely to contribute to this phenomenon.

In conclusion, the present study reports a significant correlation between the variations of circulating IL-6 and IL-10 levels in the first weeks of 3D-CRT and the risk of RP in patients with NSCLC. Further studies with particular attention to low RP grades are needed for confirmation. If confirmed, these results should give rise to novel and specific prevention strategies for RP.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank Marie-Dominique Reynaud for editorial help.

	NOTES

 
Supported by grants from the French Ministry of Health (PHRC No. 2701), La Ligue Contre le Cancer de l'Ain (France), and La Ligue Contre le Cancer du Rhône (France), and European Society of Medical Oncology.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA.

D.A., D.P., J.-Y.B., and C.C. contributed equally to this work.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted February 23, 2005; accepted August 29, 2005.

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