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      Impact of Preexisting Interstitial Lung Disease on Acute, Extensive Radiation Pneumonitis: Retrospective Analysis of Patients with Lung Cancer

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          Abstract

          Introduction

          This study investigated the clinical characteristics and predictive factors for developing acute extended radiation pneumonitis with a focus on the presence and radiological characteristics of preexisting interstitial lung disease.

          Methods

          Of 1429 irradiations for lung cancer from May 2006 to August 2013, we reviewed 651 irradiations involving the lung field. The presence, compatibility with usual interstitial pneumonia, and occupying area of preexisting interstitial lung disease were retrospectively evaluated by pretreatment computed tomography. Cases of non-infectious, non-cardiogenic, acute respiratory failure with an extended bilateral shadow developing within 30 days after the last irradiation were defined as acute extended radiation pneumonitis.

          Results

          Nine (1.4%) patients developed acute extended radiation pneumonitis a mean of 6.7 days after the last irradiation. Although preexisting interstitial lung disease was found in 13% of patients (84 patients), 78% of patients (7 patients) with acute extended radiation pneumonitis cases had preexisting interstitial lung disease, which resulted in incidences of acute extended radiation pneumonitis of 0.35 and 8.3% in patients without and with preexisting interstitial lung disease, respectively. Multivariate logistic analysis indicated that the presence of preexisting interstitial lung disease (odds ratio = 22.6; 95% confidence interval = 5.29–155; p < 0.001) and performance status (≥2; odds ratio = 4.22; 95% confidence interval = 1.06–20.8; p = 0.049) were significant predictive factors. Further analysis of the 84 patients with preexisting interstitial lung disease revealed that involvement of more than 10% of the lung field was the only independent predictive factor associated with the risk of acute extended radiation pneumonitis (odds ratio = 6.14; 95% confidence interval = 1.0–37.4); p = 0.038).

          Conclusions

          Pretreatment computed tomography evaluations of the presence of and area size occupied by preexisting interstitial lung disease should be assessed for safer irradiation of areas involving the lung field.

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          Most cited references24

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          Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study.

          Interstitial lung disease (ILD) occurs in Japanese patients with non-small cell lung cancer (NSCLC) receiving gefitinib. To elucidate risk factors for ILD in Japanese patients with NSCLC during treatment with gefitinib or chemotherapy. In a prospective epidemiologic cohort, 3,166 Japanese patients with advanced/recurrent NSCLC were followed for 12 weeks on 250 mg gefitinib (n = 1,872 treatment periods) or chemotherapy (n = 2,551). Patients who developed acute ILD (n = 122) and randomly selected control subjects (n = 574) entered a case-control study. Adjusted incidence rate ratios were estimated from case-control data by odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression. Crude (observed) incidence rates and risks were calculated from cohort data. The observed (unadjusted) incidence rate over 12 weeks was 2.8 (95% CI, 2.3-3.3) per 1,000 person-weeks, 4.5 (3.5-5.4) for gefitinib versus 1.7 (1.2-2.2) for chemotherapy; the corresponding observed naive cumulative incidence rates at the end of 12-week follow-up were 4.0% (3.0-5.1%) and 2.1% (1.5-2.9%), respectively. Adjusted for imbalances in risk factors between treatments, the overall OR for gefitinib versus chemotherapy was 3.2 (1.9-5.4), elevated chiefly during the first 4 weeks (3.8 [1.9-7.7]). Other ILD risk factors in both groups included the following: older age, poor World Health Organization performance status, smoking, recent NSCLC diagnosis, reduced normal lung on computed tomography scan, preexisting chronic ILD, concurrent cardiac disease. ILD-related deaths in patients with ILD were 31.6% (gefitinib) versus 27.9% (chemotherapy); adjusted OR, 1.05 (95% CI, 0.3-3.2). ILD was relatively common in these Japanese patients with NSCLC during therapy with gefitinib or chemotherapy, being higher in the older, smoking patient with preexisting ILD or poor performance status. The risk of developing ILD was higher with gefitinib than chemotherapy, mainly in the first 4 weeks.
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            Cumulative incidence of and predictive factors for lung cancer in IPF.

            Previous studies have indicated a high incidence of lung cancer in IPF, and some have identified its risk factors. However, those studies were retrospective and the clinical characteristics of IPF patients developing lung cancer were evaluated only when those patients had developed the cancer. The true cumulative incidence of lung cancer after the diagnosis of IPF and its predictive factors at the initial diagnosis of IPF remain unknown. The present study was conducted to elucidate the cumulative incidence and risk factors for lung cancer in IPF patients by retrospective longitudinal cohort analysis. The study group consisted of 103 IPF patients without lung cancer at the time of their initial diagnosis. The cumulative incidence of lung cancer was estimated using the Kaplan-Meier method. The strength of association between several variables present at the initial diagnosis of IPF and the development of lung cancer was assessed using Cox proportional hazards regression analysis. A total of 21 (20.4%) patients with IPF developed lung cancer during the observation period. The cumulative incidence rate of lung cancer increased as the duration of follow up increased (3.3%, 15.4% and 54.7% at 1, 5 and 10 years, respectively). Univariate Cox proportional hazards regression analysis showed that age and smoking at the initial diagnosis of IPF were significantly associated with lung cancer. Multivariate Cox proportional hazards regression analysis indicated that age at initial diagnosis was an independent significant factor predicting lung cancer. The cumulative incidence of lung cancer increased over time and age at diagnosis of IPF was independently associated with development of lung cancer.
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              The risk of cytotoxic chemotherapy-related exacerbation of interstitial lung disease with lung cancer.

              It is unknown what type of interstitial lung disease (ILD) has high risk for chemotherapy-related exacerbation of ILD. We investigated the risk of exacerbation of ILD for patients with lung cancer with ILD. One hundred nine patients with lung cancer with ILD treated with cytotoxic chemotherapy at Shizuoka Cancer Center between August 2002 and April 2010 were retrospectively reviewed. On pretreatment computed tomography (CT) of the chest, 69 patients (63%) were identified with usual interstitial pneumonia (UIP) pattern, and 40 patients (37%) had non-UIP pattern. Patients with UIP pattern developed cytotoxic chemotherapy-related exacerbation of ILD more frequently than those with non-UIP pattern (30 versus 8%, p = 0.005). The incidence of grade 5 pulmonary toxicities was 9% in patients with UIP pattern, compared with 3% in those with non-UIP pattern. Multivariate analyses demonstrated that age (<70 years) and CT pattern (UIP) were significant independent risk factors for cytotoxic chemotherapy-related exacerbation of ILD. In small cell lung cancer, overall survival (OS) from the start of first-line chemotherapy was significantly shorter in UIP pattern than non-UIP pattern (median OS: 9 versus 16 months, p = 0.0475), whereas there was no significant difference in patients with non-small cell lung cancer (median OS: 12 versus 9 months, p = 0.2529). Our results indicated that the incidence of exacerbation of ILD was significantly higher in patients with lung cancer with UIP pattern on CT findings than in those with non-UIP pattern. Therefore, great care is required when administering cytotoxic chemotherapy agents for patients with lung cancer with UIP pattern.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                13 October 2015
                2015
                : 10
                : 10
                : e0140437
                Affiliations
                [1 ]Department of Respiratory Medicine, Respiratory Disease Center, Seirei Mikatahara General Hospital, Hamamatsu, Japan
                [2 ]Department of Radiation Oncology, Seirei Mikatahara General Hospital, Hamamatsu, Japan
                [3 ]Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan
                [4 ]Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
                University of Maastricht (UM), NETHERLANDS
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YO. Performed the experiments: YO TA MO TM MK HH YE TI. Analyzed the data: YO TA. Wrote the paper: YO. Supervised the study: K. Yamada NI K. Yokomura TS.

                Article
                PONE-D-15-22288
                10.1371/journal.pone.0140437
                4603947
                26460792
                91af4d5c-aab2-41c0-8aa8-cdd3765f3642
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 22 May 2015
                : 25 September 2015
                Page count
                Figures: 2, Tables: 4, Pages: 12
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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