The Clinical Respiratory Journal

ORIGINAL ARTICLE

Prognostic factors affecting survival in non-small cell lung carcinoma patients with malignant pleural effusions Umut Sabri Kasapoglu1, Sibel Arınç1, Sinem Gungor1, Ilim Irmak2, Pinar Guney1, Ferda Aksoy3, Dilek Bandak4 and Armagan Hazar1 1 2 3 4

Department Department Department Department

of of of of

Chest Diseases, Sureyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey Chest Diseases, Dr. Sureyya Adanali Goksun State Hospital, Kahramanmaras, Turkey Pathology, Sureyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey Clinical Biochemistry, Sureyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital, Istanbul, Turkey

Abstract Background and Aims: Lung cancer is the most common cause of malignant pleural effusions (MPEs). For patients with lung cancer and MPE, median survival is only 3–4 months. The aim of this study was to evaluate lung cancer patients with MPE by clinical and laboratory findings on admission, and determine 2-year survival rate and prognostic factors. Methods: Between 2008 and 2011, we examined 199 cases of non-small cell lung carcinoma with MPE. Demographic factors of patients, tumor characteristics, treatment delivered and laboratory parameters affecting prognosis were evaluated. Survival rates were estimated by Kaplan–Meier method. Significance of each prognostic factors selected by univariate analysis were confirmed using Cox regression model. Results: The study included 139 (69.8%) male and 60 (30.2%) female patients with a median age of 64 (30–85) years. Median overall survival was 4.4 months. Adenocarcinoma was the leading cause of MPE with 80.4%. A univariate analysis showed that factors affecting mortality included gender (P < 0.001), MPE with distant metastasis (P = 0.025), lower serum albumin (P < 0.0001), lower pleural protein (P < 0.0001), increased serum lactate dehydrogenase (P = 0.003), increased serum C-reactive protein (CRP) (P < 0.0001), increased white blood cells (P < 0.0001), histopathological type (P = 0.004) and treatment decision (P < 0.0001). A multivariate analysis revealed that patients who had high level of serum CRP (P = 0.017), lower serum albumin (P = 0.009) and lower pleural protein (P = 0.003), MPE with distant metastasis (P = 0.003) and those who were chemotherapy naive (P < 0.0001) had shorter survival. Conclusion: High level of serum CRP, lower serum albumin and lower pleural protein, MPE with distant metastasis were most important prognostic factors for non-small cell lung carcinoma in patients with MPEs. Please cite this paper as: Kasapoglu US, Arınç S, Gungor S, Irmak I, Guney P, Aksoy F, Bandak D and Hazar A. Prognostic factors affecting survival in non-small cell lung carcinoma patients with malignant pleural effusions. Clin Respir J 2015; ••: ••–••. DOI:10.1111/crj.12292.

Key words distant metastasis – malignant pleural effusion – non-small cell lung cancer – prognostic factors – survival Correspondence Umut Sabri Kasapoglu, MD, Department of Chest Diseases, Sureyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital, Armaganevler Mah. Samanyolu Cad. Cardak Sok. No:53 Samanyolupark Sitesi D:29 Umraniye, 34760 Istanbul, Turkey. Tel: 00905548181919 Fax: +902164214110 email: [email protected] Received: 15 July 2014 Revision requested: 10 December 2014 Accepted: 28 February 2015 DOI:10.1111/crj.12292 Authorship and contributorship Designed the study: Sibel Arınç, Umut Sabri Kasapoglu, Sinem Gungor, Armagan Hazar and Ilim Irmak. Performed the study: Sibel Arınç, Umut Sabri Kasapoglu, Sinem Gungor and Armagan Hazar. Contributed important reagents: Armagan Hazar, Ferda Aksoy and Dilek Bandak. Collected the data: Pınar Guney, Umut Sabri Kasapoglu, Dilek Bandak, Sinem Gungor and Ferda Aksoy. Analyzed the data: Umut Sabri Kasapoglu, Sinem Gungor, Sibel Arınç and Ilim Irmak.

Ethics The study protocol was approved by local ethics committee at the Dr. Lutfi Kirdar Kartal Training and Research Hospital and fulfilled the Declaration of Helsinki.

Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article.

The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2015 John Wiley & Sons Ltd

Wrote the paper: Umut Sabri Kasapoglu, Sinem Gungor, Sibel Arınç and Armagan Hazar.

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Malignant pleural effusions in lung cancer

Introduction Malignant pleural effusion (MPE), which is defined as detection of malignant cells in the pleural fluid pleural fluid ± parietal pleura, is an indication of a common manifestation in cancer patients and reduced life expectancy. Lung cancer is the most common cause of MPE, accounting for approximately 40% of the patients. Median survival time following the diagnosis of MPE ranges from 3 to 12 months, and it depends on the stage and type of underlying malignancy. The shortest survival time is observed in malignant effusions secondary to lung cancer (1, 2). Studies have shown that the median survival time in patients with MPE associated with lung cancer was 3–4 months, which can rise up to 13 months in patients with a higher performance score (3, 4). The present study aimed to evaluate the clinical and laboratory findings on admission in lung cancer patients with MPEs, also determine the median survival time, two year survival rate, and evaluate the prognostic factors associated with survival time in patients.

Materials and methods Patients and data A retrospective cohort study was performed between January 1, 2008 and December 31, 2011 at the Sureyyapasa Chest Diseases and Thoracic Surgery Training and Research Hospital. The patient files were reviewed, and 199 patients diagnosed histopathologically with MPE associated with non-small cell lung cancer were included in the study. The patients were evaluated with respect to age, gender, presenting complaints, presence of any comorbid disease, metastatic sites, histopathological type, smoking status, biochemicals of blood and pleural fluid [albumin, protein, lactate dehydrogenase (LDH), glucose, adenosine deaminase], hemogram values (leukocytes, hemoglobin, platelets), serum C-reactive protein (CRP) level, methods used for diagnosis of MPE, any use of talc pleurodesis and treatment methods. Complaints of cough, shortness of breath, chest pain, hemoptysis and weight loss were considered as presenting complaints. A patient had to smoke cigarettes at least for 1 year to have been considered as a smoker. The serum C-reactive protein level of patients was evaluated by a nephelometric assay using a BN Prospec device of Dade Behring Corporation (Istanbul, Turkey). Biochemical parameters were measured by

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Technicon RA-XT Analyzer (Technicon Instruments Corp., Tarrytown, NY, USA). Hemogram values were evaluated using a Coulter STKS hematological analyzer (Beckman Coulter Cooperation, Miami, FL, USA). All patients’ pleural effusion histopathological analysis (pleural fluid cell block ± biopsy from parietal pleura) was performed at the Pathology Department. Immunocytochemistry was used to differentiate between malignant cell type. All patients’ mortality data were collected from http://obs.gov.tr website. This study was approved by the Local Ethical Commitee of a state training and research hospital (08.04.2014 – 89513307/1009/271 – Dr. Lutfi Kirdar Kartal Training and Research Hospital – Istanbul – Turkey).

Definitions MPE was defined as detection of malignant tumor cells in the pleural fluid ± parietal pleura. In pleural fluids, the difference between transudate and exudate was determined according to the Light criteria (pleural fluid LDH >200 U/L, pleural fluid/serum LDH >0.6, pleural fluid/serum protein >0.5). The hemithorax with pleural effusion was evaluated, and the amount of pleural effusion on the posterior anterior chest X-ray was calculated. The fluid was defined as ‘small’ when it occupied less than 1/3 of the hemithorax, ‘moderate’ when it occupied 1/3 to 2/3 of the hemithorax and ‘massive’ when it occupied more than 2/3 of the hemithorax. The small and moderate pleural fluids were grouped as non-massive pleural effusion. In patients with bilateral pleural effusion, the fluid on the more involved side was considered. The normal range was 0–5.0 mg/dL for CRP, 3.4–5.0 g/dL for albumin, 6.4–8.2 g/dL for protein, 70–110 mg/dL for glucose and 0–250 U/L for LDH. A leukocyte count of 4.8–10.0 109/L was considered normal, below 4.8 109/L as leukopenia and above 10.0 109/L as leukocytosis. The normal range of hemoglobin was from 12.0–14.0 g/dL in women and from 14.0 to 18.0 g/dL in men, and any value below this range was considered anemia; and the normal range of platelets was from 130 to 400 109/L, and any value above 400 109/L was defined as thrombocytosis and below 130 109/L as thrombocytopenia.

Statistical analysis Data with normal and homogeneous distribution were presented as mean value ± standard deviation while data without a normal and homogeneous distribution were shown as median (min-max) values as

The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2015 John Wiley & Sons Ltd

Kasapoglu et al.

well as numbers and percentages. The distribution of variables was assessed using the Kolmogorov– Simirnov test, and homogeneity using the one-way ANOVA. A t-test was used for analysis of parametric data, Mann–Whitney U-test for analysis of nonparametric data and chi-square test for analysis of categorical data. The survival curve was calculated using the Kaplan–Meier method, and a log-rank test was used to compare the difference in survival between the groups. Cox regression analysis was used for multivariate survival analysis. The results were analyzed with a confidence level of 95% and a significance level of P < 0.05. For statistical analyses, SPSS (Statistical Package for Social Sciences) for Windows 21.0 software (SPSS Inc., Chicago, IL, USA) was used.

Results Characteristics of the non small cell lung carcinoma patients with MPE Of all patients, 139 (69.8%) were male and 60 (30.2%) were female. The median age was 64 years (range, 30–85), and 105 of patients (52.8%) was under 65 years of age and 94 (47.2%) were over 65 years of age. The rate of cigarette smoking, which was a major risk factor for lung cancer, was 75.9%, and 68 patients (34.2%) had an additional condition. Histopathologically, 160 (80.4%) patients were diagnosed with adenocarcinoma, 28 (14.1%) with non-small cell lung cancer and 11 (5.5%) with MPE associated with squamous cell lung cancer. Diagnosis of MPE confirmed the detection of malignant cells in pleural fluid. Diagnostic pleural fluid sample with thoracentesis was performed in all cases, but malignant effusion was diagnosed in 133 (66.9%) cases. If the first pleural fluid cytology specimen was negative, diagnostic thoracentesis was repeated a second time. MPEs were diagnosed by invasive procedures when diagnostic thoracentesis fluid cytology was negative in 66 (33.1%) cases. Pleural fluid cytology in combination with pleural biopsy was performed in 66 (33.1%) patients. Closed pleural biopsy and video-assisted thoracoscopic surgery (VATS) were used for parietal pleura biopsy procedures. Closed pleural biopsy was performed in 28 patients, also VATS was performed in 38 patients. While 32 patients (16.1%) were diagnosed with MPE lung cancer as a result of disease progression, 167 patients (83.9%) had MPE during diagnosis. MPE was accompanied with distant metastasis in 66 patients (33.1%). We divided our patients into two groups; those with MPE only (group 1) and those with MPE and distant

The Clinical Respiratory Journal (2015) • ISSN 1752-6981 © 2015 John Wiley & Sons Ltd

Malignant pleural effusions in lung cancer

metastasis (group 2). The groups are compared with respect to their demographic characteristics, additional diseases, presenting symptoms, site and amount of effusion, and detection time of effusion in Table 1. In the group of patients MPE only (group 1), the number of patients with a median age of 65 years and over was significantly higher (P = 0.004, P = 0.002). There was a significant difference between the two groups in the detection time of MPE (P = 0.001).

Survival analysis of patients The median survival time was 4.4 months (95% confidence interval: range, 3–5.7) in 199 patients. Of these patients, 113 (56.7%) died within 6 months after being diagnosed with MPE. The 1-year, 1.5-year and 2-year survival rates were 27.1%, 19% and 13.5%, respectively (Fig. 1A). A statistically very significant difference was found in survival time between the groups by gender (P < 0.001). There was a statistically significant difference between survival time of patients by the type of histopathological lung cancer associated with MPE (P = 0.004). The survival time was longer in patients with MPE only compared with those with MPE and distant metastasis, and the difference was statistically different (P = 0.025). Table 2 summarizes the relationship between demographic characteristics and survival time. A comparison of the effects of laboratory data during presentation on the survival time showed that patients with a blood CRP level of 5.0 mg/dL and over (P < 0.0001), blood LDH level of 250 U/L (P = 0.003), blood protein level of less than 6.4 g/dL (P = 0.001), blood albumin level of less than 3.4 g/dL (P < 0.0001), pleural fluid protein level of less than 4.7 g/dL (P < 0.0001), pleural fluid albumin level of less than 2.6 g/dL (P < 0.0001) and presence of leukocytosis (P < 0.0001) during admission had statistically significant shorter survival time (Table 3, Fig. 1B). The median survival time was statistically longer in patients receiving chemo ± radiotherapy compared with those who were chemo ± radiotherapy naive with a statistically very significant difference (P < 0.0001) (Table 4, Fig. 2). An analysis of the effect of treatment modalities on the survival time showed that among 95 (47.8%) chemo ± radiotherapy-naive patients, the survival time was longer in patients who underwent talc pleurodesis than those who did not, with a statistically significant difference (P = 0.015) (Table 5). 3

Malignant pleural effusions in lung cancer

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Table 1. Patients characteristics by groups

Number of patients Median age Age ≥65 years 0.05

160 (80.4%) 28 (14.1%) 11 (5.5%)

110 (82.7%) 4 (3%) 19 (14.3%)

50 (75.7%) 7 (10.6%) 9 (13.7%)

0.87

41 (62.1%) 17 (25.7%) 16 (24.2%) 11 (16.6%)

4.7 g/dL Anemia Yes No Platelets Thrombocytosis Thrombocytopenia Normal Leukocytosis Yes No

Median survival time (months)

95% CI

P-value

22.3 3.1

4.95–39.64 2.01–4.18

Prognostic factors affecting survival in non-small cell lung carcinoma patients with malignant pleural effusions.

Lung cancer is the most common cause of malignant pleural effusions (MPEs). For patients with lung cancer and MPE, median survival is only 3-4 months...
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