Lung Cancer 84 (2014) 79–85
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Clinical signiﬁcance of the neutrophil–lymphocyte ratio in venous thromboembolism patients with lung cancer Se-Il Go a,1 , Anna Lee a,1 , Un Seok Lee a , Hye Jung Choi a , Myung Hee Kang a , Jung-Hun Kang a , Kyung Nyeo Jeon b , Mi Jung Park b , Seok-Hyun Kim c , Gyeong-Won Lee a,d,∗ a Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Republic of Korea b Department of Radiology, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Republic of Korea c Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Republic of Korea d Gyeongsang Institute of Health Science
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Article history: Received 26 December 2013 Received in revised form 18 January 2014 Accepted 20 January 2014 Keywords: Pulmonary thromboembolism Deep vein thrombosis Neutrophils Lymphocytes Lung Neoplasms
a b s t r a c t Background: The neutrophil–lymphocyte ratio (NLR) has been identiﬁed as a potentially useful marker for predicting clinical outcome in patients with cardiovascular disease, diabetes, and various malignancies. The aim of this study was to determine whether NLR at the time of venous thromboembolism (VTE) diagnosis is a prognostic factor for the response to anticoagulation and survival in lung cancer patients treated with anticoagulation for VTE. Patients and methods: We retrospectively analyzed the clinical characteristics, laboratory parameters, and NLR in 114 lung cancer patients newly diagnosed with VTE, among 991 patients pathologically conﬁrmed for lung cancer between July 2008 and August 2013. Results: High NLR was signiﬁcantly associated with high hematocrit (p = 0.028), high C-reactive protein (p = 0.002), and low albumin (p = 0.001). Compared with the low NLR group, stage IV non-small cell lung cancer (NSCLC) at the time of VTE diagnosis (55.6 vs. 74.6%, p = 0.055), central nervous system metastasis (5.8 vs. 25.8%, p = 0.004), and cancer progression (14.3 vs. 38.8%, p = 0.008) at the time of VTE diagnosis were also signiﬁcant in the high NLR group. Moreover, the poor response to anticoagulation was statistically correlated with patients with NSCLC (p = 0.037), high NLR (p = 0.004), and low albumin (p = 0.029). Conclusions: The results demonstrate that the NLR at the time of VTE diagnosis could be a useful biomarker for predicting the response and prognosis following anticoagulation in patients with lung cancer and VTE. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT), pulmonary thromboembolism (PTE), and visceral or splanchnic vein thrombosis, is a common event and a major cause of morbidity and mortality in patients with cancer . The incidence of VTE is 4–15% in patients with lung cancer [2–5], and the mortality rate of patients with VTE increased 1.6- to
∗ Corresponding author at: Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, School of Medicine Gyeongsang National University, Gangnam-ro 79, Jinju 660-702, Republic of Korea. Tel.: +82 55 750 8066; fax: +82 55 758 9122. E-mail address: [email protected]
(G.-W. Lee). 1 These authors contributed equally to this work. 0169-5002/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.lungcan.2014.01.014
2.3-fold compared with patients without VTE, according to several retrospective studies [5–7]; however, another study showed no correlation between VTE and survival . The classical mechanisms of thrombosis in cancer patients are related to abnormal vessel walls, blood ﬂow, and blood constituents . In addition, inﬂammation is associated with a prothrombotic state [10,11]. Many biomarkers have been used to assess the inﬂammatory state in patients with cancer. Among these, the neutrophil–lymphocyte ratio (NLR) is a readily-available and cost-effective biomarker used in clinical practice that has been associated with recurrence [12,13] and survival [14–16] in various cancers. In previous non-small cell lung cancer (NSCLC) studies, the NLR was associated with the response to chemoradiotherapy  and with survival after surgery [18–20], as well as with the response to chemotherapy  and with survival [22,23] in patients with
S.-I. Go et al. / Lung Cancer 84 (2014) 79–85
advanced disease. Moreover, a substantial number of studies have demonstrated the clinical signiﬁcance between thrombosis and NLR, mainly in non-cancer patients, as a novel potential marker for predicting prognosis of cardiovascular disease [24–26]. However, the association between NLR and cancer-related thrombosis has been rarely evaluated in patients with lung cancer. The purpose of this study was to evaluate the clinical impact on the NLR at the time of VTE diagnosis as a prognostic factor for response to anticoagulation and survival, as well as the clinical characteristics of lung cancer patients treated with anticoagulation for VTE.
U-test. The categorical variables were presented as the number of patients and percentages and compared using the chi-square or Fisher’s exact tests. Survival probability analyses were performed using the Kaplan–Meier method. Survival was calculated as the time from the date of VTE onset after diagnosis of lung cancer to the date of death or the most recent follow-up. Signiﬁcant differences between groups were assessed using the log-rank test. Multivariate analysis of survival was analyzed using the Cox proportional hazards model. A p-value < 0.05 was considered signiﬁcant for all statistical analyses.
2. Methods 3. Results 2.1. Patients 3.1. Incidence of VTE and patient characteristics We retrospectively reviewed patients who were newly diagnosed with VTE based on radiological evaluation (computed tomography [CT] or Doppler ultrasound) among those with pathologically-conﬁrmed lung cancer between July 2008 and August 2013 at Gyeongsang National University Hospital Regional Cancer Center, Jinju, Korea. Among the 1117 patients with lung cancer or a similar diagnosis according to electronic medical records, 126 were excluded because they were not pathologically diagnosed with lung cancer. The incidence of VTE in the remaining 991 patients was calculated, and data on patients diagnosed with VTE were collected. All patients with VTE were treated with either warfarin, low-molecular weight heparin, or both. Patients with arterial thrombosis without VTE or those who received anticoagulation without radiologic evidence of VTE were excluded from the analysis. This study was approved by the institutional review board of Gyeongsang National University Hospital. 2.2. Clinical data Baseline patient characteristics, including demographics, smoking, performance status, histology, and medical history were collected by medical chart review. Cancer stage and presence of central nervous system (CNS) metastasis were obtained both at the time of initial diagnosis and the time of VTE onset. Clinical signs and anticancer treatment at the time of VTE diagnosis were also reviewed. Anticoagulation response was evaluated in patients who underwent at least one follow-up CT scan or Doppler ultrasound. The response was classiﬁed as “resolution” versus “no resolution”. Resolution was deﬁned as those cases in which there was no evidence of VTE in one or more follow-up imaging studies. Cases in which follow-up imaging showed partial improvement and no change or aggravation in VTE without complete resolution were considered as no resolution. The relationship between anticoagulation response and clinical variables was analyzed, and the impact of the response on survival was evaluated. We examined the value of the NLR as a prognostic factor in patients with VTE. The NLR was calculated from the differential counts by dividing the neutrophil number by the lymphocyte number at the time of VTE diagnosis. NLR ≥3 was considered elevated. Patient, tumor, and VTE characteristics, laboratory data at the time of VTE diagnosis, results of anticoagulant therapy, and survival of the patients were compared according to the NLR status. 2.3. Statistical analysis We performed statistical analyses using SPSS 18.0 for Windows software (SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as the means ± standard deviations and compared between the low and high NLR groups using the Mann–Whitney
Of 991 patients diagnosed with lung cancer, 114 (11.5%) were diagnosed with VTE and treated with anticoagulation therapy. The baseline characteristics of the 114 patients are shown in Table 1. The median age at VTE diagnosis was 69 years (range, 35–84 years). The majority of patients were male (76.3%) and smokers (59.6%). A total of 100 patients (87.7%) had good performance status at the time of initial diagnosis, as indicated by an ECOG performance status