Tumor Biol. DOI 10.1007/s13277-015-3475-2
RESEARCH ARTICLE
Prognostic significance of the absolute monocyte counts in lung cancer patients with venous thromboembolism Se-Il Go 1 & Rock Bum Kim 2 & Haa-Na Song 1 & Myoung Hee Kang 1 & Un Seok Lee 1 & Hye Jung Choi 1 & Wonyong Jo 1 & Seung Jun Lee 3 & Yu Ji Cho 3 & Yi Yeong Jeong 3 & Ho Cheol Kim 3 & Jong Deog Lee 3 & Seok-Hyun Kim 4 & Jung-Hun Kang 1,5 & Gyeong-Won Lee 1,5
Received: 8 March 2015 / Accepted: 16 April 2015 # International Society of Oncology and BioMarkers (ISOBM) 2015
Abstract We investigated the clinical significance of the absolute monocyte count (AMC) as a predictor of the response to anticoagulation and survival in lung cancer patients with venous thromboembolism (VTE). We retrospectively reviewed 1707 patients with pathologically proven lung cancer who visited the hospital between July 2008 and May 2014. Among them, the clinical data of patients newly diagnosed with VTE and treated with anticoagulation were compared between the low and high AMC groups according to the median value of AMC (640/μL) at the time of VTE diagnosis. The incidence of VTE was 7.9 % during the study period. Most of the patients had non-small-cell lung cancer (82.1 %), stage IV (64.2 %), and pulmonary thromboembolism (76.1 %) and were incidentally diagnosed with VTE (76.9 %). The patients’ characteristics and
* Gyeong-Won Lee [email protected] 1
Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Gangnam-ro 79, Jinju 660-702, Republic of Korea
2
Department of Preventive Medicine and Environmental Health Center, Dong-A University College of Medicine, Busan 602-715, Republic of Korea
3
Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea
4
Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 630-723, Republic of Korea
5
Gyeongsang Institute of Health Sciences, Jinju 660-702, Republic of Korea
laboratory values were not significantly different between the low and high AMC groups. Among patients available for evaluation of the response to anticoagulation, the high AMC group was significantly more refractory to anticoagulation than the low AMC group (no response to anticoagulation, 21.7 vs. 6.8 %, respectively; p=0.044). Additionally, the high AMC group showed worse overall survival (OS) than the low AMC group (median, 9.6 vs. 5.9 months; p=0.038). On multivariate analysis, high AMC, low albumin, and advanced stage were independent poor prognostic factors for OS. High AMC is associated with refractoriness to anticoagulation and poor prognosis in lung cancer patients with VTE. Keywords Monocyte . Lung neoplasm . Pulmonary thromboembolism . Deep vein thrombosis
Introduction Malignancy is associated with a hypercoagulable or prothrombotic state [1]. Venous thromboembolism (VTE), including deep vein thrombosis (DVT), pulmonary thromboembolism (PTE), and visceral or splanchnic vein thrombosis, is a frequent complication with an incidence of 7–15 % in patients with cancer [1–3]. Among malignancies presenting with VTE, lung cancer is one of the most prevalent types of cancer in which VTE occurs [2, 4, 5]. Advanced disease stage, elderly, adenocarcinoma, smoking history, comorbidities, and chemotherapy have been reported to be risk factors for VTE in patients with lung cancer [4, 6–8]. VTE in lung cancer is associated with an increased risk of mortality [7, 9, 10]. The recommended management of cancer-related VTE is low-molecular-weight heparin (LMWH) for at least 6 months [11, 12]. However, there has been little evidence for predictors of the response to anticoagulation in cancer-related VTE.
Tumor Biol.
Recently, several clinical studies have reported the significant association of thrombosis with monocytes. Rezende et al. reported that a high blood monocyte count, even within the reference range, was associated with an increased risk of VTE [13]. In the general population, the monocyte count was possibly associated with incident VTE events during the first years of follow-up [14]. Another cohort study showed that CD14+ CD16+ monocytes predict adverse cardiovascular outcomes in 951 subjects referred for elective coronary angiography [15]. In a study of 280 solid tumor patients, a monocyte count greater than 500/ μL on admission was related to a fivefold increased risk of subsequent VTE in hospitalized cancer patients [16]. However, aside from the incidence of VTE itself, no clinical data for the association between monocytes and the response to treatment for VTE, particularly in patients with lung cancer, are extant. In the present study, we investigated the roles of monocytes and other clinical factors as predictors of the response to anticoagulation in lung cancer patients with VTE. Additionally, the prognostic significance of monocytes at the VTE diagnosis was also evaluated.
Methods Study design and patients selection All consecutive patients with pathologically proven lung cancer who visited the Gyeongsang National University Hospital between July 2008 and May 2014 were retrospectively reviewed. For this period, patients newly diagnosed with VTE by radiological studies including computed tomography or Doppler ultrasonography and treated with therapeutic anticoagulation were included in the current study. The exclusion criteria were as follows: patients without radiological evidence of VTE irrespective of symptoms and clinical signs of VTE, patients in whom the monocyte count was not available within 1 week before and after the time of VTE diagnosis, patients with ongoing VTE from before the diagnosis of lung cancer, patients not treated with anticoagulation or those treated with prophylactic anticoagulation only, and patients with arterial thrombosis without VTE. Data collection Clinical data were obtained from electronic medical records. Baseline demographic information (age and gender), tumor characteristics (histology, stage, and the treatment status for cancer at the VTE diagnosis), and data for VTE (risk factors and clinical signs for VTE, PTE location and bilaterality, and anticoagulant drugs used) were reviewed. Laboratory values
on the nearest day within 1 week before and after the time of VTE diagnosis, including the absolute monocyte count (AMC), hemoglobin, hematocrit, platelet, albumin, Creactive protein (CRP), and coagulation indices, were collected. The response to anticoagulation was evaluated in patients who had undergone at least one follow-up radiological assessment for VTE. Patients treated with chemotherapy were radiologically assessed every 2 cycles of chemotherapy, and regular radiological assessments were performed every 2 months in those who were not treated with chemotherapy. The response to anticoagulation was classified as Bresponse^ and Bno response.^ Response was defined as complete or partial improvement of VTE in at least one follow-up radiological assessment. No response was defined as persistence or aggravation of VTE following anticoagulation. Additionally, Bresolution^ was defined as complete improvement of VTE in at least one follow-up radiological assessment and Bno resolution^ was defined as partial improvement, persistence, or aggravation of VTE. Survival data since the VTE diagnosis were obtained and analyzed irrespective of the availability of information for the response to anticoagulation. The median value of AMC (640/ μL) at the VTE diagnosis was determined as the cut-off level for comparison of the clinical data. This study was approved by the Institutional Review Board of Gyeongsang National University Hospital. Statistical analysis Categorical variables were expressed as numbers and percentages. Chi-squared and Fisher’s exact tests were used to compare categorical variables. Continuous variables were presented as means±standard deviations and compared using the Mann–Whitney U test. The missing data were omitted from analysis and the remaining data were analyzed. Overall survival (OS) was calculated as the time from the date of VTE onset to the date of death or the last follow-up visit. Survival was estimated using the Kaplan–Meier method and the differences between groups were compared by the log-rank test. A multivariate analysis for OS was performed using the Cox proportional hazards model with enter selection method. All variables with a p value less than 0.10 on univariate analysis were included, and variables with too many missing data, such as fibrinogen, D-dimer, and fibrin degradation product (FDP), were excluded on multivariate analysis. The proportionality assumption for Cox regression was assessed by inspection of log-minus-log curves, indicating that all variables met the proportional hazards assumption. A twosided p value less than 0.05 was considered to indicate statistical significance. All of the statistical analyses were performed using the SPSS 21.0 for Windows software (SPSS Inc., Chicago, IL, USA).
Tumor Biol. Table 1
Patients’ characteristics according to the AMC at the time of VTE diagnosis
Variable
P
AMC 0.990
0.101
SD
Non-specific Comorbidity
SCLC
0.909
0.652 11 (16.4 %) 56 (83.6 %)
Tumor status at the VTE diagnosis (n=116) CR or NEDa PR
NSCLC
0.838
Anticoagulant drug
0.532
AMC absolute monocyte count, VTE venous thromboembolism, SCLC small cell lung cancer, NSCLC non-small cell lung cancer, NED no evidence of disease, CNS central nervous system, CR complete response, PR partial response, SD stable disease, PD progressive disease, PTE pulmonary thromboembolism a
No evidence of disease (NED) was defined as the absence of disease after the primary treatment
Tumor Biol.
Results Patients’ characteristics A total of 1707 patients with lung cancer had visited the hospital during the study period. Among them, 134 (7.9 %) consecutive patients newly diagnosed with VTE were enrolled in the study. Patients were divided into the low and high AMC groups by means of the AMC cut-off value. Patients in the two groups had similar baseline characteristics (Table 1). The median age was 68.5 years (69 years for the low AMC group and 67 years for the high AMC group). Male gender was predominant, and adenocarcinoma was the most common histology. Approximately 60 % of patients with non-small-cell lung cancer (NSCLC) and 30 % of those with small-cell lung cancer (SCLC) had stage IV disease according to the TNM (tumor, node, metastases) classification of malignant tumors from the American Joint Committee on Cancer (AJCC) at the time of cancer diagnosis in two groups. At the time of VTE diagnosis, tumor stage was more advanced with a similar distribution between two groups. Eleven (16.4 %) and thirteen (19.4 %) patients had central nervous system metastasis at the VTE diagnosis in the low and high AMC groups, respectively. Among 116 patients in whom the tumor response at the VTE diagnosis was available, the proportion of patients with complete response was higher in the low group than in the high AMC group. However, this result was not statistically significant (p=0.101). VTE was detected during chemotherapy in more than half of the patients in the two groups. Seventy percent of patients in the two groups Table 2 Laboratory values according to the AMC at the time of the VTE diagnosis
Variable
Hemoglobin, g/dL (n=134) Hematocrit, % (n=134) Platelet, × 109/L (n=134) Albumin, g/dL (n=n=134) C-reactive protein, mg/L (n=118) PT, second (n=121) aPTT, second (n=119) Fibrinogen, mg/dL (n=47) D-dimer, μg/mL (n=85)a
RESEARCH ARTICLE
Prognostic significance of the absolute monocyte counts in lung cancer patients with venous thromboembolism Se-Il Go 1 & Rock Bum Kim 2 & Haa-Na Song 1 & Myoung Hee Kang 1 & Un Seok Lee 1 & Hye Jung Choi 1 & Wonyong Jo 1 & Seung Jun Lee 3 & Yu Ji Cho 3 & Yi Yeong Jeong 3 & Ho Cheol Kim 3 & Jong Deog Lee 3 & Seok-Hyun Kim 4 & Jung-Hun Kang 1,5 & Gyeong-Won Lee 1,5
Received: 8 March 2015 / Accepted: 16 April 2015 # International Society of Oncology and BioMarkers (ISOBM) 2015
Abstract We investigated the clinical significance of the absolute monocyte count (AMC) as a predictor of the response to anticoagulation and survival in lung cancer patients with venous thromboembolism (VTE). We retrospectively reviewed 1707 patients with pathologically proven lung cancer who visited the hospital between July 2008 and May 2014. Among them, the clinical data of patients newly diagnosed with VTE and treated with anticoagulation were compared between the low and high AMC groups according to the median value of AMC (640/μL) at the time of VTE diagnosis. The incidence of VTE was 7.9 % during the study period. Most of the patients had non-small-cell lung cancer (82.1 %), stage IV (64.2 %), and pulmonary thromboembolism (76.1 %) and were incidentally diagnosed with VTE (76.9 %). The patients’ characteristics and
* Gyeong-Won Lee [email protected] 1
Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Gangnam-ro 79, Jinju 660-702, Republic of Korea
2
Department of Preventive Medicine and Environmental Health Center, Dong-A University College of Medicine, Busan 602-715, Republic of Korea
3
Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju 660-702, Republic of Korea
4
Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon 630-723, Republic of Korea
5
Gyeongsang Institute of Health Sciences, Jinju 660-702, Republic of Korea
laboratory values were not significantly different between the low and high AMC groups. Among patients available for evaluation of the response to anticoagulation, the high AMC group was significantly more refractory to anticoagulation than the low AMC group (no response to anticoagulation, 21.7 vs. 6.8 %, respectively; p=0.044). Additionally, the high AMC group showed worse overall survival (OS) than the low AMC group (median, 9.6 vs. 5.9 months; p=0.038). On multivariate analysis, high AMC, low albumin, and advanced stage were independent poor prognostic factors for OS. High AMC is associated with refractoriness to anticoagulation and poor prognosis in lung cancer patients with VTE. Keywords Monocyte . Lung neoplasm . Pulmonary thromboembolism . Deep vein thrombosis
Introduction Malignancy is associated with a hypercoagulable or prothrombotic state [1]. Venous thromboembolism (VTE), including deep vein thrombosis (DVT), pulmonary thromboembolism (PTE), and visceral or splanchnic vein thrombosis, is a frequent complication with an incidence of 7–15 % in patients with cancer [1–3]. Among malignancies presenting with VTE, lung cancer is one of the most prevalent types of cancer in which VTE occurs [2, 4, 5]. Advanced disease stage, elderly, adenocarcinoma, smoking history, comorbidities, and chemotherapy have been reported to be risk factors for VTE in patients with lung cancer [4, 6–8]. VTE in lung cancer is associated with an increased risk of mortality [7, 9, 10]. The recommended management of cancer-related VTE is low-molecular-weight heparin (LMWH) for at least 6 months [11, 12]. However, there has been little evidence for predictors of the response to anticoagulation in cancer-related VTE.
Tumor Biol.
Recently, several clinical studies have reported the significant association of thrombosis with monocytes. Rezende et al. reported that a high blood monocyte count, even within the reference range, was associated with an increased risk of VTE [13]. In the general population, the monocyte count was possibly associated with incident VTE events during the first years of follow-up [14]. Another cohort study showed that CD14+ CD16+ monocytes predict adverse cardiovascular outcomes in 951 subjects referred for elective coronary angiography [15]. In a study of 280 solid tumor patients, a monocyte count greater than 500/ μL on admission was related to a fivefold increased risk of subsequent VTE in hospitalized cancer patients [16]. However, aside from the incidence of VTE itself, no clinical data for the association between monocytes and the response to treatment for VTE, particularly in patients with lung cancer, are extant. In the present study, we investigated the roles of monocytes and other clinical factors as predictors of the response to anticoagulation in lung cancer patients with VTE. Additionally, the prognostic significance of monocytes at the VTE diagnosis was also evaluated.
Methods Study design and patients selection All consecutive patients with pathologically proven lung cancer who visited the Gyeongsang National University Hospital between July 2008 and May 2014 were retrospectively reviewed. For this period, patients newly diagnosed with VTE by radiological studies including computed tomography or Doppler ultrasonography and treated with therapeutic anticoagulation were included in the current study. The exclusion criteria were as follows: patients without radiological evidence of VTE irrespective of symptoms and clinical signs of VTE, patients in whom the monocyte count was not available within 1 week before and after the time of VTE diagnosis, patients with ongoing VTE from before the diagnosis of lung cancer, patients not treated with anticoagulation or those treated with prophylactic anticoagulation only, and patients with arterial thrombosis without VTE. Data collection Clinical data were obtained from electronic medical records. Baseline demographic information (age and gender), tumor characteristics (histology, stage, and the treatment status for cancer at the VTE diagnosis), and data for VTE (risk factors and clinical signs for VTE, PTE location and bilaterality, and anticoagulant drugs used) were reviewed. Laboratory values
on the nearest day within 1 week before and after the time of VTE diagnosis, including the absolute monocyte count (AMC), hemoglobin, hematocrit, platelet, albumin, Creactive protein (CRP), and coagulation indices, were collected. The response to anticoagulation was evaluated in patients who had undergone at least one follow-up radiological assessment for VTE. Patients treated with chemotherapy were radiologically assessed every 2 cycles of chemotherapy, and regular radiological assessments were performed every 2 months in those who were not treated with chemotherapy. The response to anticoagulation was classified as Bresponse^ and Bno response.^ Response was defined as complete or partial improvement of VTE in at least one follow-up radiological assessment. No response was defined as persistence or aggravation of VTE following anticoagulation. Additionally, Bresolution^ was defined as complete improvement of VTE in at least one follow-up radiological assessment and Bno resolution^ was defined as partial improvement, persistence, or aggravation of VTE. Survival data since the VTE diagnosis were obtained and analyzed irrespective of the availability of information for the response to anticoagulation. The median value of AMC (640/ μL) at the VTE diagnosis was determined as the cut-off level for comparison of the clinical data. This study was approved by the Institutional Review Board of Gyeongsang National University Hospital. Statistical analysis Categorical variables were expressed as numbers and percentages. Chi-squared and Fisher’s exact tests were used to compare categorical variables. Continuous variables were presented as means±standard deviations and compared using the Mann–Whitney U test. The missing data were omitted from analysis and the remaining data were analyzed. Overall survival (OS) was calculated as the time from the date of VTE onset to the date of death or the last follow-up visit. Survival was estimated using the Kaplan–Meier method and the differences between groups were compared by the log-rank test. A multivariate analysis for OS was performed using the Cox proportional hazards model with enter selection method. All variables with a p value less than 0.10 on univariate analysis were included, and variables with too many missing data, such as fibrinogen, D-dimer, and fibrin degradation product (FDP), were excluded on multivariate analysis. The proportionality assumption for Cox regression was assessed by inspection of log-minus-log curves, indicating that all variables met the proportional hazards assumption. A twosided p value less than 0.05 was considered to indicate statistical significance. All of the statistical analyses were performed using the SPSS 21.0 for Windows software (SPSS Inc., Chicago, IL, USA).
Tumor Biol. Table 1
Patients’ characteristics according to the AMC at the time of VTE diagnosis
Variable
P
AMC 0.990
0.101
SD
Non-specific Comorbidity
SCLC
0.909
0.652 11 (16.4 %) 56 (83.6 %)
Tumor status at the VTE diagnosis (n=116) CR or NEDa PR
NSCLC
0.838
Anticoagulant drug
0.532
AMC absolute monocyte count, VTE venous thromboembolism, SCLC small cell lung cancer, NSCLC non-small cell lung cancer, NED no evidence of disease, CNS central nervous system, CR complete response, PR partial response, SD stable disease, PD progressive disease, PTE pulmonary thromboembolism a
No evidence of disease (NED) was defined as the absence of disease after the primary treatment
Tumor Biol.
Results Patients’ characteristics A total of 1707 patients with lung cancer had visited the hospital during the study period. Among them, 134 (7.9 %) consecutive patients newly diagnosed with VTE were enrolled in the study. Patients were divided into the low and high AMC groups by means of the AMC cut-off value. Patients in the two groups had similar baseline characteristics (Table 1). The median age was 68.5 years (69 years for the low AMC group and 67 years for the high AMC group). Male gender was predominant, and adenocarcinoma was the most common histology. Approximately 60 % of patients with non-small-cell lung cancer (NSCLC) and 30 % of those with small-cell lung cancer (SCLC) had stage IV disease according to the TNM (tumor, node, metastases) classification of malignant tumors from the American Joint Committee on Cancer (AJCC) at the time of cancer diagnosis in two groups. At the time of VTE diagnosis, tumor stage was more advanced with a similar distribution between two groups. Eleven (16.4 %) and thirteen (19.4 %) patients had central nervous system metastasis at the VTE diagnosis in the low and high AMC groups, respectively. Among 116 patients in whom the tumor response at the VTE diagnosis was available, the proportion of patients with complete response was higher in the low group than in the high AMC group. However, this result was not statistically significant (p=0.101). VTE was detected during chemotherapy in more than half of the patients in the two groups. Seventy percent of patients in the two groups Table 2 Laboratory values according to the AMC at the time of the VTE diagnosis
Variable
Hemoglobin, g/dL (n=134) Hematocrit, % (n=134) Platelet, × 109/L (n=134) Albumin, g/dL (n=n=134) C-reactive protein, mg/L (n=118) PT, second (n=121) aPTT, second (n=119) Fibrinogen, mg/dL (n=47) D-dimer, μg/mL (n=85)a
