Thromboembolic Events in Malignant Pleural Mesothelioma

Clinical and Applied Thrombosis/Hemostasis 1-5 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029614564861 cat.sagepub.com

Deniz Koksal, MD1, Ozge Safak, MD2, Aysenaz Ozcan, MD2, Yetkin Agackiran, MD3, Hakan Erturk, MD4, and Gokturk Findik, MD5

Abstract Aim: Malignant pleural mesothelioma (MPM) increases the risk of thromboembolic events (TEEs). In this retrospective study, we aimed to determine the rate of TEEs in MPM and investigate its relationship with the presence of thrombocytosis, the disease stage, and the tumor histopathology. Methods: The study included 178 patients who were histopathologically diagnosed as MPM between the years January 2008 and June 2014. Results: The mean age was 58.7 + 11.8 years, and the median follow-up time was 8 months. Seventy-one patients (39.9%) had thrombocytosis (>350  103/mL). In total, 14 (7.9%) TEEs were identified: 6 (3.4%) pulmonary thromboembolism, 6 (3.4%) deep venous thrombosis, and 2 (1.1%) myocardial infarctions. Although 5 (2.8%) of the TEEs preceded the diagnosis of MPM, 1 (0.6%) occurred simultaneously with the diagnosis of MPM and 8 (4.5%) followed the diagnosis of MPM. Thromboembolic event rates were not statistically different based on the presence of thrombocytosis (P ¼ .51), disease stage (P ¼ .14), and histopathology (P ¼ .38). Conclusion: The rate of TEEs was 7.9%. Presence of thrombocytosis, disease stage, and histopathology did not affect the incidence of TEEs. Keywords malignant pleural mesothelioma, thrombosis, thromboembolic event

Introduction Malignant pleural mesothelioma (MPM) is a rare and very aggressive tumor originating from mesothelial cells lining the pleural cavity. It is a highly resistant tumor to chemotherapy and radiotherapy, with a median survival less than 1 year.1,2 Thromboembolic events (TEE) including deep venous thrombosis, pulmonary embolism, arterial thrombosis, and myocardial infarction frequently develop in the course of disease and are reported to be as high as 27.7% in MPM.3 In a recent multicenter phase II study investigating the efficacy of cisplatin, pemetrexed, and bevacizumab regimen on patients with MPM, the rate of venous thromboembolism was reported to be 13%.4 Thromboembolic events are particularly common problems in patients with cancer.5 Although the incidence of TEEs is estimated to be 0.1% to 2% in general population,6 it is 10% to 15% in population with cancer7 and 12.3% in patients receiving multimodality therapy for thoracic malignancies.8 A recent large retrospective population study reported a venous thromboembolism rate of 12.6% in the cohort of patient with cancer compared to a rate of 1.4% in the control noncancer cohort.9 It is certain that the clinical characteristics, types, and stages of cancer substantially influence the venous thromboembolism rates. The pathogenetic mechanisms of thrombosis involve a complex interaction between tumor cells, the hemostatic system,

and characteristics of the patient.10 Tumor cells are capable of activating the host hemostatic system in multiple ways. In mesothelioma, tumor cells secrete procoagulant factors and interleukin 6, which can enhance platelet function and thrombosis while stimulating inhibition of fibrinolysis.11,12 Additionally thrombocytosis, which can be considered as a risk factor for thrombosis, is frequently observed in patients with MPM.12 In this retrospective study, we aimed to determine the rate of TEEs in patients with MPM and investigate its relationship with the presence of thrombocytosis, the disease stage, and the tumor histopathology.

1

Department of Chest Diseases, Hacettepe University Medical Faculty, Ankara, Turkey 2 Department of Chest Diseases, Ataturk Chest Diseases and Chest Surgery Education and Research Hospital, Ankara, Turkey 3 Department of Pathology, Ataturk Education and Research Hospital, Ankara, Turkey 4 Department of Radiology, Ataturk Chest Diseases and Chest Surgery Education and Research Hospital, Ankara, Turkey 5 Department of Chest Surgery, Ataturk Chest Diseases and Chest Surgery Education and Research Hospital, Ankara, Turkey Corresponding Author: Deniz Koksal, Department of Chest Diseases, Hacettepe University Medical Faculty, Sihhiye, 06100 Altındag, Ankara, Turkey. Email: [email protected]

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Materials and Methods

Table 1. Patient Characteristics.

The study included 178 patients (106 males/72 females) who were histopathologically diagnosed as MPM between January 1, 2008, and June 30, 2014, at Atatu¨rk Chest Diseases and Chest Surgery Education and Research Hospital. Immunohistochemical stains were used on all the patients to confirm the diagnosis of MPM. With the retrospective design, the study was approved by the institutional ethics committee. The files of patients were retrieved from the archive, and available study forms were duly filled in. The demographic data, clinical, radiological, and pathological findings, diagnostic methods, basal laboratory parameters, thrombocyte counts, applied therapies, and the TEEs were noted on these forms. Thrombocytosis was defined as a thrombocyte count >350  103/mL.13 Thromboembolic events were objectively confirmed by imaging studies (venous Doppler ultrasound and computed tomography [CT] angiography) or electrocardiographic changes compatible with myocardial infarction. All of the patients had an initial evaluation with a contrastenhanced CT of thorax. Ninety-eight (55.1%) patients also had an integrated CT and 18F-fluoro-2-deoxy-D-glucose positron emission tomography (PET/CT) evaluation. Magnetic resonance imaging (MRI) was used to complement CT of thorax or PET/CT in the multimodality treatment group. Cranial CT or MRI was performed if necessary. The staging of the patients were performed based on the clinical and radiological findings according to the TNM (tumor, node, metastasis) staging system proposed by the International Mesothelioma Interest Group (IMIG).14 The chemotherapy regimen was pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) or carboplatin (5AUC) in the entire group receiving chemotherapy. Folic acid and vitamin B12 supplementation were also given according to the guidelines. Adjuvant hemithoracic radiotherapy (180 cGy/d, 28 fractions, 5040 cGy totally) was delivered to patients who had undergone extrapleural pneumonectomy. Talc was used for pleurodesis.

Characteristic

Statistical Analysis SPSS for windows release 16.0 package program was used to carry out the statistical analysis. The descriptive analysis was expressed in terms of frequency (%), median, mean, and standard deviation. Comparison of ordinal parameters between different groups was performed by Fisher exact chi-square test. Any result with a P value less than .05 was considered to be statistically significant.

Results The demographic characteristics of the patients, diagnostic methods, histological diagnosis, disease stages, and thrombocyte counts are presented in Table 1. The study included 178 patients (106 males and 72 females) with a mean age of 58.7 + 11.8 years (min: 31-max: 83). History of exposure to asbestos was present in 74.8% of the patients and most of them were

Gender Male Female Mean age + SD (min-max), years Exposure to asbestos Environmental Occupational Both None Smoking history Smokers Nonsmokers Unknown Diagnostic method VATS pleural biopsy Closed pleural biopsy Transthoracic needle biopsy Thoracotomy Mediastinoscopy Histological diagnosis Epithelial Biphasic Sarcomatous Unidentified Stage I II III IV Mean thrombocyte count, 103/mL Thrombocyte count 350  103/mL >350  103/mL

Number of Patients (%) 106 (59.6) 72 (40.4) 58.7 + 11.8 (31-83) 129 3 1 45

(72.5) (1.7) (0.6) (25.2)

100 (56.2) 73 (41) 5 (2.8) 104 36 14 23 1

(58.4) (20.2) (7.9) (12.9) (0.6)

97 31 4 46

(54.5) (17.4) (2.2) (25.8)

14 75 57 32 345

(7.9) (42.1) (32) (18) + 135 (161-1250)

107 (60.1) 71 (39.9)

Abbreviations: min, minimum; max, maximum; SD, standard deviation; VATS, video-assisted thoracoscopic surgery.

environmental. Smoking history was present in 56.2% of the patients. The histological diagnosis was epithelial in 97 (54.5%), biphasic in 31 (17.4%), sarcomatoid in 4 (2.2%), and unidentified in 46 (25.8%) patients. Video-assisted thoracoscopic surgery (VATS) pleural biopsy was the most common (n ¼ 104, 58.4%) way of diagnosis. Mean thrombocyte count of the study group was 345 + 135 (161-1250)  103/mL. While 71 (39.9%) patients had thrombocytosis (>350  103/ mL), 107 (60.1%) patients had normal thrombocyte counts (350  103/mL). In Table 2, applied therapeutic modalities are presented. The applied therapy was chemotherapy in 109 (61.2%), multimodality therapy in 14 (7.9%), and supportive therapy in 41 (23%) patients. Radiotherapy to intervention side and palliative radiotherapy was given to 24 (13.5%) and 18 (10.1%) patients, respectively. Pleurodesis was performed in 94 (52.8%) patients. The mean and median follow-up time were 11.5 + 1.2 and 8 (min 0.1-max 74) months, respectively. In total, 14 (7.9%) TEEs were identified, that is, 6 (3.4%) pulmonary thromboembolisms, 6 (3.4%) deep venous thromboses (4 lower and 2

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Table 2. Applied Therapies. Applied Therapies

Table 3. The Characteristics of Thromboembolic Events. Number of Patients (%)

Chemotherapy P/D and chemotherapy EPP, chemotherapy, and radiotherapy EPP Supportive therapy Refused therapy Radiotherapy to intervention site Palliative radiotherapy Pleurodesis Abbreviations: P/D, pleuropneumonectomy.

109 (61.2) 9 (5.1) 5 (2.8) 1 (0.6) 41 (23) 13 (7.3) 24 (13.5) 18 (10.1) 94 (52.8)

pleurectomy/decortication;

EPP,

extrapleural

upper extremity thrombosis), and 2 (1.1%) myocardial infarctions. The 2 patients with myocardial infarctions denied any previous diagnosis of coronary artery disease. Although more than half of the TEEs (n ¼ 8, 57.1%) occurred after the diagnosis of MPM (median 2.5 months), 5 events (35.7%) were diagnosed before the diagnosis (median 10 months), and 1 (7.2%) event simultaneously with the diagnosis of MPM. All the TEEs before the diagnosis of MPM were unprovoked. The characteristics of TEEs are presented in Table 3. More TEEs occurred in advanced stages (n ¼ 9, 64.3%) but that was not statistically significant (P ¼ .14). Thromboembolic event rates were not statistically different between the patients with thrombocytosis (n ¼ 6, 8.5%) or not (n ¼ 8, 7.5%; P ¼ .51). Thromboembolic event rates were not statistically different based on the disease stage (P ¼ .14) and the histopathology (P ¼ .38).

Thromboembolic Events The rate of thromboembolic events Preceding the diagnosis of MPM Simultaneously or following diagnosis of MPM Pulmonary embolism Deep venous thrombosis Lower extremity Upper extremity Myocardial infarction Time of diagnosis Before diagnosis of MPM Simultaneously with the diagnosis of MPM After diagnosis of MPM Thrombocytosis Absent (n ¼ 107) Present (n ¼ 71)

Number of Patients (%) 14 (7.9) 5 (2.8) 9 (5.1) 6 (3.4) 6 (3.4) 4 2 2 (1.1) 5 (35.7) median: 10 months (1-48) 1 (7.2) 8 (57.1) median: 2.5 months (0.7-18) 8 (7.5) median: 231  103 (min:203  103-349  103) 6 (8.5) median: 466  103 (min: 355  103-536  103)

Disease stages Stage 1 Stage 2 Stage 3 Stage 4 Histopathology Epithelial (n ¼ 97) Biphasic (n ¼ 31) Sarcomatous (n ¼ 4) Unidentified (n ¼ 46)

– 5 (35.7) 8 (57.1) 1 (7.2) 7 (7.2) 1 (3.2) – 6 (13)

Discussion

Abbreviation: MPM, malignant pleural mesothelioma.

The pathogenesis of cancer-related thrombosis is exceptionally complex. Tumor cells are capable of activating the host hemostatic system in multiple ways. These are mucin production by tumors, exposure to tissue factor-rich surfaces, exposure to tissue factor-bearing microparticles, and cysteine production leading to thrombin generation and local hypoxia.15-17 Additionally, patient, cancer, and treatment-related clinical risk factors contribute to the activation of blood coagulation and the TEEs in patients with cancer.18,19 The risk of venous thromboembolism is 7 times higher among patients with cancer compared to the general population.20 The risk of venous thromboembolism varies among patients with cancer, and it depends on a number of factors such as the type of tumor, disease stage, applied therapies, and the presence of coexisting diseases. The risk is the highest for patients with certain types of solid tumors such as pancreas, stomach, liver, lung, kidney, and hematologic malignancies. Besides, applied aggressive and prothrombotic treatment modalities including chemotherapy, hormonal therapy, antiangiogenic agents, radiotherapy, and operative procedures promote the onset of venous thromboembolism.21,22 In the present study, we investigated the incidence of TEEs on a group of patients with MPM and found an incidence rate of 7.9%. The TEEs were deep venous thrombosis

in 6 (3.4%), pulmonary embolism in 6 (3.4%), and myocardial infarction in 2 (1.1%) patients. Although 5 (2.8%) of the TEEs preceded the diagnosis of MPM, 8 (4.5%) followed the diagnosis, and 1 (0.6%) occurred simultaneously with the diagnosis of MPM. Actually we related all the TEEs with the diagnosis of MPM, since all the TEEs before the diagnosis of MPM were unprovoked. In the literature, venous thromboembolism including deep venous thrombosis and pulmonary embolism is the most thoroughly studied thrombosis type among patients with cancer. But arterial thromboembolism is also in the spectrum of clotting complications of cancer, and the incidence of arterial thrombosis is reported to be around 2% to 5%.23,24 In the present study, it was slightly less. The overall TEE rate was higher compared to normal population rates but lower than the reported ratios that was as high as 27.7%.3 This ratio is the highest in the literature. In a recent multicenter phase II study, it was reported to be 13%. Our relatively low ratio of TEEs can be a consequence of retrospective nature of the data and short follow-up time. Because routine imaging studies are not performed in all the patients, asymptomatic TEEs might have been missed.

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Venous thromboembolism might precede or coincide with the diagnosis of cancer. There is evidence that about 10% of patients with idiopathic venous thromboembolism have underlying malignant disorder that can be detected by extensive diagnostic investigation.10 In our study group, 5 patients were diagnosed with a TEE before the diagnosis of MPM. One of the patients was coincidentally diagnosed with pulmonary embolism and MPM. There is conflicting data about the time interval between initial thromboembolism and cancer diagnosis. Sorensen et al followed up more than 25.000 patients for 10 years and realized that the risk of cancer substantially elevated during the first 6 months of follow-up and decreased rapidly to a constant level after a year.25 Another study in accordance with Sorensen study determined 596 (0.11%) unprovoked thromboembolic cases among 528.693 cases with cancer. The number of unprovoked thromboembolisms was modestly higher in the year preceding the diagnosis of cancer.26 But in another study, the authors investigated 183 patients with thromboembolism and 48 patients were diagnosed with cancer following the diagnosis of thromboembolism. The time interval between initial thromboembolism and cancer diagnosis was 5 years in 4 (8.3%).27 In our study, there was a patient with a previous diagnosis of TEE as long as 48 months. We know that there are rare cases of epitheloid mesothelioma with indolent course, and this patient can be such a patient. In the present study, despite the fact that all patients underwent a contrast-enhanced thorax CT at the time of initial diagnosis, an asymptomatic segmental pulmonary embolism that could be seen in CT angiography might have been missed. A CT angiography or a venous Doppler ultrasound was only performed for symptomatic patients. More than half of the patients (n ¼ 8) were diagnosed with a TEE after the diagnosis of MPM, which is probably due to long hospital in-stays and applied therapies such as chemotherapy and surgical procedures. Thrombocytes have a newly appreciated and important role in many cancer-related processes, including tumor growth and metastases, angiogenesis, and promotion of a hypercoagulable state. Elevated thrombocyte counts have shown to be associated with a higher incidence of venous thromboembolism.28 A thrombocyte count higher than 350  103/mL is considered as a risk factor in a recently approved risk assessment model for chemotherapy-associated venous thromboembolism.13 In this study, almost 40% of the patients had thrombocytosis, but the rate of TEEs was not significantly different in patients with thrombocytosis compared to patients with normal thrombocyte counts. Advanced disease stages are known to be associated with higher risks of TEEs. In the present study, the rate of TEEs was not significantly different based on disease stages. This finding may be a consequence of various staging problems in MPM. Almost all the patients were staged based on the clinical and radiological findings according to the TNM staging system proposed by IMIG.14 In MPM, unlike many other cancers where the size and location of the primary tumor can be

reproducibly measured, the extent of the tumor is not easily measured. The current T (Tumour) descriptors are qualitative and mostly applicable to surgical and pathological staging.29 In the present study, we also investigated whether tumor histopathology affected the incidence rate of TEEs and did not find a difference. But it is important to notice that the unidentified histology ratio was high (25.8%) in the study population, probably due to the high ratio of diagnostic procedures such as closed pleural biopsy or transthoracic needle aspirations. These techniques provide smaller biopsies compared to VATS. The limitations of this study were its retrospective design and slightly short follow-up time (median 8 months). Due to retrospective nature of the data we could not reach the applied therapies other than the chemotherapy protocols. We do not have data of the number of patients using anticoagulant prophylaxis, but the study consists of an acceptably high number of patients and the study findings represent real-life data. In conclusion, the rate of TEEs was found to be 7.9%. Despite being a retrospective observational study, this result demonstrated the high incidence of TEEs in patients with MPM. Thrombocytosis, disease stage, and histopathology did not affect the incidence of TEEs. Authors’ Note Deniz Koksal, and Yetkin Agackiran formerly worked at Ataturk Chest Diseases and Chest Surgery Education and Research Hospital, Ankara, Turkey.

Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Thromboembolic Events in Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) increases the risk of thromboembolic events (TEEs). In this retrospective study, we aimed to determine the rate o...
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