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Ann Thorac Surg 2008;85:1032-1038. doi:10.1016/j.athoracsur.2007.11.064
© 2008 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

Rate of Thromboembolic Events in Mesothelioma

Derrick Nguyen, MD, Sang-Joon Lee, PhD, Edward Libby, MD, Claire Verschraegen, MD*

University of New Mexico Cancer Research and Treatment Center, Albuquerque, New Mexico

Accepted for publication November 26, 2007.

* Address correspondence to Dr Verschraegen, Cancer Treatment and Research Center, University of New Mexico Cancer Research and Treatment Center, 900 Camino de Salud NE MSC08-4630, Albuquerque, NM 87131-0009 (Email: cverschraegen{at}salud.unm.edu).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 References
 
Background: Thromboembolic event (TEE) rates in the general population and the cancer population are 0.1% to 2% and 10% to 15%, respectively. Our clinical observation is that mesothelioma patients are very susceptible to TEE, including arterial thromboses, but the TEE incidence has not been reported. This retrospective study attempts to determine the rates of TEE in patients with mesothelioma.

Methods: Three hundred seventy-four patients with mesothelioma were identified through the New Mexico SEER database. Sixty-five of them were included in the University of New Mexico tumor registry from 1973 to 2003. Documented TEE rates were abstracted from the patient charts. Chi-square test, Fisher’s exact test, and logistic regression were used to identify potentially associated prognostic factors.

Results: Fifty-four medical records were reviewed. Patients had a median of six visits (range, 1 to 63 visits). Median age was 60 years (range, 29 to 79 years). Sex distribution was 11 women and 43 men. Anatomic locations of the primary tumor were 35 pleural, 17 peritoneal, 1 pericardial, and 1 pericardial or pleural mesothelioma. The TEE rate was 27.7% (15 of 54), including 10 deep venous thromboses, 2 arterial clots, 2 myocardial infarctions, and 1 pulmonary embolus. No association between the development of TEE and any known prognostic factors were observed.

Conclusions: The 27.7% TEE incidence rate in mesothelioma patients is higher than in other cancer patients. The true incidence of TEE in mesothelioma is likely to be higher than the rate observed in our review, owing to the retrospective nature of the data. Prophylactic anticoagulation trials are recommended to determine the prevention benefit in this high-risk population.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 References
 
Mesothelioma is a rare type of cancer that arises from mesothelial cells within the pleura, the peritoneum, the pericardium, and the tunica vaginalis. The pleura is the most frequently diseased organ seen in about 80% of cases. The median survival of patients is generally short once mesothelioma is diagnosed; untreated and treated patients survive between 4 and 13 and 6 and 18 months, respectively [1, 2].

Thromboembolic events (TEE) are common in cancer patients [3, 4]. Such events include deep venous thrombosis (DVT), pulmonary embolism, and more rarely, but not infrequently, arterial thrombosis. The incidence of first episode of symptomatic TEE has been estimated to be 0.1% to 2% in the general population [5] and 10% to 15% in the cancer population [6]. About 40% of all patients with TEE develop clinical symptoms [7]. Pulmonary embolism often develops as a sequelae of DVT and accounts for 10% of all hospital deaths in nonmalignant patients, and death occurs in another 5% independent of diagnosis and treatment [8]. In patients who have developed TEE, the risk of developing cancer is increased in the first 6 months to 1 year, with a continued risk for up to 10 years [9]. A strong association between cancer and thrombosis has been documented in several large-scale retrospective studies [10]. One in every 7 hospitalized cancer patients dies secondary to pulmonary embolism [11].

A dual diagnosis of TEE and malignancy often is an indicator of a more aggressive cancer with a worse prognosis and decreased survival [11]. Ovarian, pancreatic, brain, and hepatic cancers induce a hypercoagulable state and are associated with a high incidence of TEE [12]. Mesothelioma cells secrete procoagulant factors and interleukin 6, which could enhance platelet function and thrombosis while promoting inhibition of fibrinolysis [13, 14]. Several studies have examined DVT prophylaxis in cancer patients, including the CLOT, FAMOUS, and MALT trials [15–17]. Data emerging from these large-scale studies have confirmed that a survival benefit is conferred from low-molecular-weight heparin prophylaxis. Low-molecular-weight heparin in combination with chemotherapy may also improve outcomes secondary to an antineoplastic effect [18].

Our study attempts to determine the rate of TEE in patients with mesothelioma and to possibly correlate known prognostic factors with the development of TEE. Factors of poor prognosis in mesothelioma include site of origin, male sex, older age, and poor performance status. Other factors that have been reported to affect prognosis are leukocytosis, anemia, thrombocytosis, increased lactate dehydrogenase levels, nonepithelial histologic identification, chest pain, and fever [19, 20]. We have also included possibly relevant factors such as neutrophilia, low albumin, and weight loss [21].


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 References
 
A retrospective chart review, authorized by the institutional review board, was performed using patients diagnosed with mesothelioma within New Mexico from 1973 to 2003 through the Surveillance, Epidemiology, and End Results Program (SEER) database and the New Mexico Tumor Registry. A total of 374 patients with mesothelioma were identified using histology codes 9050 through 9055. Of these, 65 patients were included in the University of New Mexico tumor registry. Diagnosis of TEE in our study required the following inclusion and exclusion criteria. Enrolled patients must have documented histologic confirmation of mesothelioma. Thromboembolic events included objectively confirmed evidence of DVT, pulmonary embolism, stroke, arterial thrombosis, or myocardial infarction. Events such as DVT or pulmonary embolism were confirmed using duplex ultrasonography, fibrinogen leg scanning or contrast venography, ventilation/perfusion scanning, helical CT scanning, or pulmonary angiography. Patients with multiple reported episodes of TEE or recurrent TEE were counted as only one episode of TEE.

Chi-square testing, Fisher’s exact test, and logistic regression were used to look at associations with previously identified mesothelioma survival prognostic factors at or near the time of diagnosis of mesothelioma, but before initiation of chemotherapy, surgery, or any other cancer-related treatment that may have confounded the prognosis. Such factors include white blood cell count greater than 10.6 x 103 cells/mm3, hemoglobin lower than 12.0 g/dL, platelet count greater than 400 x 109 cells/mm3, serum lactate dehydrogenase value, male sex, age older than 69 years (the SEER reported median age), Eastern Cooperative Oncology Group (ECOG) performance status greater than 0, nonepithelial histologic identification, chest pain, and fever of unknown origin or night sweats at diagnosis. We have also included possibly relevant factors such as neutrophil shift greater than 76%, albumin level less than 3.1 g/dL, and weight loss. The chosen values reflect the limit of the normal range at our institution. For survival outcomes, data were also examined by univariate and multivariate Cox proportional hazard regression model and Kaplan–Meier product estimator, testing the differences of survival curves for TEE by the log-rank test. The survival estimates by known prognostic factors (site of origin, sex, age, and performance status) were done to confirm the validity of our small sample.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 References
 
Sixty-five patients were diagnosed with mesothelioma from 1973 to 2003 in the University of New Mexico tumor registry. The records of 54 patients were reviewed. Eleven patients were excluded: 8 had insufficient medical records and 3 did not have mesothelioma. Patients had a median of six clinic visits (range, 1 to 63 visits). Median age was 60 years (range, 29 to 79 years). Sex distribution was 11 women and 43 men. Anatomic locations of the primary tumor were 35 pleural, 17 peritoneal, 1 pericardial, and 1 pericardial or pleural mesothelioma (Table 1). The sample studied was representative of a typical mesothelioma cohort, as the prognosis was different for women and men (Fig 1A), for site of origin (pleural conferring a worse survival [Fig 1B]), as described with the SEER data [21], and for Eastern Cooperative Oncology Group performance status (Fig 1C). Corresponding probability values from log-rank test are presented on the figures. Table 2 also shows probability values from likelihood ratio test based on univariate Cox proportional hazard regression model. Using objective diagnostic tools, the incidence rate of TEE in mesothelioma patients was 27.7% (15 of 54) including 10 DVT, 2 arterial clots, 2 myocardial infarctions, and 1 pulmonary embolism.


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  		Table 1 Patient Characteristics
 

Figure 1
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  		Fig 1. Kaplan–Meier survival curves for sex (A), site (B), and Eastern Cooperative Oncology Group performance status (PS) (C). Survival curve differences were tested by log-rank test. Sex, site, and performance status are significant variables (p = 0.078, p = 0.085, and p = 0.002, respectively) with 10% significance level. These data confirm the validity of the sample.

 

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  		Table 2 Fitted Univariate Cox Proportional Hazards Model for Survival Time
 
Using {chi}2 testing, Fisher’s exact test, and logistic regression, no association was found between the development of TEE and any of the known factors of poor prognosis (Tables 3, 4). Go Patients with multiple cancers were not excluded if they had mesothelioma, and we did not observe an increased incidence of TEE in these patients.


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  		Table 3 Chi-Square Test and Fisher’s Exact Test for Thromboembolic Event
 

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  		Table 4 Logistic Regression for Thromboembolic Event
 
The Cox proportional hazards model was used to find statistically significant predictors of survival outcomes in this trial. The univariate Cox model fit results are summarized in Table 2. The most significant predictor was Eastern Cooperative Oncology Group performance status (p < 0.0009) dichotomized by cutoff value of 0. The reason for using 0 as the cutoff value is that the effects of performance status for 1, 2, and 3 were very similar (see Fig 1C). Other interesting predictors with less than 10% significance level are sex (p = 0.0630), site (p = 0.0791), age (p = 0.0846), and number of visits (p = 0.0334). Next, we performed model selection procedures using a multivariate Cox proportional hazards model. We found that the Eastern Cooperative Oncology Group performance status was the most significant predictor, and that any additional predictors did not improve the model significantly when we considered the four significant variables (p < 10%) into the model. The other interesting result is that when all variables are included into the model, then site (p = 0.0497) and the number of visits (p = 0.0155) were identified as the most significant predictors.

Survival data in function of TEE is shown in Figure 2. Occurrence of TEE was not associated with survival in this small sample.


Figure 2
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  		Fig 2. Kaplan–Meier survival curves for thromboembolic event (TEE), testing survival curves for thromboembolic event by log-rank test. There is no significant difference.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
References
 
Our data demonstrate that the incidence of TEE is significantly increased in patients with mesothelioma. Although the rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy are 12% and 0.17%, respectively [6], the rate of TEE in mesothelioma patients is much higher at 27.7%. Because of the retrospective nature of these data, the rate is most likely underreported. Before 1980, the accurate diagnosis and chart documentation of TEE was limited. There were no autopsy reports to determine the presence of asymptomatic TEE. Given the dismal prognosis of mesothelioma and the lack of effective treatments, many patients opted for hospice. Many patients were not systematically followed at our institution for medical, geographic, or other reasons. In this review, no correlation was established between known mesothelioma prognostic factors and the development of TEE [22]. Additionally, no other related factors were found (Table 3). Therefore, it is not possible to accurately predict which mesothelioma patients will be susceptible to TEE. Patients with cancer may have an increased production of procoagulant factors such as fibrinogen or factors V, VII, VIII, IX, and XI [23] or a direct release of tissue factor by the neoplastic cells [24]. Tissue factor complexes with coagulation factors, such as factor VIIa, and activates the coagulation cascade [25]. Excessive release of procoagulant factors will lead to TEEs. Several procoagulant activators have been identified in extracts of human tumors. The most well-known procoagulant activators are the tissue factor and the cancer procoagulant [26]. The tissue factor is a factor VII–dependent procoagulant activator found in peripheral blood, pulmonary alveoli, peritoneum, breast milk, and monocytoid cell lines [25]. Cancer procoagulant is a direct factor X activator that functions in the absence of factor VII; it has been isolated from lung cancer cells [25]. Tumor cells have been shown to be capable of binding factors Va and Xa, with subsequent assembly of the prothrombinase complex [27]. The most common abnormalities of routine clotting tests in cancer patients include elevation of plasma coagulation factors (fibrinogen and factors V, VIII, IX, and XI) and thrombocytosis, which is common in patients with mesothelioma (Table 1). Platelet aggregation and adhesion are increased in patients with cancer [28], and plasma viscosity, erythrocyte aggregation, fibrinogen, and globulin levels may be significantly elevated. A known consequence of hypercoagulable states is the migratory thrombosis syndrome or Trousseau disease, which is relatively unresponsive to standard anticoagulant therapy [29]. New molecular markers such as interleukin 6, mesothelin, or osteopontin may help diagnose mesothelioma patients early and may define patients at risk for TEE [30–33]. Osteopontin is known for activating thrombin and should be studied as a marker for TEE [34].

Anticoagulation is commonly used in cancer patients. Unfractionated heparin causes unwanted side effects such as thrombocytopenia, osteoporosis, and bleeding. Warfarin carries the risk of increased TEE if the level is subtherapeutic or unwanted bleeding if it is supratherapeutic, and the dose needs to be adjusted when given concomitantly with many anticancer drugs. In many studies, low-molecular-weight heparins are superior or equivalent to unfractionated heparin or warfarin with fewer adverse effects and a decreased incidence of major bleeding in patients with cancer (Table 5) [15–17, 35, 36]. In some of these studies, a survival advantage was observed in patients with good prognosis, but not in patients with very advanced cancers. low-molecular-weight heparin may also act synergistically in combination with chemotherapy to produce an anti-cancer effect and promote improved survival. In patients with small cell lung cancer randomized to dalteparin or no low-molecular-weight heparin while receiving chemotherapy, dalteparin increased progression free survival and overall survival [37].


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  		Table 5 Randomized Studies of Anticoagulation in Patients With Cancer
 
Quality of life is an important consideration in cancer patients. Patients diagnosed with thrombosis often have to endure physical discomfort, diagnostic procedures, hospitalization, and intense medical treatments. The quality of life of mesothelioma patients, with their average survival of 6 to 12 months, will be significantly impacted by a thrombotic event. We recommend that a true population study verify the results of this retrospective analysis. If the data are confirmed, multi-institutional randomized, placebo-controlled studies to determine the efficacy of prophylactic anticoagulation in this high-risk patient population would be appropriate. Outcomes of such a study should include pathophysiologic translational components to evaluate the hypercoagulable state, survival, quality of life, and incidence of side effects. In the interim, vigilant care must be taken to accurately and promptly diagnose and treat clinical TEE in mesothelioma patients.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 References
 

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