Lung cancer associated venous thromboembolic disease: A comprehensive review

Lung Cancer 75 (2012) 1–8

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Review

Lung cancer associated venous thromboembolic disease: A comprehensive review Luis Corrales-Rodriguez 1 , Normand Blais ∗ Hematology and Medical Oncology, Hôpital Notre-Dame, Centre Hospitalier de l’Université de Montréal, 1560 Sherbrooke Est, 6ième étage, Pavillon Deschamps, Montreal, QC, Canada H2L 4M1

a r t i c l e

i n f o

Article history: Received 13 April 2011 Received in revised form 6 July 2011 Accepted 9 July 2011 Keywords: Lung cancer NSCLC Thrombosis Tissue factor Venous thromboembolism

a b s t r a c t The association of cancer and thrombotic events was first described by Trousseau in 1865. The spectrum of these episodes vary in severity, and these can present during or even prior to the diagnosis of cancer. Multiple factors in patients with lung cancer are associated with a higher risk of thrombosis. Patient-related, cancer-related and treatment-related factors contribute to the development of a thrombotic event. The incidence of thrombotic events in patients with lung cancer is one of the highest among all cancers. Certain particular conditions in lung cancer may be responsible to elevate this risk. Tissue factor (TF) over-expression is considered to be the most important element in cancer-related thrombosis. Several oncogenes and tumor suppressor genes have been implicated with this over-expression. The development of thrombosis in a cancer patient adversely influences prognosis. The use of prophylactic anticoagulation in lung cancer patients has been investigated but no consensus has been obtained regarding which patients are more likely to benefit. Models exist that can help predict this risk, but validation is required. Treatment guidelines of anticoagulation in patients who develop a thrombotic event are also discussed, but lung cancer patients have distinct characteristics that have to be taken in consideration. It is of great importance to identify the elements that will predict the risk of developing cancer-associated thrombosis because it will consequently influence the management and prognosis of the patient. © 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction The association of cancer and thrombotic events was first described by Trousseau in 1865 [1]. The spectrum of thrombotic episodes vary in severity, and these can present during or even prior to the diagnosis of cancer [2,3]. In a study of 17,475 patients with acute venous thromboembolism, 16% had a history of cancer, while hidden cancers were detected in 1.2% of patients [4]. Venous thrombotic events (VTE) include deep vein thrombosis (DVT), migratory thrombophlebitis (Trousseau syndrome), and pulmonary embolism (PE). VTE has been reported in as many as 20% of patients diagnosed with cancer, and in selected populations this risk can rise up to 70% [5–7]. A thrombotic event in a cancer patient can have devastating consequences related to its treatment. Some of these consequences

∗ Corresponding author. Tel.: +1 514 890 8000x25381; fax: +1 514 412 7572. E-mail addresses: [email protected] (L. Corrales-Rodriguez), [email protected] (N. Blais). 1 Tel.: +1 514 890 8000x25381. 0169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2011.07.004

are: risk of bleeding, delays in delivering the chemotherapy, interactions with medications, high risk of recurrent thrombotic events, a decreased quality of life, and increased consumption of health care resources [8,9]. It has been described that cancers associated with thrombotic events are more aggressive and usually associated with worse prognosis [10]. Lung cancer has been related to VTE in 7.3–13.6% of patients [11–13]. Due to its high prevalence, lung cancer may be responsible for the highest incidence of thrombotic events associated with cancer [14]. This incidence is higher in patients with nonsmall cell lung cancer (NSCLC) compared to patients with small cell lung cancer (SCLC) [15]. Patients harboring an advanced disease and those receiving chemotherapy are at higher risk of a VTE [13]. This review will discuss the pathogenesis and the different factors associated with the increased risk of VTE in lung cancer patients. It will also describe diagnostic tools and recommendations regarding prophylaxis and treatment of VTE in the particular setting of lung cancer. 2. Epidemiology Rudolph Virchow proposed, in 1884, that thrombosis resulted from a combination of the following: vascular endothelial

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Table 1 Factors related to the development of thrombosis in cancer patients. Patient-related factors Age Race Poor performance status Obesity Prior history of thrombosis Cancer-related factors Origin of cancer Histology of cancer Treatment-related factors Recent surgery Chemotherapy Antiangiogenic drugs Erythropoiesis-stimulating agents

damage, stasis of blood flow, and hypercoagulability [16]. These factors appear to be present in cancer patients and can be classified as: patient-related, cancer-related, and treatment-related factors (Table 1). 2.1. Patient-related factors A retrospective case-control study of VTE in cancer identified advanced age as a risk factor for venous thromboembolism (36.8 vs. 57.2 years of age; p < 0.001) in a multivariate analysis (OR 1.05 yr; CI 95%: 1.03–1.08) [17]. Contrarily, in a large lung cancer population-based study, the rate of VTE was much higher in patients less than 45 years of age, suggesting that many factors including tumor biology, use of chemotherapy and/or increased thromboprophylaxis in older patients may confound this risk [15]. Regarding race, in a large retrospective study, Asian American cancer patients had significantly lower incidence of thromboembolism than Caucasians [18]. This was confirmed in a population based study which included only lung cancer patients [15]. Still, most studies have not been consistent in this regards [19–21]. Poor performance status with prolonged immobility, frequently seen in cancer patients, and a prior history of a thrombotic event has also been implicated with increased risk of thrombosis [22,23]. In a study by Chew et al., patients with lung cancer having comorbidities were found to have a significantly increased incidence of venous thromboembolism when compared to patients without comorbidities [15]. 2.2. Cancer-related factors Cancer type and stage can influence the risk of VTE. Studies have consistently showed an increased risk in patients with pancreatic, brain, ovarian, renal, uterine, gastric, and lung cancer [19,20,24,25]. Lung cancer may account up to 21% of cancer-associated thrombotic cases [25–27]. In a retrospective cohort study by Tagalakis et al., 13.6% of 493 NSCLC patients developed an objectively confirmed DVT [11]. Histological subtype appears to be an independent risk factor. In the previously cited study, adenocarcinomas accounted 60% of the NSCLC patients who developed a DVT, while squamous cell carcinomas accounted for 25% of cases [11]. In a study of 91,933 lung cancer patients, adenocarcinomas had a two-year cumulative incidence of VTE of 5%, squamous cell carcinomas of 2.6%, and large cell carcinomas of 3.2%. The difference between adenocarcinoma and squamous cell carcinoma was statistically significant (HR = 1.9; 95% CI: 1.7–2.1) [15]. Previous published data have obtained similar results [12,28]. The production of mucin by adenocarcinomas may be related to this higher risk, as discussed below.

2.3. Treatment-related factors Surgery and chemotherapy have been related to the development of thrombotic events in patients with cancer [29–32]. The role that radiation therapy has on thrombosis is not clear [33]. In a population-based study of cancer patients receiving chemotherapy, the OR of developing a thrombotic event was 9.90 (95% CI: 3.89–25.18), while the OR for cancer patients not receiving chemotherapy was 6.90 (95% CI: 3.92–12.17) [30]. In lung cancer patients, the risk of VTE is higher in the first months of chemotherapy [34]. A study by Zecchina et al. including lung cancer patients undergoing chemotherapy suggested that thrombocytosis was related to VTE while alterations of coagulation inhibitors or intravascular coagulopathy/fibrinolysis were not associated with chemotherapy-induced thrombosis [35]. In lung cancer, specific chemotherapeutic regimens have not been directly related with venous thrombotic events, although no study was directed to answer this question [36–39]. The study by Scagliotti et al. comparing three platinum-based doublets in advanced NSCLC reported 17 serious vascular adverse events (2.8%). Four patients had DVT (one treated with gemcitabine/cisplatin (GC), two with paclitaxel/carboplatin (PCb), and one with vinorelbine/cisplatin (VC)), one PE (with VC), three cerebral ischemias (all with GC), three myocardial infarctions (one with GC, one with PCb, and one with VC), and six cardiovascular arrests or failures (one with GC, two with PCb, and three with VC) [40]. In a study by Numico et al., 108 stages III and IV NSCLC patients who underwent chemotherapy with GC were evaluated for vascular events. A total of 22 vascular events (10 arterial and 12 venous) were diagnosed in 19 patients (17.6%), for a cumulative proportion at 1 year after the start of chemotherapy of 22.0% and an overall mortality of 3.7% [41]. New therapies in the treatment of lung cancer such as bevacizumab, erlotinib and gefitinib have been implicated with the development of VTE. Of these, only bevacizumab has been related to the development of thrombotic events. A meta-analysis conducted by Nalluri et al. with a compilation of 7956 patients treated with bevacizumab evidenced an increased relative risk of 1.33 (95% CI: 1.13–1.56) of developing VTE [42]. In this study, the relative risk in NSCLC patients was of 1.59 (95% CI: 0.47–5.37). In the phase 4 study by Crinò et al., bevacizumab was associated with VTE in 324 of 2212 patients with NSCLC [43]. Another meta-analysis including 1084 patients from 2 randomized studies in NSCLC showed a possible increase in VTE (OR 1.25, 95% CI: 0.83–1.87) in univariate analysis and suggested an apparent inverse trend (with an exposure-adjusted method of analysis (OR = 0.78, 95% CI:0.53–1.14) in patient treated for NSCLC [44]. Considering that patients were censored after chemotherapy in the observation arms and after the end of bevacizumab in the experimental arms (including a maintenance component) in these two studies, this type of analysis may favor the bevacizumab groups if the risk of thrombosis is less important in the maintenance phase than the induction chemotherapy phase, as recently suggested by Connolly et al [34]. Other antiangiogenic drugs, such as sunitinib or sorafenib, can also increase the risk of a VTE [45,46]. Socinski et al. studied 63 patients diagnosed with stage IIIB and IV NSCLC who were treated with sunitinib. One patient died due to complications of anticoagulation treatment given to treat a PE. No other thrombotic events were mentioned [47]. A phase III study that included sorafenib showed a non-significant higher risk of thrombosis in NSCLC patients treated with chemotherapy and sorafenib versus chemotherapy and placebo (1.7% vs. 1.1%; p = 0.58) [48]. Anemia lowers the response to chemotherapy and decreases survival in patients diagnosed with NSCLC [49–51]. Erythropoiesisstimulating agents (ESA), such as erythropoietin and darbepoetin,

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are used in the treatment of chemotherapy-associated anemia [52], but have been associated with an increased risk in thrombosis. A review of phase III trials by Bennett et al. demonstrated a higher risk of VTE in patients receiving ESA (RR = 1.57; 95% CI: 1.37–1.87) with a consequently higher mortality rate [53]. Therefore, special consideration is recommended in lung cancer patients receiving ESA due to a greater underlying risk of developing a VTE. 3. Pathogenesis Although many factors associated with cancer will contribute to the development of a thrombotic event, cancer by itself is a risk factor. Pathogenesis of the hypercoagulable state in cancer has been attributed to various elements, including mucin and tissue factor. Mucin producing tumors have been linked to a higher incidence of cancer-related thrombosis. Early reports suggested that mucus extracts could activate the coagulation pathways, both in vitro and in vivo, by activation of factor X, and that these mucus extracts, when infused to animals, induced intravascular coagulation [54]. It is not well established whether mucin by itself triggered coagulation or whether these experiments were confounded by contamination of tissue factor (TF) [55]. There is evidence that, even though the majority of mucin that is produced is rapidly cleared by the liver, a small amount can interact with P- and L-selectins, inducing formation of platelet-rich microthrombi by multiple mechanisms [55]. It appears that the predominant factor in cancer-related thrombosis is the overexpression of TF. Thrombin, formed as a response to TF, induces clot formation, stimulates and activates platelets, and finally leads to fibrin deposition. Also, thrombin is responsible for multiple cellular responses including angiogenesis. Increased levels of thrombin-anti-thrombin complexes have been associated with poor prognosis in lung cancer patients [56]. Accordingly, aberrant TF expression or deregulation of mechanisms controlling TF procoagulant activity, contribute to the systemic hypercoagulability of patients with cancer [57,58]. TF expression by tumor cells may eventually stimulate different pathways in cancer formation. Zhang et al. suggested that TF along with cell proliferation allow tumor cells to stimulate angiogenesis [59], suggesting that the activation of the coagulation cascade produces components that regulate angiogenesis [60]. The most frequent mechanism by which TF regulates angiogenesis is by an upregulation of VEGF and downregulation of thrombospondin [61]. 4. Biomarkers The elements that regulate the expression of TF in cancer have been subject of study. It has been shown that TF expression by cancer cells is controlled by oncogenes and tumor suppressor genes, such as the epidermal growth factor receptor (EGFR) family, RAS, TP53, and PTEN [62–64]. Recently, the mutated form of EGFR present in glioblastoma multiforme (GBM), EGFRvIII, was associated with the overexpression of TF, protease-activated receptors 1 and 2 (PAR1 and PAR2), and ectopic synthesis of factor VII [65]. Yu et al. suggested that TF expression is controlled by at least 2 of the most common genetic alterations in cancer which are the presence of K-ras oncogene mutation and the inactivation of the TP53 tumor suppressor gene [63]. In 64 patients with NCSCLC, Regina et al. demonstrated that the TF gene is more highly expressed in tumors of advanced stage or presenting a K-ras mutation [66]. Also, there is evidence that combined oncogenic events affected by tumor suppressor genes dramatically increase TF gene expression in lung tumors [67]. MET can also influence cancer-related thrombosis. Amplification of MET has been reported in up to 61% of NSCLC [68–70] and has

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Table 2 Frequency of incidental venous thrombosis in cancer patients. Reference

Total patients (n)

Frequency of IVTa (%)

Cronin et al. [79] Beck-Razi et al. [80] Douma et al. [81] Di Nisio et al. [82] Font et al. [83]

339 44 838 1921 340

6.3 34.1 1.3 3.2 27.6

a

Incidental venous thrombosis.

been reported in 20% of lung adenocarcinomas that acquire resistance to EGFR tyrosine kinase inhibitors [71]. Bocaccio et al. were able to transplant a MET oncogene to an animal model, leading to the developement of carcinogenesis as well as a thrombohemorrhagic syndrome through the induction of plasminogen-activator inhibitor type 1 (PAI-1) and the cyclo-oxygenase-2 (COX-2) pathways [72]. PAI-1 inhibits urinary-type plasminogen activator and tissue plasminogen activator, thus inhibiting fibrinolysis. PAI-1 constitutes one of the elements that play a role in thrombotic vascular disease [73,74]. Similarly, COX-2 expression by inflammatory cells significantly contributes to thromboxane A2 formation, a possible contributor to the genesis of thrombosis [75]. Nonetheless, clinical studies have not confirmed an association between MET expression and the incidence of VTE in cancer [76]. 5. Diagnosis The diagnosis of VTE in a patient with lung cancer usually is the sum of the clinical signs and symptoms, supported by laboratory and imaging findings. Furthermore, there are patients in which VTE is diagnosed incidentally (Table 2). Incidental venous thrombosis (IVT) in cancer patients is primarily a consequence of staging imaging studies. The overall prevalence of IVT was 6.3% in 397 patients with cancer in a study by Cronin et al. [77]. In a small study of 44 nonambulatory cancer patients (12 having lung cancer) who were asymptomatic for DVT, 15 patients were diagnosed with DVT when screening lower extremity Doppler sonography was performed [78]. Another study of 838 cancer patients (120 patients had lung cancer) found 1.3% of incidental DVT or PE [79]. In another retrospective analysis of 1921 cancer patients with chemotherapy, 62 patients (3.2%) were diagnosed with IVT and half of all events were diagnosed in the first 3–6 months of chemotherapy [80]. Another study by Font et al. found IVT in 94 out of 340 cancer patients. Of these 94 patients, 26 were lung cancer patients. Investigators concluded that IVT is common, especially in patients with advanced age, metastatic disease, and usually involves larger vessels [81]. Despite the frequency of IVT, the impact it has on the patient is not fully understood, and no consensus on treatment has been reached due to the lack of proper studies in this field [82]. 5.1. D-dimer D-dimer is a product of the degradation of polymerized fibrin. In patients with a clinical suspicion of DVT, D-dimer can help in the exclusion of VTE due to the high negative predictive value [83]. Also, combining results of D-dimer with imaging techniques such as multidetector-row CT can help in the diagnosis of VTE [84–86]. Unfortunately, cancer patients rarely have negative D-dimer results owing to the underlying activation of fibrin formation [87], therefore D-dimer by itself should not be taken in consideration in the diagnosis of a VTE in a cancer patient. D-dimer has been used as a predictor of the development of a thrombotic event in cancer patients. In a study by Arpaia et al.,

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baseline D-dimer levels were correlated with the development of a thrombotic event in cancer patients that had not started chemotherapy [88]. Doucet et al. also concluded that D-dimer testing after central venous catheter insertion might help stratify patients for the risk of thrombotic complications [89]. This marker could potentially target high-risk populations for prophylactic anticoagulation in the cancer-patient population.

5.2. Imaging techniques Imaging techniques are of great importance in determining the diagnosis and the extension of a thrombosis. For deep venous thrombosis, duplex venous ultrasound is considered to be the most appropriate tool, although its sensitivity is not optimal for infrapopliteal thrombi [90,91]. Ultrasound is also useful for the diagnosis of thrombi in the upper extremities as well as catheter-associated deep venous thrombosis. A systematic review of 17 studies suggested a sensitivity of 97% for compression ultrasonography and no added value to the addition of Doppler assistance. The authors suggested that compression ultrasonography may be considered an alternative to venography [92,93]. For PE, CT angiography is the study of choice. A randomized controlled trial of 1417 patients with probable PE concluded that CT angiography was 5% more sensitive than pulmonary scintigraphy (95% CI: 1.1–8.9%; p = 0.01) [94]. Pulmonary scintigraphy is often impaired in lung cancer patients due to the cancer itself as well as the various treatments for the disease. Ventilation could be diminished due to underlying COPD and obstruction of bronchus and bronchioles due to tumor [95]. Also, if the patient has a history of lung surgery or has been treated with radiotherapy, the results of lung ventilation or perfusion can be altered [96–98]. CT angiography has the added value of being able to diagnose other common comorbidities frequently found in lung cancer patients.

6. Impact of thrombosis Thrombosis influences prognosis and survival of a cancer patient [99]. In fact, cancer patients who develop venous thromboembolism have up to three times greater risk of mortality at 1 year compared to patients without thrombosis and with the same stage of the disease [10,18]. A cohort study comparing the survival of patients with cancer with or without VTE identified a higher mortality in patients who experienced a VTE (OR 2.20, CI 95%: 2.05–2.40). Patients whose cancer diagnosis was made within one year after the VTE diagnosis, the mortality ratio was of 1.30 (CI 95%: 1.18–1.42) compared to patients without a VTE [10]. This increased mortality is also influenced by the anticoagulation therapy patients are exposed to [100]. Regarding DVT, Anderson et al. reviewed 412,008 patients of whom 2.5% had an IVT prior or during their cancer diagnosis. These patients had a higher mortality rate when compared to those patients without a thrombotic event (HR = 1.38; 1.28–1.49). Specifically, in lung cancer, patients had a 1.29 higher risk of mortality (95% CI: 1.12–1.48) [99]. A study of lung cancer patients diagnosed with pulmonary embolism found a significantly shorter survival than control patients (243.5 vs. 327 days, p = 0.01). This difference was even more significant when the diagnosis of PE and lung cancer were simultaneous [101]. Additionally, in a study by de Meis, thrombosis, IL-6, lupus anticoagulant activity, factor VIII levels, and IgM anti-␤2 GPI influenced survival in patients with lung adenocarcinomas [102].

Table 3 Model predicting risk of chemotherapy-induced thrombosis in cancer patients [101]. Characteristics

Score

1-Site of cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, bladder, testicular) 2-Prechemotherapy platelet count ≥350 × 109 /L 3-Hemoglobin ≤100 g/L or use of red cell growth factors 4-Prechemotherapy leukocyte count ≥11 × 109 /L 5-Body mass index ≥35 kg/m2

2 1 1 1 1 1

Risk

Total scorea

High Intermediate Low

≥3 1–2 0

a Total score accounts the sum of the scores according to the characteristics described above.

7. Prophylaxis and treatment of thrombotic events 7.1. Prophylaxis in lung cancer Models predicting the risk of chemotherapy induced thrombosis have been published using clinical and laboratory parameters [103,104]. Khorana et al. established and validated a predictive model for cancer patients on ambulatory chemotherapy (Table 3). It is noteworthy that in this model, lung cancer is considered a very high risk tumor site. Patients with low risk had a 0.3–0.8% chance of a VTE, while patients with a high risk had a 6.7–7.1% chance of a VTE over a median of 2.5 months [103]. This model could identify patients at a higher risk of a VTE during treatment, suggesting that this model could be used to stratify the use of thromboprophylaxis. Earlier studies documented that the survival of patients with SCLC was prolonged with the use of warfarin in combination with chemotherapy [105]. This issue was addressed in a review of five studies that failed to show any clinical benefit of warfarin prophylaxis. Nevertheless, a subgroup of patients with extensive stage SCLC seemed to gain a mortality benefit at 6 months with warfarin prophylaxis. Unfortunately, warfarin significantly increased both major and minor bleeding [106]. The Prophylaxis of Thromboembolism during Chemotherapy Trial (PROTECHT) evaluated the use of nadroparin, a low molecular weight heparin (LMWH), as prophylaxis in 1150 cancer patients (279 had lung cancer) considered at high risk for VTE. Nadroparin or placebo was administered during the duration of the chemotherapy or for a maximum of 4 months. Results showed a 50% reduction in the risk of thrombosis without a survival benefit, and an increase in major bleeding events in patients treated with nadroparin [107]. The TOPIC-2 evaluated prophylaxis with certoparin in 532 patients with advanced or metastatic NSCLC. Certoparin or placebo was administered for a total of 6 months. The administration of certoparin showed a non-significant decrease in the development of thrombosis, but with a higher rate of major bleeding complications [108]. A combined analysis of these two studies evidenced a reduction of symptomatic or asymptomatic VTE events by 46% with a LMWH, with a relative risk of 1.5 (CI 95%: 0.57–3.95) for major bleeding [109]. Therefore, although there is a benefit with LMWH prophylaxis in outpatients treated for lung cancer, the risk of developing a major bleeding event, although not statistically significant in this study, is of concern. More recently, data from the SAVE ONCO study, a double-blind study that randomized 3212 patients with locally advanced or metastatic cancers that were starting chemotherapy to be treated with semuloparin or placebo. The use of semuloparin resulted in a statistically significant risk reduction of 64% in developing a VTE

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without an increased risk of bleeding [110]. Larger controlled studies should be planned to evaluate these potential tradeoff benefits. Several studies addressing this question in lung cancer patients are currently underway using fondaparinux [111], tinzaparin [112], dalterapin [113], enoxaparin [114], and apixaban [115]. It is important to state that there are no studies evaluating the impact of prophylactic anticoagulation in the subgroup of hospitalized cancer patients. The major studies evaluating prophylaxis in hospitalized patients [116–118] do not include an important group of cancer patients. Nonetheless, the fact that cancer patients may have equal or even higher risk of VTE as hospitalized noncancer patients, has led to recommendations, discussed ahead, for prophylaxis in this subgroup of patients [82]. 7.2. Treatment of thrombosis Acute management of a thrombotic event in cancer patients rely on a rapid-acting parentally administered anticoagulant. Warfarin is not the treatment of choice given the necessary follow-up with INR, oral presentation in patients susceptible of nausea and emesis, and drug interactions such as gemcitabine [119], etoposide [120], and erlotinib [121]. Still, it may be used in selected cases, particularly in patients that prefer to avoid injections [100]. LMWHs are the preferred initial treatment but still can have drug interactions and adverse events. In lung cancer, Le Maître et al. reported severe bleeding in 2% of anticoagulated patients, and in the adjusted analyses, warfarin use was the only significant bleeding risk factor (p = 0.007) [122]. Studies have demonstrated that LMWHs are more effective in reducing the risk of recurrent thrombotic events without a higher risk of bleeding when compared to oral anticoagulants [123,124]. The CLOT trial analyzed the risk of recurrence of thrombosis in cancer patients diagnosed with a VTE who were randomized to warfarin or dalteparin. Investigators reported a probability of recurrent thromboembolism at six months of 17% in patients using warfarin compared to 9% in patients treated with dalteparin [123]. Similar results have also been published in smaller trials comparing enoxaparin or tinzaparin to vitamin K antagonists [124–126]. Risk of recurrence on therapy is still higher than the risk reported in noncancer patients [127,128], suggesting that some patients might still be at a high risk of a recurrent VTE even though they are treated with LMWH. Current recommendations of the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), the Italian Association of Medical Oncology (IAOM), the French National Federation of the League of Centers against Cancer (FNCLCC), and the European Society of Medical Oncology (ESMO) for the management of VTE in cancer patients have been published. A LMWH is the preferred initial treatment for duration of 3–6 months or permanently in patients with an active cancer. Inferior vena cava filters are recommended in patients that have contraindication of anticoagulation or a high risk of pulmonary embolism despite being anticoagulated. Finally, in patients with catheter-related thrombosis, treatment can be administered while the catheter is in place and, after its removal, treatment with LMWH or vitamin K antagonist should be continued for 6 weeks in a nonactive cancer patient or for 3–6 months in an active cancer patient [82]. The antithrombotic therapeutic decision in patients diagnosed with lung cancer has to be individualized. Patients with central nervous system (CNS) metastases appear to be safely treated with LMWH. Studies in glioma patients who developed a DVT and were treated with LMWH did not experience excessive bleeding complications [129]. In a study with 203 metastatic cancer patients of whom 44 had brain metastases, patients received dalteparin and no increased incidence of a major bleeding episode was observed

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[130]. In a study by Vitale et al., 26 lung cancer patients with CNS metastases were treated with a LMWH and no patient developed intracranial hemorrhage [131]. Other complications of lung cancer such as hemoptysis should also be taken in consideration. Until now, there is no consensus of whether the LMWH increases the risk of bleeding in a patient with a history of hemoptysis. When patients are treated with bevacizumab and develop a severe arterial thromboembolic event, bevacizumab should be discontinued. Canadian and European monographs advise to discontinue the drug after severe pulmonary embolism, but there are no recommendations for the modification of bevacizumab when other venous thromboembolic events occur. In one meta-analysis, bleeding events did not appear to increase in patients anticoagulated for VTE while being treated with bevacizumab [44]. In the near future, new oral anticoagulation drugs will be investigated in cancer patients. Apixaban and rivaroxaban, both direct inhibitors of Factor Xa as well as a direct thrombin inhibitor, dabigatran, have shown interesting results in surgical thromboprophylaxis with a lower risk of bleeding complications [132,133] and studies are currently open to evaluate this in the setting of cancer associated VTE [134]. Treatment of thrombotic events with LMWH may also influence survival of cancer patients by affecting many pathways including the release of tissue factor pathway inhibitor (TFPI) and thus inhibiting angiogenesis leading to an inhibition of tumor growth and metastasis [135,136]. Several subgroup analyses of different studies have evidenced a survival advantage in cancer patients treated with LMWH [137,138]. In lung cancer patients, Altinbas et al. documented a 5-month statistically significant increase in median overall survival in SCLC patients treated with dalteparin plus chemotherapy versus chemotherapy alone [139]. Therefore, anticoagulation therapy may not only influence survival by treating a thrombotic event, but also by direct effect on tumor growth and the development of metastases. The results of ongoing trials to confirm this hypothesis are therefore eagerly awaited. 8. Conclusions Lung cancer is intimately associated with thrombosis and this increased risk is due to patient, treatment, and cancer biology related features. Therefore, clinicians should consider this higher risk in lung cancer patients and further investigate to diagnose a VTE if the clinical history proves necessary. Consequently, prognosis and mortality are influenced by the thrombotic event and by the treatments implicated. Prophylaxis in patients receiving anticancer treatments is still controversial and studies are on the way to address this issue. LMWH are the preferred treatment of a VTE, but the therapeutic decision must be individualized. There are multiple agents used as prophylaxis or approved as treatment, and many others are under investigation. The traditional approach of evaluating patients with lung cancer has dramatically changed as the identification of mutations has become important in the prognosis and therapeutic approach in NSCLC. There is no strong evidence that links mutations with VTE, but tumor biology markers may improve the predictive information of the currently available risk prediction models. Conflict of interest statement (1) Luis Corrales-Rodriguez: None declared. (2) Normand Blais: Pfizer: Research grant. References [1] Trousseau A. Phlegmasia alba dolens. Clinique Médicale de l’Hotel-Dieu de Paris 1868;3:43, 1868.

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