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Original Research: Lung Cancer |

Prevalence and Associations of VTE in Patients With Newly Diagnosed Lung CancerVTE in Patients With Newly Diagnosed Lung Cancer FREE TO VIEW

Yuhui Zhang, MD, PhD; Yuanhua Yang, MD, PhD; Wenhui Chen, MD; Lijuan Guo, MD, PhD; Lirong Liang, MD, PhD; Zhenguo Zhai, MD, PhD; Chen Wang, MD, PhD; for the China Venous Thromboembolism (VTE) Study Group
Author and Funding Information

From the Beijing Institute of Respiratory Medicine, Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.

CORRESPONDENCE TO: Chen Wang, MD, PhD, Beijing Institute of Respiratory Medicine, Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongtinan Rd, Chaoyang District, Beijing, 100020, Beijing Hospital, Ministry of Health, China; e-mail: zhangyhcy86@hotmail.com


*A complete list of study participants is located in e-Appendix 1.

FUNDING/SUPPORT: This study was supported by China Key Research Projects of the 12th National Five-Year Development Plan [Grant 2011BAI11B00], Wu Jieping Medical Foundation [Grant 320.6750.12623], and the Natural Science Foundation of China [Grant 30810103904].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(3):650-658. doi:10.1378/chest.13-2379
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Published online

BACKGROUND:  The risk of VTE before anticancer therapy in patients with lung cancer is not well defined.

METHODS:  A total of 673 hospitalized patients with newly diagnosed lung cancer were examined for VTE within 1 week after admission at five hospitals between January 2009 and January 2011. Additionally, VTE diagnoses within the last 3 months were reviewed. All VTE events were confirmed with imaging studies. Blood cell count and serum carcinoembryonic antigen (CEA) levels were measured before initial treatment.

RESULTS:  VTE events occurred in 89 of the 673 patients (13.2%) enrolled in this study. Forty-two patients (6.2%) developed lower extremity DVT alone, 33 patients (4.9%) developed pulmonary embolism (PE) alone, and 14 patients (2.1%) developed both DVT and PE. By multivariate logistic regression analysis, distant metastasis (OR, 2.2; 95% CI, 1.2-3.9) and leukocytosis (OR, 2.8; 95% CI, 1.5-5.4) were significantly associated with DVT, adenocarcinoma (OR, 2.1; 95% CI, 1.1-4.4) and anemia (OR, 4.6; 95% CI, 1.4-14.5) were significantly associated with PE, and an elevated CEA level in tertiles was linearly associated with PE (P for trend = .06). The area under the receiver operating characteristic curve for the prognostic or diagnostic CEA values was 0.68 (95% CI, 0.59-0.76; P < .001).

CONCLUSIONS:  The prevalence of VTE was high in patients with newly diagnosed lung cancer. In patients with lung cancer, the factors associated with DVT might be different from those associated with PE. An elevated CEA level might facilitate the identification of patients at a higher risk of developing PE.

Figures in this Article

VTE is a serious complication in patients with lung cancer because of its impact on morbidity and mortality.13 In patients with lung cancer, the incidence of VTE in the postoperative period or during the course of chemotherapy or radiotherapy is 7.4% to 13.9%.1,37 At present, because of its high incidence, lung cancer may be responsible for the highest incidence of VTE associated with cancer.8 Several guidelines have focused on the prevention of VTE in some high-risk populations, such as patients hospitalized for anticancer therapy or patients in the postoperative setting.911 However, before initiating lung cancer treatment, patients may already be in a hypercoagulable state; VTE can present prior to the diagnosis of cancer.1214 Moreover, large tumor and metastatic lymph nodes in patients with lung cancer may compress intrathoracic blood vessels. Although all these factors may increase the risk of VTE in patients with newly diagnosed lung cancer, the occurrence of VTE in patients with lung cancer before the initiation of anticancer treatment has not been well defined.

Clinical and laboratory parameters have been evaluated for their predictive abilities for cancer-associated VTE.1517 Leukocytosis is a predictor of coronary heart disease and arterial vascular events.18 An elevated leukocyte count before the initiation of chemotherapy has been reported to be associated with an increased risk of VTE and mortality in patients with cancer receiving chemotherapy.19 Moreover, serum carcinoembryonic antigen (CEA) is a useful marker of adenocarcinoma in patients with lung cancer.20 VTE occurs more frequently in patients with adenocarcinoma.1,21,22 Based on these findings, we hypothesize that the CEA level may be associated with the presence of VTE in patients with lung cancer. To test this hypothesis, we performed the present study to clarify the prevalence of VTE in patients with newly diagnosed and histologically confirmed lung cancer and to determine the significant factors for VTE development. The relationship between CEA level before initial treatment and the occurrence of VTE was also investigated.

Study Population

From January 2009 to January 2011, hospitalized patients with newly diagnosed lung cancer who met the following inclusion criteria were enrolled in this study: histologic confirmation of diagnosis, > 18 years of age, normal cardiac and renal function, willingness to participate, and completion of the written informed consent. The exclusion criteria were as follows: any surgery, chemotherapy, or radiotherapy within the past 3 months; the presence of overt bacteria or a viral infection; VTE diagnosis at least 3 months before recruitment; and continuous anticoagulation treatment with vitamin K antagonists or low-molecular-weight heparins. The study was approved by the central ethic committees of Beijing Chao-Yang Hospital, Capital Medical University (No. 2009-4). Data were collected from all patients.

For this study, tumor histology was categorized as non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The NSCLC tumors were further histologically divided into adenocarcinoma, squamous cell carcinoma, or other NSCLCs (including large cell carcinoma and carcinoma not otherwise specified). NSCLCs were categorized as stage I, II, III, or IV according to a TNM system developed by the International Association for the Study of Lung Cancer in 2009.23 SCLCs were categorized into two stages (limited and extensive) according to a system developed by the Veterans Administration Lung Cancer Study Group.24 To analyze NSCLC and SCLC tumors collectively, the tumors were histologically categorized as adenocarcinoma or other lung cancers (all lung cancers except for adenocarcinoma); tumor stage was categorized as localized (confined to ipsilateral hemithorax) or distant metastasis.

Diagnosis of VTE

All the included patients with newly diagnosed lung cancer were enrolled and examined for VTE using imaging techniques within 1 week after admission to the hospital (average, 5-7 days). Furthermore, data for all patients for the 3 months before recruitment (demographic characteristics, medical history, presenting symptoms, diagnosis, treatment practices, and follow-up data) were retrospectively collected.

DVT events were confirmed by venous ultrasound imaging or a CT venous angiogram. Pulmonary embolism (PE) events were confirmed by a CT pulmonary angiogram or a ventilation-perfusion scan. All VTE events were evaluated by the independent adjudication committee.

Statistical Analysis

Continuous variables were summarized as medians with interquartile ranges. For categorical variables, the percentages of patients in each category were calculated. Clinical characteristics were compared between subgroups of patients with and without DVT and PE by using the χ2 test or Fisher exact test, as appropriate. Multiple logistic regression analysis was used to identify factors independently associated with DVT or PE in patients with lung cancer. A P value < .05 was considered statistically significant. All analyses were performed using SPSS software for Windows, version 15.0 (IBM).

Characteristics of Patients

A total of 698 hospitalized patients with newly diagnosed lung cancer were enrolled in this study. Nine patients were excluded because of insufficient data. Sixteen patients were excluded because they had a history more than 3 months before recruitment of DVT or PE. Finally, 673 eligible and consecutive patients were included in our study (Fig 1).

The 673 included patients with lung cancer had a median age of 64 years, and 72.2% of the patients were men. Regarding tumor histology, 46.1% of the tumors were adenocarcinomas, 29.3% were squamous cell carcinomas, 16.0% were SCLCs, and 8.6% were other NSCLCs. Distant metastases were found in 293 patients (43.5%) at the time of recruitment (Table 1).

Table Graphic Jump Location
TABLE 1  ] Demographic and Clinical Characteristics of the Total Study Population at Baseline (n = 673)

CEA = carcinoembryonic antigen; ECOG = Eastern Cooperative Oncology Group; NSCLC = non-small cell lung cancer; SCLC = small cell lung cancer.

a 

NSCLC staging of constituent ratio.

b 

SCLC staging of constituent ratio.

Prevalence and Clinical Features of VTE

Overall, VTE events occurred in 89 of the 673 patients (13.2%). Forty-two patients (6.2%) developed lower extremity DVT alone, 33 patients (4.9%) developed PE alone, and 14 patients (2.1%) developed both DVT and PE (Fig 2A). Of all VTE cases, VTE was found in 16 patients (18.0%) before admission and in 73 patients (82.0%) after admission.

Figure Jump LinkFigure 2  A, The prevalence and type of VTE in patients with newly diagnosed lung cancer. B, The location of VTE in patients with newly diagnosed lung cancer. PE = pulmonary embolism.Grahic Jump Location

Of all DVT and PE events, 46 DVT events (44.6%) were limited to the distal leg vein, and 10 events (9.7%) involved the proximal leg vein; 42 PE events (40.8%) were located in the segmental or subsegmental pulmonary artery, and five PE events (4.9%) were above the segmental pulmonary artery (Fig 2B). For the DVT cases, 75.0% (42 of 56, including 37 distal DVTs, three proximal DVTs, and two DVTs with PEs) were asymptomatic when the DVT was found; 80.9% of the PE cases (38 of 47) remained asymptomatic, and 19.1% of the PE cases (nine of 47) presented with nonspecific symptoms (dyspnea, cough, and chest pain) that were difficult to distinguish from those of lung cancer. None of the PE events was fatal.

Factors Associated With VTE

In Table 2, the demographic and clinical characteristics are compared between patients with and without DVT and PE. Leukocytosis was defined as a WBC count ≥ 10 × 109 cells/L based on the upper normal limits of a central reference laboratory. The prevalence of both DVT and PE was higher in patients with adenocarcinoma than in patients with other lung cancers (P < .05 for both). Moreover, DVT occurred more frequently in patients with distant metastasis or leukocytosis than in patients without them (P < .05 for both), whereas PE occurred more frequently in patients with an elevated CEA level or anemia (hemoglobin ≤ 10 g/dL) than in patients without them (P < .05 for both). Subsequently, we performed a multivariate logistic regression analysis that included age, sex, smoking history, Eastern Cooperative Oncology Group performance status, comorbidities, tumor histology, tumor stage, blood cell count, and CEA level to identify factors associated with VTE (Table 3). Distant metastasis (vs localized stage: OR, 2.2; 95% CI, 1.2-3.9; P = .011) and leukocytosis (vs WBC count < 10 × 109/L: OR, 2.8; 95% CI, 1.5-5.4; P = .002) were significantly associated with DVT. Younger age, adenocarcinoma (vs other lung cancers: OR, 2.1; 95% CI, 1.1-4.4; P = .002), and anemia (vs hemoglobin > 10 g/dL: OR, 4.6; 95% CI, 1.4-14.5; P = .011) were significantly associated with PE. An elevated CEA level in the tertiles was linearly associated with an increased risk of PE with borderline significance; the ORs of PE in the tertiles were 1, 1.3, and 2.2 (P for trend = .06). By the receiver operating characteristic (ROC) analysis for the prognostic or diagnostic CEA values for PE risk, the area under the ROC curve was 0.68 (95% CI, 0.59-0.76; P < .001) (Fig 3).

Table Graphic Jump Location
TABLE 2  ] Comparison of Clinical Characteristics Between Patients With and Without VTE

PE = pulmonary embolism. See Table 1 legend for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 3  ] Factors Associated with DVT and PE in Patients With Newly Diagnosed Lung Cancer

The variables were entered simultaneously into the multivariate logistic regression model and included age, sex, smoking history, ECOG performance status, diabetes, hypertension, coronary heart disease, WBC count, hemoglobin, platelet count, lung cancer histology (adenocarcinoma vs other lung cancers), lung cancer stage (localized vs distant metastasis), and serum CEA levels in tertiles. Only variables with P values less than or close to .05 are shown in the table. See Table 1 and 2 legends for expansion of abbreviations.

Figure Jump LinkFigure 3  The receiver operating characteristic curve for carcinoembryonic antigen levels for evaluating the risk of PE. See Figure 2 legend for expansion of abbreviation.Grahic Jump Location
Management of VTE in Patients With Lung Cancer

Five patients who presented with hemoptysis caused by cancer before being enrolled in the study were followed frequently for changes in their clinical statuses; they were also evaluated for the risks and benefits of anticoagulation therapy and received anticoagulant therapy at intervals after VTE diagnosis. For the remaining 84 patients, anticoagulation therapy was performed after VTE diagnosis. The anticoagulation therapy was continued until the initiation of cancer treatment, including surgery, chemotherapy, or radiotherapy. We always administered anticoagulation therapy after surgery and during chemotherapy and radiotherapy. No patients developed fatal PE after receiving cancer treatment.

In this study population of patients with newly diagnosed lung cancer, the prevalence of DVT, PE, and VTE was high, at 8.3%, 7.0%, and 13.2%, respectively. The prevalence of VTE was higher in this population than in patients from previous studies with lung cancer undergoing surgery, chemotherapy, or radiotherapy (Table 4).1,37 Those studies documented symptomatic DVT and PE, whereas our study included all DVT and PE events. Moreover, we analyzed the clinical features of VTE and found that the majority of DVT and PE events in the patients with lung cancer before the initiation of anticancer treatment were asymptomatic or had nonspecific symptoms. Although DVT is generally believed to be a precursor of PE, and both DVT and PE are considered the same disease,26 we found that the factors associated with DVT were different from those associated with PE in patients with lung cancer. Possible explanations for this finding include the differences between a general population and a population of patients with lung cancer whose large tumors and metastatic lymph nodes directly compress intrathoracic blood vessels.

Table Graphic Jump Location
TABLE 4  ] Incidence/Prevalence of VTE in Patients With Lung Cancer

VTE risk varies considerably in patients with lung cancer. It has been reported that 7.4% of patients with lung cancer have a postoperative VTE, with a peak incidence of 7 days after pneumonectomy.25 In patients with both early-stage and advanced-stage NSCLC who received chemotherapy, VTE has been found to occur more frequently than in patients who did not receive chemotherapy.3,5,7 The incidence of VTE has been found to be higher in patients with NSCLC than in patients with SCLC. Furthermore, among patients with NSCLC, patients with adenocarcinoma have been reported to have a higher risk of VTE than those with squamous cell carcinoma.1,21,22 Patients with NSCLC with advanced disease have been reported to have a higher risk of VTE than those with early disease.1,5,6,22

In our study, DVT occurred more frequently in patients with distant metastasis than in patients without it (P < .05), and this finding remained significant in the multivariate analysis. This finding was in agreement with published reports indicating that advanced cancer stage was a significant predictor of VTE after surgery, chemotherapy, and radiotherapy in patients with NSCLC.1,5,6,22 Patients with advanced cancer are more likely to suffer from complications, such as immobility, which increases the risk of thrombosis, than patients with localized cancer.

In patients with cancer, leukocytosis prior to the initiation of chemotherapy has been identified as one of the predictive factors of an increased risk for VTE.15 In our study, leukocytosis was significantly associated with an increased risk of developing DVT in patients with lung cancer. This finding supported the report that leukocytosis (WBC count > 11 × 109/L), particularly neutrophilic leukocytosis, was strongly associated with VTE in patients with cancer receiving systemic chemotherapy.19 Leukocytosis is likely associated with inflammation, cancer aggressiveness, or disease progression, which results in an increased risk of thrombosis.

Interestingly, in our study, patients > 60 years of age had one-half as much of a risk of experiencing PE as the patients < 60 years of age (P < .05). This finding was supported by the report that younger age was an independent risk factor of VTE in patients with NSCLC; in that report, the incidence of VTE in patients with NSCLC was highest in patients < 45 years of age.1 However, this finding was different from those of several other reports2729 that indicated that cancer-associated VTE frequently occurred in on older age group. Patients with different types of cancer were included in most previous studies. Lung cancer might be a biologically more aggressive cancer in younger patients, which results in an increased risk of thrombosis in younger patients.

PE was more frequent in patients with lung adenocarcinoma than those with other lung cancers (P < .05), and this finding remained significant in the multivariate analysis. This finding was consistent with previous reports.1,21,22 The production of mucin by adenocarcinomas and the subsequent activation of platelets and microthrombi in the microvasculature may be related to this higher PE risk in patients with lung adenocarcinoma.8

In our study, anemia (hemoglobin ≤ 10 g/dL) was a factor independently associated with PE risk. This finding supports previous reports that anemia is a predictive variable of VTE in patients with cancer.15 Anemia is likely associated with advanced stage, cancer aggressiveness, or more significant comorbidities, which increases the risk of thrombosis in patients with cancer.

In this study, an elevated CEA level in the tertiles was linearly associated with an increased risk of PE with borderline significance. The area under the ROC curve was 0.68, which demonstrated the potential role of CEA level for evaluating the risk of PE in patients with newly diagnosed lung cancer. The meta-analysis revealed that the serum CEA level carried prognostic and predictive information of the risk of recurrence and death in patients with NSCLC independent of treatment or study design.20 An elevated CEA level is likely associated with NSCLC histology, cancer aggressiveness, or advanced stage, which increases the risk of PE. Whether measuring CEA levels is clinically useful for stratifying patients for PE risk needs to be made clear. Future larger-scale studies are needed to address this issue.

Limitations

Our study has some limitations. First, although we excluded the patients with a prior history of VTE, some patients may still have had VTE coexisting with their lung cancer, because this study was a short-term survey. Second, the prevalence of DVT may have been underestimated, because the diagnoses of DVT in some patients were made by venous ultrasound imaging, which is insensitive to asymptomatic distal DVT.30 Finally, we did not detect DVT of the upper extremity because of its relative rareness before anticancer treatment.

In conclusion, our study provided data regarding patients with newly diagnosed lung cancer. The prevalence of VTE was high in patients with lung cancer before anticancer treatment. DVT risk was higher in patients with distant metastasis and leukocytosis, whereas PE risk was higher in patients of younger age with adenocarcinoma and anemia. An elevated CEA level might facilitate the identification of patients at a higher risk of developing PE. However, whether screening patients with lung cancer for an elevated CEA level should be performed needs to be determined through future large-scale prospective studies.

Author contributions: C. W. is guarantor of the manuscript. Y. Z., Y. Y., and C. W. contributed to study design; Y. Z. and W. C. contributed to patient enrollment; Y. Z., L. G., and L. L. contributed to statistical analyses; W. C. and L. G. contributed to data collection; L. G. and L. L. contributed to the database; C. W. contributed to data analyses; Z. Z. contributed as an external author and did a critical reading of the manuscript; Y. Z., Y. Y., W. C., L. G., L. L., Z. Z., and C. W. contributed to the writing and revision of the manuscript; and Y. Y. contributed to the approval of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Other contributions: We thank the members of the independent adjudication committee (Yuanhua Yang, MD, PhD; Lei Zhang, MD; Zhanhong Ma, MD; and Liming Zhang, MD, PhD) for the evaluation of VTE in this study.

Additional information: The e-Appendix can be found in the Supplemental Materials section of the online article.

CEA

carcinoembryonic antigen

NSCLC

non-small cell lung cancer

PE

pulmonary embolism

ROC

receiver operating characteristic

SCLC

small cell lung cancer

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Huang H, Korn JR, Mallick R, Friedman M, Nichols C, Menzin J. Incidence of venous thromboembolism among chemotherapy-treated patients with lung cancer and its association with mortality: a retrospective database study. J Thromb Thrombolysis. 2012;34(4):446-456. [CrossRef] [PubMed]
 
Dentali F, Malato A, Ageno W, et al. Incidence of venous thromboembolism in patients undergoing thoracotomy for lung cancer. J Thorac Cardiovasc Surg. 2008;135(3):705-706. [CrossRef] [PubMed]
 
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Figures

Figure Jump LinkFigure 2  A, The prevalence and type of VTE in patients with newly diagnosed lung cancer. B, The location of VTE in patients with newly diagnosed lung cancer. PE = pulmonary embolism.Grahic Jump Location
Figure Jump LinkFigure 3  The receiver operating characteristic curve for carcinoembryonic antigen levels for evaluating the risk of PE. See Figure 2 legend for expansion of abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1  ] Demographic and Clinical Characteristics of the Total Study Population at Baseline (n = 673)

CEA = carcinoembryonic antigen; ECOG = Eastern Cooperative Oncology Group; NSCLC = non-small cell lung cancer; SCLC = small cell lung cancer.

a 

NSCLC staging of constituent ratio.

b 

SCLC staging of constituent ratio.

Table Graphic Jump Location
TABLE 2  ] Comparison of Clinical Characteristics Between Patients With and Without VTE

PE = pulmonary embolism. See Table 1 legend for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 3  ] Factors Associated with DVT and PE in Patients With Newly Diagnosed Lung Cancer

The variables were entered simultaneously into the multivariate logistic regression model and included age, sex, smoking history, ECOG performance status, diabetes, hypertension, coronary heart disease, WBC count, hemoglobin, platelet count, lung cancer histology (adenocarcinoma vs other lung cancers), lung cancer stage (localized vs distant metastasis), and serum CEA levels in tertiles. Only variables with P values less than or close to .05 are shown in the table. See Table 1 and 2 legends for expansion of abbreviations.

Table Graphic Jump Location
TABLE 4  ] Incidence/Prevalence of VTE in Patients With Lung Cancer

References

Chew HK, Davies AM, Wun T, Harvey D, Zhou H, White RH. The incidence of venous thromboembolism among patients with primary lung cancer. J Thromb Haemost. 2008;6(4):601-608. [CrossRef] [PubMed]
 
Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5(3):632-634. [CrossRef] [PubMed]
 
Huang H, Korn JR, Mallick R, Friedman M, Nichols C, Menzin J. Incidence of venous thromboembolism among chemotherapy-treated patients with lung cancer and its association with mortality: a retrospective database study. J Thromb Thrombolysis. 2012;34(4):446-456. [CrossRef] [PubMed]
 
Dentali F, Malato A, Ageno W, et al. Incidence of venous thromboembolism in patients undergoing thoracotomy for lung cancer. J Thorac Cardiovasc Surg. 2008;135(3):705-706. [CrossRef] [PubMed]
 
Hicks LK, Cheung MC, Ding K, et al. Venous thromboembolism and nonsmall cell lung cancer: a pooled analysis of National Cancer Institute of Canada Clinical Trials Group trials. Cancer. 2009;115(23):5516-5525. [CrossRef] [PubMed]
 
Tagalakis V, Levi D, Agulnik JS, Cohen V, Kasymjanova G, Small D. High risk of deep vein thrombosis in patients with non-small cell lung cancer: a cohort study of 493 patients. J Thorac Oncol. 2007;2(8):729-734. [CrossRef] [PubMed]
 
Connolly GC, Dalal M, Lin J, Khorana AA. Incidence and predictors of venous thromboembolism (VTE) among ambulatory patients with lung cancer. Lung Cancer. 2012;78(3):253-258. [CrossRef] [PubMed]
 
Corrales-Rodriguez L, Blais N. Lung cancer associated venous thromboembolic disease: a comprehensive review. Lung Cancer. 2012;75(1):1-8. [CrossRef] [PubMed]
 
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