Abstract
Objectives
Pulmonary embolism (PE) is a life‐threatening complication that can occur in patients with lung cancer. In this study, we aimed to identify risk factors and examine the clinical characteristics of advanced lung cancer patients with PE.
Methods
We conducted a retrospective review of patients admitted to our two hospitals between January 2020 and June 2022. The case group consisted of patients with lung cancer and PE, and a closely matched control group was included to identify risk factors. Statistical analysis was conducted using R language.
Results
A total of 4957 patients were reviewed, and 162 patients (comprising 54 cases and 108 controls) were included in this study. The prevalence of lung cancer with PE in the study population was 1.08%. The majority of patients were male, and the most common histological subtype was adenocarcinoma (67%), followed by squamous cell carcinoma, small cell carcinoma, and poorly differentiated non‐small cell lung cancer. The majority of patients had a high performance status (PS) score, with 50% experiencing respiratory failure (mainly hypoxia) and 33% with deep vein thrombosis (DVT). Forty‐eight percent of patients were diagnosed with concurrent PE. Further analysis showed that PE was an independent predictor of poor survival, and a PS score of >1 was an independent risk factor for PE in patients with lung cancer.
Conclusion
Our study provides valuable insights into the epidemiology and prognosis of PE in lung cancer patients and suggests that a poor ECOG PS, which has not been previously reported, is an independent risk factor for PE.
Keywords: characteristic, lung cancer, prevalence, risk factors, survival
This study examined the clinical characteristics and potential risk factors of pulmonary embolism (PE) in advanced lung cancer patients. Notably, dyspnea was the most common complaint in lung cancer patients with PE, while a poor performance status (PS) score was found to be an independent risk factor for PE in lung cancer patients.
1. INTRODUCTION
Pulmonary embolism (PE) is a life‐threatening syndrome caused by an embolism in pulmonary arteries and/or their branches, usually resulting from detachment of deep venous thrombosis (DVT). According to epidemiological studies, the current annual incidence rates of PE in Europe have been reported to reach as high as 115 per 100 000 population. 1 In some cases, it can lead to sudden death. 2 Patients with cancer are at an increased risk for both the development of PE and the development of more severe forms of the disease. The overall risk of venous thromboembolism (VTE), which consists of DVT and PE, in patients with malignant tumors was reported to be nearly seven times higher than in those without cancer. 3 As one of the most common cancers worldwide, lung cancer was reported to be the most frequent cancer susceptible to PE, 4 , 5 , 6 , 7 accounting for 23.5% 4 of PE patients with malignancy. Moreover, lung cancer patients with PE were at higher risk of in‐hospital death compared to patients with PE and other malignancies combined. 4
Published studies have shown that most lung cancer patients with PE present in an advanced stage, and dyspnea is one of the most frequent complaints in these patients. High D‐dimer, 8 , 9 chemotherapy, 8 presence of DVT, 8 a TNM stage of III–IV, 8 , 9 adenocarcinoma, 8 , 9 ALK mutation, 10 , 11 , 12 and positive PD‐L1 expression 12 were associated with an increased risk of PE in lung cancer patients. However, these studies featured small sample sizes or were cross‐sectional studies without a control group or were based on pan‐cancer studies, and the characteristics and risk factors of lung cancer with PE were not sufficiently reported. In this study, we described the clinical presentation, characteristics of clinical tests, treatment, and prognosis of lung cancer patients with PE from two tertiary hospitals and compared them with a matched control group to further identify risk factors.
2. MATERIALS AND METHODS
This was a two‐center, retrospective study. The study was reported as per the STROBE statement. 13 The study flow is shown in Figure 1.
FIGURE 1.
Study flow.
2.1. Study population
Patients who were admitted into our hospitals from January 2020 to June 2022 and diagnosed with lung cancer were retrospectively reviewed. To be included in the case group, patients had to meet the following criteria: (1) Lung cancer should be diagnosed pathologically, and (2) PE should be diagnosed based on contrast‐enhanced chest CT or CT pulmonary angiogram (CTPA) by at least two radiologists. Patients with clinically inferred PE or lung cancer were excluded. If multiple admissions met the criteria, the first hospitalization of the patient was preferred. For each case identified, two control patients without PE matched according to age, sex, whether it was the patient's first admission for lung cancer or not, and admission date (within 1 year) were enrolled consecutively to identify risk factors.
2.2. Clinical data
The following data were collected, which included (1) demographic and baseline data such as age, gender, body mass index (BMI), pathological type of lung cancer, smoking history, prophylactic anticoagulation and symptoms; (2) blood test results including arterial blood gas analysis, biochemical testing, blood routine, D‐Dimer, serum carcinoma embryonic antigen (CEA), serum cytokeratin 19 (also known as CYFRA 21‐1), and serum neuron‐specific enolase (NSE); (3) equipment inspections such as ultrasound scanning, CT scanning, and electrocardiogram; (4) treatment‐related information including anticoagulation therapy, whether a central venous catheterization was conducted, whether chemotherapy, antiangiogenic therapy, or immunotherapy was administered; and (5) prognosis data focusing on whether the PE was resolved detected by contrast‐enhanced chest CT or CTPA and the overall survival (OS) of the patients. In the abovementioned data, we collected the pretreatment data at the time of admission for those who had PE at the first admission. For those who developed PE during the follow‐up period for lung cancer, we collected the data before or at the initial PE diagnosis. Survival data for the patients in this study were obtained through telephone follow‐up. The follow‐up process began 2 months after the patients' discharge and continued every 2 months thereafter. The last follow‐up was conducted on December 31, 2022.
2.3. Statistical analysis
Statistical analyses were carried out by R (version 4.1.1) or SPSS (version 22.0). Frequency and proportion were reported for dichotomous data, and the chi‐square test was used for hypothesis testing. Continuous variables were reported as mean and SD or median and interquartiles, and were tested using t‐tests or Wilcoxon signed rank tests where applicable. Survival characteristics were visualized using the Kaplan–Meier curve, and the relationships between variables and survival were tested and adjusted by Cox regression analysis. Considering the limited case sample, only those variables that were well‐acknowledged factors or got a p‐value of no more than 0.05 on univariate conditional logistic regression analysis were subjected to multivariate conditional logistic regression models when exploring the risk factors for lung cancer with PE. A p‐value of less than 0.05 was used to indicate statistical significance.
3. RESULTS
3.1. Characteristics of lung cancer with PE
A total of 4957 patients diagnosed with lung cancer were reviewed; 57 patients with PE were retained for further assessment, and 54 patients (1.08%) were finally included in the case group. Subsequently, 108 lung cancer patients without PE were enrolled correspondingly in the control group as mentioned before. The study flow is shown in Figure 1.
The cases had a mean age of 67 ± 10 years, and a mean BMI of 22.80 ± 2.54 kg/m2, and all cases were in an advanced TNM stage (III–IV). Male patients were in the majority, making up about 67% (n = 36/54) of the population, and smokers or ex‐smokers accounting for about 46% (n = 24/54). Adenocarcinoma was the predominant pathological type, responsible for 67% of cases (n = 36/54), followed by squamous carcinoma (22%, n = 12/54), small cell carcinoma (7.4%, n = 4/54) and poorly differentiated cancer (3.7%, n = 2/54). The patients with an ECOG PS score greater than or equal to 2 points were 28 (52%), and 21 cases (39%) of patients were with chronic airway disease including chronic obstructive pulmonary disease (COPD), asthma, or bronchiectasis. The characteristics of cases and controls are summarized in Table 1.
TABLE 1.
The demographics and characteristics of patients.
| Variable | Non‐PE, N = 108 | PE, N = 54 |
|---|---|---|
| Sex | ||
| Female | 37/108 (34%) | 18/54 (33%) |
| Male | 71/108 (66%) | 36/54 (67%) |
| Age (years) | 67 (10) | 67 (10) |
| Histological type | ||
| LUAD | 67/108 (62%) | 36/54 (67%) |
| LUSC | 19/108 (18%) | 12/54 (22%) |
| SCLC | 20/108 (19%) | 4/54 (7.4%) |
| Poorly differentiated NSCLC | 2/108 (1.9%) | 2/54 (3.7%) |
| BMI | 22.81 (3.25) | 22.80 (2.54) |
| Driver gene mutation | ||
| Positive | 39/108 (36%) | 17/54 (31%) |
| Negative | 37/108 (34%) | 18/54 (33%) |
| Not Available | 13/108 (12%) | 15/54 (28%) |
| Not applicable | 19/108 (18%) | 4/54 (7.4%) |
| Smoking history | 61/108 (56%) | 25/54 (46%) |
| Chronic lung disease | 34/108 (31%) | 21/54 (39%) |
| Hypertension | 46/108 (43%) | 25/54 (46%) |
| Diabetes | 18/108 (17%) | 9/54 (17%) |
| Prophylactic anticoagulation | 2/108 (2%) | 0/54 (0%) |
| HB (g/L) | 126 (114, 136) | 123 (102, 138) |
| PLT (× 109/L) | 230 (95) | 208 (85) |
| WBC (× 109/L) | 6.40 (4.98, 8.00) | 7.64 (5.85, 9.40) |
| ALT (U/L) | 19 (13, 27) | 23 (15, 39) |
| AST (U/L) | 23 (18, 30) | 26 (19, 40) |
| Cr (μmol/L) | 63 (54, 76) | 60 (53, 78) |
| D‐Dimer | 0.72 (0.39, 1.33) | 3.98 (1.79, 13.81) |
| CEA | 57/108 (53%) | 29/54 (54%) |
| CYFRA 21‐1 | 56/108 (52%) | 39/54 (72%) |
| NSE (positive) | 34/108 (31%) | 25/54 (46%) |
| PS score | ||
| 1 | 94/108 (87%) | 26/54 (48%) |
| 2 | 13/108 (12%) | 14/54 (26%) |
| 3 | 1/108 (0.9%) | 14/54 (26%) |
| Central venous catheterization | 44/108 (41%) | 20/54 (37%) |
| Chemotherapy | 48/108 (44%) | 20/54 (37%) |
| Antiangiogenesis therapy | 25/108 (23%) | 10/54 (19%) |
| Immunotherapy | 27/108 (25%) | 7/54 (13%) |
| Overall survival | 17 (9, 28) | 10 (3, 21) |
Note: Variables are expressed as n/N (%), or mean (SD); median (lower quartile, upper quartile); median (IQR).
At the time of lung cancer diagnosis, 26 patients (48%) were diagnosed with concurrent PE. Of these cases, 25 were symptomatic with cough (n = 17, 65.4%) and dyspnea (n = 17, 65.4%) being the most prominent complaints. Other symptoms included expectoration (n = 9, 34.6%), chest pain (n = 5, 19.2%), and bloody phlegm (n = 2, 7.6%). Only one patient was asymptomatic and PE was incidentally diagnosed on routine enhanced CT scanning. However, 28 patients developed PE during follow‐up, with the median time for diagnosis being 14 months. Most of these cases (n = 19, 67.8%) were characterized by dyspnea as the primary symptom, while four cases were characterized by confusion, and three cases were asymptomatic. The symptoms of the patients are summarized and visualized in Figure 2.
FIGURE 2.
Symptoms of lung cancer patients with pulmonary embolism. The cases were divided into two groups. The cases with concomitant pulmonary embolism (PE) subgroup included those who were diagnosed with PE at the same time as lung cancer, while the others were grouped into cases with subsequent PE. Symptoms were accordingly collected and summarized.
3.2. Arterial blood gas analysis
There were 34 cases of patients who completed arterial blood gas analysis, with half of them (n = 17/34) developing respiratory failure. Among those complicated with respiratory failure, 16 presented with hypoxic respiratory failure, while one case had hypoxemia and hypercapnia. Nine patients had elevated lactic acid levels. In the subgroup with respiratory failure, eight were classified as having intermediate‐risk PE.
3.3. Gene mutation patterns
For patients with non‐small cell lung cancer (NSCLC), molecular testing is usually recommended to identify those who harbor positive driver gene mutations and may benefit from targeted therapy. 14 , 15 In our study, 35 of 50 cases of NSCLC patients underwent next‐generation sequencing (NGS) analysis, and EGFR, ALK, and ROS1 mutation patterns were collected. Of these, 13 and 3 cases harbored a common mutation in the EGFR and ALK genes, respectively, while no ROS1 mutations were found.
3.4. Blood tests
Fifty‐one patients in the case group completed tumor marker tests, revealing increases in CEA, CYFRA 21‐1, and NSE in 28, 37, and 19 patients, respectively. Additionally, 52 patients had NT‐proBNP and troponin T (TnT) tests, which revealed elevated NT‐proBNP in 15 cases and elevated TnT in 13.
3.5. Auxiliary inspections
Of the 54 cases, 38 underwent Doppler ultrasonography of the lower extremities, revealing 13 cases (34.2%) with deep vein thrombosis (DVT) and nine (23.6%) with superficial vein thrombus, and no thrombus detected in the remaining cases (42.1%).
A cardiac echocardiogram was performed in 30 patients, with a median ejection fraction of 65% (range: 39.11%–79%). Pulmonary hypertension was observed in 11 cases, and six cases displayed acute dilated right atrium and/or ventricle. Electrocardiograms (ECG) were available for 20 patients, with most showing no abnormality. T‐wave changes, right bundle branch block, SIQIIITIII, and sinus tachycardia were noted in eight, four, two, and two patients, respectively. Premature contraction, atrial fibrillation, and sinus arrhythmia each occurred in one patient.
3.6. Treatments and outcomes
Stratified by classification of PE severity, 1 the majority of patients (31/54) were in the low‐risk group, and 23 of 54 in the intermediate‐risk group. None of the patients received thrombolytic therapy; instead, 51 of 54 received anticoagulant therapy following confirmation of PE. Of these, 49 out of 51 were treated with low molecular weight heparin when hospitalized and received oral anticoagulant therapy when discharged, while two patients were administered rivaroxaban throughout the treatment. Three patients were unable to receive anticoagulation due to contraindications (one complicated with gastrointestinal bleeding, two with high blood risk and low platelet count).
Twelve patients died during their hospitalization, while 42 were discharged after their symptoms improved and were prescribed oral anticoagulants as sequential therapy at discharge: 38 were given direct oral anticoagulants and four warfarin. Of the 42 patients, chest CT or CTPA data were available for review in 16 during follow‐up. Anticoagulation therapy was found to be effective in 10 cases, with embolism removed from the lung vessels in three cases within 1 month, four within 3 months, and three within 6 months. Thrombus shrunk in four cases, but two experienced repeated aggravation and improvement.
3.7. The impact of PE on the survival of lung cancer patients
In order to explore the influence of PE on the prognosis of lung cancer patients, 108 patients without PE were enrolled in the control group as previously described. The Kaplan–Meier curve (shown in Figure 3A) showed that patients with PE had significantly shorter median survival than those without PE (19.7 months vs. 54.0 months, log‐rank test p < 0.001). Moreover, univariate Cox regression analysis revealed that PE was associated with survival (unadjusted HR = 3.36, 95% CI 2.03–5.55, p < 0.001), as well as pathological type of lung cancer, NSE, white blood cell (WBC) count, and ECOG PS score (all p < 0.05). Subsequent multivariate Cox regression analysis further confirmed that PE was an independent prognostic factor (adjusted HR = 2.26, 95% CI 1.25–4.10, p < 0.001), after adjusting for age, sex, pathological type of lung cancer, NSE, WBC count, chemotherapy, antiangiogenesis therapy, immunotherapy, and ECOG PS score, which is consistent with the previous analysis. The findings of the analyses are visualized by forest plot shown in Figure 3B.
FIGURE 3.
Survival curve and risk factors to survival of lung cancer patients. (A) The Kaplan–Meier plot that compares the overall survival (OS) of patients with lung cancer who were classified into two groups, PE and non‐PE, based on their association with pulmonary embolism. (B) The forest plots that depict the results of univariate and multifactor cox regression analyses of the factors that potentially impact the OS of the patients.
3.8. Risk factors of lung cancer with PE
We further investigated the association between easily obtainable clinical variables and the onset of PE. These variables were subjected to univariate conditional logistic regression analysis, including smoking history, BMI, histopathology types, complications (chronic lung disease, hypertension, diabetes), tumor markers (CEA, CYFRA 21‐1, NSE), treatment‐related characteristics (central venous catheterization, chemotherapy, anti‐vascular, immunotherapy), and ECOG PS score. The results suggested that smoking history (OR = 0.324, 95% CI 0.106–0.986, p = 0.047) and immunotherapy (OR = 0.305, 95% CI 0.097–0.964, p = 0.043) were associated with lower odds of PE, while CYFRA 21‐1 (OR = 2.427, 95% CI 1.189–4.956, p = 0.014), WBC (OR = 1.223, 95% CI 1.081–1.383, p = 0.001), AST (OR = 1.017, 95% CI 1.001–1.035, p = 0.043), and PS score of more than 1 (PS > 1) (OR = 10.849, 95% CI 3.752–31.37, p < 0.001) were associated with higher odds of PE. However, the multivariate conditional logistic analysis indicated that only the PS score was a significant independent risk factor for lung cancer with PE (adjusted OR = 11.40, 95% CI 3.28–39.70, p < 0.001). The findings of the analyses are summarized in Table 2.
TABLE 2.
Correlation between potential predictors and lung cancer with PE by univariate and multivariate conditional logistic regression analysis.
| Variables | Univariate logistic regression | Multivariate logistic regression | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p‐value | Adjusted HR | 95% CI | p‐value | |
| Sex (male) | 1.69 | (0.14, 21.13) | 0.685 | |||
| Age | 0.93 | (0.75, 1.17) | 0.549 | |||
| LUAD | 1.26 | (0.60, 2.63) | 0.539 | |||
| LUSC | 1.40 | (0.58, 3.35) | 0.453 | |||
| SCLC | 0.35 | (0.11, 1.08) | 0.067 | |||
| Poor differentiated NSCLC | 2.00 | (0.28, 14.20) | 0.488 | |||
| BMI | 1.00 | (0.90, 1.11) | 0.977 | |||
| Smoking history | 0.32 | (0.11, 0.99) | 0.047 | 0.31 | (0.07, 1.50) | 0.147 |
| Chronic lung disease | 1.65 | (0.70, 3.88) | 0.252 | |||
| Hypertension | 1.18 | (0.59, 2.33) | 0.642 | |||
| CEA | 1.04 | (0.55, 1.94) | 0.915 | |||
| CYFRA 21‐1 | 2.43 | (1.19, 4.96) | 0.015 | 1.41 | (0.55, 3.60) | 0.477 |
| NSE | 1.82 | (0.94, 3.54) | 0.077 | |||
| Central venous catheterization | 0.61 | (0.18, 2.03) | 0.418 | 3.33 | (0.51, 21.80) | 0.209 |
| Chemotherapy | 0.37 | (0.11, 1.27) | 0.114 | |||
| Antiangiogenesis | 0.73 | (0.30, 1.74) | 0.472 | 0.93 | (0.27, 3.17) | 0.905 |
| Immunotherapy | 0.31 | (0.10, 0.97) | 0.043 | 0.24 | (0.06, 1.03) | 0.056 |
| WBC | 1.22 | (1.08, 1.38) | 0.001 | 1.15 | (0.98, 1.35) | 0.087 |
| HB | 1.00 | (0.98, 1.01) | 0.497 | |||
| PLT | 1.00 | (0.99, 1.00) | 0.174 | |||
| AST | 1.02 | (1.00, 1.04) | 0.043 | 1.02 | (0.99, 1.04) | 0.174 |
| ALT | 1.01 | (0.99, 1.02) | 0.077 | |||
| Cr | 1.00 | (0.98, 1.01) | 0.880 | |||
| PS(> = 1) | 10.85 | (3.75, 31.37) | 0.001 | 11.40 | (3.28, 39.7) | <0.001 |
Abbreviations: CI, confidence interval; HR, hazard ratio.
4. DISCUSSION
DVT was the primary cause of PE, which necessitated Virchow's Triad comprising stagnation of blood flow, endothelial injury, and hypercoagulability. 16 Malignant tumors, such as lung cancer, have been observed to elicit cytokine secretion from immune cells 17 while simultaneously releasing fibrinolytic inhibitors, ultimately leading to a state of hypercoagulability. 18 Moreover, tumor cells can directly invade blood vessels, damage the endothelium, and eventually result in the formation of thrombi. In this study, we examined the occurrence of lung cancer in combination with PE in our region. We conducted a comprehensive analysis of the clinical characteristics of these patients and found it is not uncommon to see patients with PE at the first diagnosis of lung cancer. In addition, a poor ECOG PS, which has not been previously reported, is an independent risk factor for PE.
Enhanced CT is routinely used in our two clinical centers to aid in further biopsy specimens and TNM staging for patients suspected of having lung cancer. As a result, we are confident in our ability to accurately detect PE in lung cancer patients. In this retrospective study, we found that the prevalence of PE in lung cancer patients was 1.08%. Although the rate is similar, it is slightly higher than that reported by Tsubata et al (0.62%) 19 and Awano et al (0.6%). 20 This difference could be attributed to the racial composition of our study population and the higher proportion of patients with advanced TNM stages.
Our study found that lung cancer patients with PE had a significantly reduced OS and that PE was an independent risk factor for poor prognosis in lung cancer. Therefore, identifying lung cancer patients who are at high risk for PE is crucial for determining appropriate treatment. Unfortunately, the conventional D‐dimer cutoff value in our population had good sensitivity (98.1%) but poor specificity (36.1%). The specificity was improved at 48.1% using age‐adjusted D dimer, 16 but this is still unsatisfactory. Furthermore, half of the lung cancer patients with PE did not develop respiratory failure, and hypoxia was a more prominent feature in other patients. Our study also revealed that lower extremity vascular ultrasound was not sufficiently sensitive to detect PE, with nearly two‐thirds of patients showing no deep vein thrombosis. While ECG and echocardiography had limited diagnostic value, PE should still be considered if relevant results are present. Dyspnea was a prominent complaint among our patients, while chest pain and hemoptysis were less frequent. When lung cancer patients present with dyspnea that cannot be attributed to their cancer, especially if accompanied by hypoxia or respiratory failure, PE should be suspected.
Previous literature showed that adenocarcinoma was the most common subtype of lung cancer with PE 9 , 21 and that it was also a risk factor for PE. 8 In this study, adenocarcinoma was indeed the most frequent pathological type associated with PE, accounting for approximately 67% of cases. However, we did not observe a significant difference in the proportion of adenocarcinoma between the case group and control group, suggesting that it may not be a risk factor. This may be explained by the fact that adenocarcinoma is the most common histopathological subtype of lung cancer 22 and has a high prevalence among patients with lung cancer. Similar results were also found in the study of Liu et al 9 (28/53 vs. 23/53, p = 0.3311) and Xiong et al 23 (46.7% vs. 43.6%, p = 0.33) where no significant difference was found in the incidence of PE between the adenocarcinoma group and the control. Interestingly, small cell lung cancer seems to be less frequently associated with PE, but the intergroup difference did not reach statistical significance (OR = 0.35, 95% CI 0.11–1.08, p = 0.067).
Several studies have shown that positive PD‐L1 is correlated with the occurrence of PE in NSCLC patients, 12 , 24 , 25 suggesting that immunotherapy targeting PD‐1/PD‐L1 axis might have a protective effect against PE. A retrospective cohort study also showed a reduced VTE incidence for patients receiving immune checkpoint inhibitors (ICI) based regimens compared with those receiving chemotherapy‐based and ICI + chemotherapy regimens. 26 In our study, immunotherapy served as a protective factor against lung cancer with PE in univariate analysis; however, it did not reach significance in multivariate logistic analysis. Moreover, a recent meta‐analysis found no significant difference in VTE risk between ICI and non‐ICI regimens. 27 The observation will need to be validated in prospectively designed studies. Although smoking is a well‐known risk factor for lung cancer and has also been reported as a risk factor for VTE, 28 , 29 it did not increase the risk of PE in our lung cancer patients. In fact, it turned out to be a protective factor for lung cancer with PE, consistent with the pan‐cancer study by Au et al (9.2% vs. 21.1%, p < 0.01). 30 After performing univariate analysis, we found that lung cancer patients who had positive CYFRA 21‐1, elevated WBC, AST, and higher ECOG PS score were predisposed to an increased risk of PE. However, after multivariate adjustment, we found that only a high PS score (PS > 1) was an independent risk factor for lung cancer patients with PE.
Nevertheless, there were a few shortcomings in our study that need to be addressed. Firstly, the study only included patients from the respiratory department, which resulted in the inclusion of mostly advanced TNM stage lung cancer patients. Secondly, the sample size was small, which might have impacted the generalizability of the findings. Additionally, due to the retrospective nature of the study, we faced difficulties in obtaining certain test results such as partial pressure of oxygen and NT‐proBNP, which hindered our ability to provide a comprehensive summary of the features.
5. CONCLUSION
The prevalence of PE in advanced lung cancer patients in this study was 1.08% and it was associated with a shortened OS. Dyspnea was the most dominant complaint, and poor PS score was found to be an independent risk factor for lung cancer with PE. Larger and prospective studies are needed to confirm our findings.
AUTHOR CONTRIBUTIONS
Yongkang Huang: Conceptualization; writing (original draft); writing (review and editing). Beilei Zhang: Data curation; formal analysis; software; writing (review and editing). Shiyuan Gao: Data curation; formal analysis; software; writing (review and editing). Ting Li: Data curation; formal analysis; software; visualization; writing (review and editing). Juan Du: Data curation; writing (review and editing). Yajuan Qian: Validation; writing (review and editing). Yufei Xing: Validation; writing (review and editing). Tong Zhou: Writing (review and editing). Minhua Shi: Writing (review and editing). Jian‐an Huang: Conceptualization; funding acquisition; project administration; supervision. Yixin Lian: Conceptualization; funding acquisition; project administration; supervision.
CONFLICT OF INTEREST STATEMENT
The authors have no conflicts of interest to declare.
ETHICS STATEMENT
The study was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). The study protocol was approved by the ethics committee of the Second Affiliated Hospital of Soochow University (No. JD‐HG‐2022‐63). Informed consents were obtained from all patients or their families. The data underwent anonymization prior to statistical analyses and were handled in accordance with standard data protection regulations.
ACKNOWLEDGMENTS
We would like to extend sincere appreciation to Wei Lei for the advice and help in data curation of the study.
Huang Y, Gao S, Li T, et al. Characteristics and risk factors for advanced lung cancer with pulmonary embolism: A cross‐sectional, case–control study. Clin Respir J. 2023;17(10):1048‐1057. doi: 10.1111/crj.13692
Yongkang Huang, Shiyuan Gao, and Ting Li contributed equally to this work.
Contributor Information
Jian‐an Huang, Email: huang_jian_an@163.com.
Yixin Lian, Email: lianyxsoochow@163.com.
DATA AVAILABILITY STATEMENT
Data about the clinical patients could be obtained from corresponding authors on a reasonable request.
REFERENCES
- 1. Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543‐603. doi: 10.1093/eurheartj/ehz405 [DOI] [PubMed] [Google Scholar]
- 2. Shimi M, Allouche M, Ben AH, et al. Sudden death due to pulmonary embolism in north Tunisia: 37 cases study. Tunis Med. 2014;92(10):610‐614. [PubMed] [Google Scholar]
- 3. Blom JW. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. Jama. 2005;293(6):715. doi: 10.1001/jama.293.6.715 [DOI] [PubMed] [Google Scholar]
- 4. Park DY, An S, Kashoor I, Ezegwu O, Gupta S. In‐hospital prognosis of malignancy‐related pulmonary embolism: an analysis of the national inpatient sample 2016–2018. J Thromb Thrombolysis. 2022;54(4):630‐638. doi: 10.1007/s11239-022-02684-8 [DOI] [PubMed] [Google Scholar]
- 5. Chlapoutakis S, Georgakopoulou VE, Trakas N, et al. Characteristics and outcomes of cancer patients who develop pulmonary embolism: a cross‐sectional study. Oncol Lett. 2022;23(5):168. doi: 10.3892/ol.2022.13288 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Anagnostopoulos I, Lagou S, Spanorriga MK, et al. Epidemiology and diagnosis of pulmonary embolism in lung cancer patients: is there a role for age adjusted D‐dimers cutoff? J Thromb Thrombolysis. 2020;49(4):572‐577. doi: 10.1007/s11239-019-02003-8 [DOI] [PubMed] [Google Scholar]
- 7. Kraaijpoel N, Bleker SM, Meyer G, et al. Treatment and long‐term clinical outcomes of incidental pulmonary embolism in patients with cancer: an international prospective cohort study. J Clin Oncol. 2019;37(20):1713‐1720. doi: 10.1200/JCO.18.01977 [DOI] [PubMed] [Google Scholar]
- 8. Cui YQ, Tan XM, Liu B, et al. Analysis on risk factors of lung cancer complicated with pulmonary embolism. Clin Respir J. 2021;15(1):65‐73. doi: 10.1111/crj.13270 [DOI] [PubMed] [Google Scholar]
- 9. Junjun L, Pei W, Ying Y, Kui S. Prognosis and risk factors in older patients with lung cancer and pulmonary embolism: a propensity score matching analysis. Sci Rep. 2020;10(1):1272. doi: 10.1038/s41598-020-58345-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Zhu VW, Zhao JJ, Gao Y, et al. Thromboembolism in ALK+ and ROS1+ NSCLC patients: a systematic review and meta‐analysis. Lung Cancer. 2021;157:147‐155. doi: 10.1016/j.lungcan.2021.05.019 [DOI] [PubMed] [Google Scholar]
- 11. Roopkumar J, Poudel SK, Gervaso L, et al. Risk of thromboembolism in patients with ALK and EGFR‐mutant lung cancer: a cohort study. J Thromb Haemost. 2021;19(3):822‐829. [DOI] [PubMed] [Google Scholar]
- 12. Xiong W, Du H, Ding W, et al. The association between pulmonary embolism and the cancer‐related genomic alterations in patients with NSCLC. Respir Res. 2020;21(1):185. doi: 10.1186/s12931-020-01437-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. von Elm E, Altman DG, Egger M, et al. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. Ann Intern Med. 2007;147(8):573‐577. doi: 10.7326/0003-4819-147-8-200710160-00010 [DOI] [PubMed] [Google Scholar]
- 14. Imyanitov EN, Iyevleva AG, Levchenko EV. Molecular testing and targeted therapy for non‐small cell lung cancer: current status and perspectives. Crit Rev Oncol Hematol. 2021;157:103194. doi: 10.1016/j.critrevonc.2020.103194 [DOI] [PubMed] [Google Scholar]
- 15. Wu G, Zhou C, Bai C, Qian G. Chinese expert consensus on molecularly targeted therapy for advanced non‐small cell lung cancer (2013 edition). J Thorac Dis. 2014;6(10):1489‐1498. doi: 10.3978/j.issn.2072-1439.2014.09.20 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Stone J, Hangge P, Albadawi H, et al. Deep vein thrombosis: pathogenesis, diagnosis, and medical management. Cardiovasc Diagn Ther. 2017;7(Suppl 3):S276‐S284. doi: 10.21037/cdt.2017.09.01 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Marinho FC, Takagaki TY. Hypercoagulability and lung cancer. J Bras Pneumol. 2008;34(5):312‐322. doi: 10.1590/S1806-37132008000500011 [DOI] [PubMed] [Google Scholar]
- 18. De Cicco M. The prothrombotic state in cancer: pathogenic mechanisms. Crit Rev Oncol Hematol. 2004;50(3):187‐196. doi: 10.1016/j.critrevonc.2003.10.003 [DOI] [PubMed] [Google Scholar]
- 19. Tsubata Y, Hotta T, Hamai K, et al. Incidence of venous thromboembolism in advanced lung cancer and efficacy and safety of direct oral anticoagulants: a multicenter, prospective, observational study (Rising‐VTE/NEJ037 study). Ther Adv Med Oncol. 2022;14:17588359221110171. doi: 10.1177/17588359221110171 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Awano N, Okano T, Kawachi R, et al. One‐year incidences of venous thromboembolism, bleeding, and death in patients with lung cancer (Cancer‐VTE subanalysis). JTO Clin Res Rep. 2022;3(9):100392. doi: 10.1016/j.jtocrr.2022.100392 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Maia R, Neves I, Morais A, Queiroga H. Venous and lung thromboembolism in the context of lung cancer: clinical manifestations, risk factors and prognosis. Acta Med Port. 2019;32(10):647‐653. doi: 10.20344/amp.10260 [DOI] [PubMed] [Google Scholar]
- 22. Ganti AK, Klein AB, Cotarla I, Seal B, Chou E. Update of incidence, prevalence, survival, and initial treatment in patients with non‐small cell lung cancer in the US. JAMA Oncol. 2021;7(12):1824‐1832. doi: 10.1001/jamaoncol.2021.4932 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Xiong W, Zhao Y, Xu M, et al. The relationship between tumor markers and pulmonary embolism in lung cancer. Oncotarget. 2017;8(25):41412‐41421. doi: 10.18632/oncotarget.17916 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Deschênes‐Simard X, Richard C, Galland L, et al. Venous thrombotic events in patients treated with immune checkpoint inhibitors for non‐small cell lung cancer: a retrospective multicentric cohort study. Thromb Res. 2021;205:29‐39. doi: 10.1016/j.thromres.2021.06.018 [DOI] [PubMed] [Google Scholar]
- 25. Söyler Y, Akın KP, Kavurgacı S, et al. Could PD‐L1 positivity be associated with venous thrombosis in patients with non‐small cell lung cancer? J Thromb Thrombolysis. 2023;55(2):382‐391. doi: 10.1007/s11239-022-02753-y [DOI] [PubMed] [Google Scholar]
- 26. Khorana AA, Palaia J, Rosenblatt L, et al. Venous thromboembolism incidence and risk factors associated with immune checkpoint inhibitors among patients with advanced non‐small cell lung cancer. J Immunother Cancer. 2023;11(1):e006072. doi: 10.1136/jitc-2022-006072 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Ma Z, Sun X, Zhang Y, et al. Risk of thromboembolic events in cancer patients treated with immune checkpoint inhibitors: a meta‐analysis of randomized controlled trials. Thromb Haemost. 2022;122(10):1757‐1766. doi: 10.1055/s-0042-1749185 [DOI] [PubMed] [Google Scholar]
- 28. Zhang G, Xu X, Su W, Xu Q. Smoking and risk of venous thromboembolism: a systematic review. Southeast Asian J Trop Med Public Health. 2014;45(3):736‐745. [PubMed] [Google Scholar]
- 29. Cheng YJ, Liu ZH, Yao FJ, et al. Current and former smoking and risk for venous thromboembolism: a systematic review and meta‐analysis. PLoS Med. 2013;10(9):e1001515. doi: 10.1371/journal.pmed.1001515 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Au C, Gupta E, Khaing P, et al. Clinical presentations and outcomes in pulmonary embolism patients with cancer. J Thromb Thrombolysis. 2021;51(2):430‐436. doi: 10.1007/s11239-020-02298-y [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data about the clinical patients could be obtained from corresponding authors on a reasonable request.