Abstract
The purpose of this work was to compare the clinical characteristics, rate of recurrent venous thromboembolism (VTE), bleeding complications and mortality of incidental and symptomatic pulmonary embolism (PE) detected on computed tomography in patients with lung cancer. Clinical data of lung cancer patients with PE were obtained from the Department of Respiratory and Critical Care Medicine of Ningbo First affiliated hospital of Ningbo University during January 2016 and June 2021 and were reviewed retrospectively. We compared clinical and radiological characteristics in lung cancer patients with incidental PE (IPE) and symptomatic PE (SPE) and identified variables associated with the 1-year survival on multivariate Cox analysis. All patients were followed up for 1 year to compare the risks of recurrent VTE, bleeding complications, and mortality. Survival analysis was performed by use of Kaplan–Meier. A total of 223 lung cancer patients with PE were enrolled over the period. Of these, 117 (52%) patients had symptomatic whereas 106 (48%) patients had incidental PE. Those with IPE were more likely to have adenocarcinoma, VTE history, chronic respiratory disease and chemotherapy within 30 days prior to PE, while SPE was more frequently observed in patients with squamous cancer, concomitant VTE, performance status 0-1, chronic heart disease and major surgery within 30 days prior to PE. During 1 year of follow-up, recurrent VTE was diagnosed in 10 patients (9.3%) in lung cancer patients with IPE and 13 patients (11.2%) with SPE. The 12-month cumulative recurrent VTE incidence was 9.6% for patients with incidental and 11.4% for patients with symptomatic PE (P = .61). The 12-month cumulative incidences of major bleeding complications were also comparable in the 2 groups (8.1% for incidental patients and 9.8% for symptomatic patients; P = .62). However, the respective 12-month mortality risks were 34.6% and 30.2% in lung cancer patients with IPE and SPE respectively (P = .03). On multivariate Cox analysis, we found that IPE occurrence was an independent risk factor associated with 1-year mortality in lung cancer patients complicated with PE after adjusting for age and sex (HR 1.517; 95% CI: 1.366-1.684; P = .027). Our findings suggest that lung cancer patients diagnosed with and treated for incidental PE had a similar rate of recurrent VTE, and incidence of hemorrhagic complications, but a significantly higher 1-year cumulative mortality rate after PE compared to those with symptomatic PE. IPE may be a marker of poor prognosis.
Introduction
Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication in patients with cancer and a major cause of death, second only to the tumor itself. 1 The introduction of newer systemic therapies for cancer patients comprising targeted tyrosine kinase inhibitors, anti-angiogenic agents, immunomodulatory drug combinations and immunotherapy has improved the outcomes of cancer patients significantly, but they also seem to be associated with an increased risk of VTE.2–4 Previous studies indicated that the incidence of cancer-associated VTE, including PE, has risen over the past 2 decades.5,6
Traditionally, the examination of a patient for PE has included nuclear medicine ventilation-perfusion scanning and computed tomographic pulmonary angiography. With recent advances in the quality of computed tomography (CT) examinations, in particular, with the introduction of high-resolution CT scanners, and its growing utilization of thoracic CT in cancer patients, incidental pulmonary embolism (IPE) has been commonly detected as incidental findings, particularly in patients with malignancy.1,7 IPE also known as clinically unsuspected or asymptomatic PE, refers to PEs detected on scans ordered for reasons other than suspicion of PE. In the oncological setting, these scans are usually performed for cancer staging, evaluation of treatment response, or routine follow-up.8–10 The prevalence of incidental PE in the population of patients with cancer is estimated to range from 1% to 5% depending on tumor type and stage, hospitalization status and presence of additional risk factors. 11 Nevertheless, the incidence and prevalence of IPE may be significantly underestimated as it is strictly related to the imaging used for assessment. Finally, in autopsy studies the prevalence of IPE that was unsuspected ante-mortem was as high as 23% in cancer patients.12,13 Despite being unsuspected or asymptomatic, IPE in oncology patients is not necessarily a benign finding. Previous studies found that cancer patients with incidental PE have high complications, recurrent VTE and mortality rates similar to those of oncology patients with symptomatic PE (SPE).7,14 Thus, international guidelines suggest the same anticoagulant treatment for patients with cancer with incidentally detected PE as for those with symptomatic PE. 15 However, due to a lack of direct evidence regarding the treatment of IPE, optimal management of IPE, in particular subsegmental cases, remains debated.
Data on the absolute IPE incidence stratified by tumor type is scarce. In a large retrospective cohort including a population of 13 783 oncologic outpatients, Shinagare et al reported the highest IPE incidence in patients with pancreatic (4.9%), hepatobiliary (4.8%), upper gastrointestinal tract (3.7%), colorectal (2.6%) and lung/pleural (1.7%) malignancy. However, patients with lung cancer consist of the largest subcohort of the population that developed IPE. 16 We have previously investigated the prevalence of incidental and SPE in patients with solid organ malignancies at our institution over a five year period and found that the overall incidence of PE was 3.12%, of which up to 51.9% of the PEs were noted incidentally for cancer staging or treatment evaluation or cancer recurrence detection. 17 During the course of the analysis of the data, it came to our attention that the patients with lung cancer listed as one of four cancer types which had significantly higher risk for PE compared to others and lung cancer patients account for the largest population that developed IPE which is consistent with previous study.
While high incidence of PE in lung cancer patients is known, to our knowledge, there is limited knowledge on the characteristics and outcome of incidental PE in patients with lung cancer. Therefore, this study was performed in aim to assess the clinical characteristics of patients with IPE as opposed to patients with SPE in lung cancer patients. In addition, we sought to compare the outcome with respect to survival, recurrent thromboembolism and bleeding complications associated with anticoagulant therapy.
Methods
Patients and Design
A single-center, retrospective cohort study was conducted at the Ningbo First affiliated hospital of Ningbo University, a large metropolitan teaching hospital in southeast of China but different cancer with the earlier study. 17 All adult lung cancer patients (age ≥ 18 years) who developed incidental PE and symptomatic PE between January 2016 and June 2021 were eligible. Lung cancers were diagnosed by histologic or cytological examination and PE had to be objectively confirmed by standard radiological methods showing a high probability of PE. IPE was defined as PE incidentally detected on a CT scan performed for reasons other than a clinical suspicion of PE (ie CT scans performed for lung cancer staging, treatment evaluation or cancer recurrence detection). If patients had two or more independent events of PE, only the first event was left in the database. Patients were excluded from the study if they had the following characteristics: (1) already received anticoagulant therapy at the time of PE diagnosis; (2) non-acute PE (ie past history); (3) lung cancer in remission (without disease or treatment for 1 year); (4) incomplete patients data or incomplete follow-up; (5) lack of available CT data; (6) pulmonary artery obstruction by tumor emboli.
The study was approved by the ethics committee of the study site and was conducted in accordance with the Declaration of Helsinki. Based on the observational and retrospective nature of the study data, written informed consent was not required.
Clinical Data
Clinical data of all eligible patients were collected from the electronic medical records system, including age, gender, body mass index(BMI), pathological type and stage, biological features such as EGFR and ALK mutations, performance status according to the World Health Organization criteria, chronic cardiopulmonary conditions, blood laboratory data at the diagnosis of IPE, anti-cancer therapy status within 1 month before pulmonary embolism, management of PE, type and duration of anticoagulation therapy, recurrent VTE events, the occurrence of major bleeding incidents and date of death.
The radiological variables analyzed for the present study were categorized as (1) unilateral or bilateral lung-involved PE; (2) main, lobar, segmental or subsegmental PE according to the most proximal clot seen in pulmonary arteries. PE involving main or lobar pulmonary arteries was considered to be proximal, and that involving segmental and subsegmental arteries was considered to be distal according to previous studies.18,19 The main PE included PE involving the main pulmonary arterial trunk or the right and left main pulmonary arteries. The lobar PE included the lobar and interlobar arteries. When PE involved multiple locations, the most proximal location was recorded. Questionable radiology reports were verified by two senior thoracic radiologists.
Outcome
All patients were retrospectively observed during 1 year after initial PE to ascertain the patients’ outcome. Main study outcomes were recurrent VTE, major bleeding events, and survival of lung cancer patients with PE. Recurrent PE was defined as a new intraluminal filling defect in a pulmonary artery branch. Documentation of a single episode of PE on multiple subsequent scans was not considered a recurrence. Recurrent deep vein thrombosis (DVT) was confirmed by compression duplex ultrasonography or contrast venography. Major bleeding was defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL that required transfusion of two or more units of RBCs, or that occurred in a critical site, or as fatal bleeding according to ISTH guidelines. 20 The last follow-up time and death time were recorded. For patients who were lost to follow-up, the attending physicians were contacted to determine whether end points had occurred. In case of death, the likely cause of death was also verified with the attending physician. Follow-up visit was suspended until the death of patients or until the last study visit after 1 year following initial PE. Survival time was recorded in unit of month.
Statistical Analysis
SPSS software (version 22, SPSS Inc. Chicago, IL, USA) was used for the statistical analyses, and a two-sided P-value < .05 was considered to be statistically significant. Continuous variables were presented as median and interquartile rang (IQR, 25th-75th) and compared using Student's t-test or the Mann-Whitney U-test if non-normally distributed. Categorical variables were presented as number and percentage (n, %) and the Chi-squared test (or Fisher's exact test where appropriate) was used to compare categorical variables. The Kaplan-Meier method was used to estimate the 1 year cumulative incidence of recurrent VTE, major bleeding, and survival analysis. Incidental and symptomatic PE groups were compared for statistical differences with the log-rank test. To find the most independently contributing factors to survival of lung cancer patients complicated with PE, we used the Cox proportional hazards model. The stepwise method was used to find a set of independently contributing factors, including incidental or symptomatic PE.
Results
Patients Characteristics
A total of 290 lung cancer patients with PE were identified between January 2016 and June 2021. 67 patients were excluded for reasons: chronic PE (n = 14), two PE episodes for a single patient (n = 2), missing radiological data of PE (n = 6) or important values (n = 14), incomplete follow-up (n = 7), finally diagnosed with tumor emboli (n = 2) and cancer in remission (n = 22). Finally, 223 patients were included in the present study, including 107 with IPE and 116 with SPE, and the flow chart of patient inclusion is presented in Figure 1. There were no significant differences between the two groups (IPE vs SPE) regarding age and sex. BMI was significantly lower in the IPE group than SPE group (22.9 vs 24.9, P = .021). We found that those with IPE were more likely to have adenocarcinoma, VTE history, chronic respiratory disease and chemotherapy within 30 days prior to PE compared to patients with SPE. In turn, squamous cancer, concomitant VTE, good performance status 0-1, chronic heart disease and major surgery were more frequently observed in patients with SPE. In laboratory findings, hemoglobin and albumin in the IPE group were significantly lower than that in the SPE group, while the white blood cell count, platelet, D-dimer and C-reactive protein showed no statistical difference (Table 1).
Flow chart of patients included in the analysis.
Baseline Characteristics According to the Presence of IPE or SPE.
Abbreviations: IPE, incidental pulmonary embolism; SPE, symptomatic pulmonary embolism; BMI, body mass index; PS, performance status; NSCLC, nonsmall cell lung cancer; ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; CVC, central venous catheter; WBC, white blood cell; ALB, albumin; Hb, hemoglobin; PLT, platelet; CRP, C-reactive protein.
With regard to the radiological variables analyzed, we found that patients with SPE were more likely to have bilateral PE compared to patients with incidental events (99/116, 85.3% in the SPE group vs 58/107, 54.2% in IPE group, P < .001) (Figure 2, Table 2). It was of note that IPE was more likely to be distal, involving segmental and/or subsegmental arteries than SPE, but the difference did not meet the criteria for statistical significance (68/116, 58.6% in SPE group vs 76/107, 71.0% in IPE group, respectively) (Figure 2, Table 2).
Comparison of location of IPE and SPE.
Comparation of Location of IPE and SPE.
Abbreviations: IPE, incidental pulmonary embolism; SPE, symptomatic pulmonary embolism.
Treatment of PE and major Outcomes
Table 3 summarizes the treatment regimens of IPE and SPE. Most of the cases (70.0%) were initially treated with low molecular weight heparin (LMWH), reflecting the standard treatment of cancer-associated VTE during the period studied in our medical center, with no difference between the IPE and SPE groups (70/107, 65.4% vs 86/116, 74.1%, respectively). DOACs (direct oral anticoagulants) were as initial therapy prescribed to 21.5% of patients in the incidental group and 9.5% of the patients of symptomatic group, and the difference was statistically significant (P = .013). Eighteen patients (8.1%) had no initial treatment, including 8 patients(7.6%) in IPE group and 10 patients(8.6%) in the SPE group. The most common reasons for no initial treatment were active bleeding in 11 patients, thrombocytopenia in 4 patients, and brain metastasis in 3 patients. Upon discharge treatment, most patients with PE continue treatment with anticoagulants, mainly with DOACs. 147 of 223 patients (65.9%) were discharged with DOACs, with significant difference in number of treated patients between the incidental and symptomatic groups (78/107, 72.9% vs 69/116, 59.5%, respectively, P = .035). Conversely, the number of patients treated with warfarin in the SPE group was significantly more than that in the IPE group (29/116, 25.0% vs 15/107, 14.0%, respectively, P = .040). An IVC filter was implanted in 11 patients (4.9%), with no difference between the IPE and SPE groups (4.7% vs 5.2%, respectively).
Initial and Discharged Treatment Regimens for Lung Cancer Patients With IPE and SPE.
Abbreviations: IPE, incidental pulmonary embolism; SPE, symptomatic pulmonary embolism; LMWH, low molecular weight heparin; IVC, Inferior vena cava; UFH, unfractionated heparin; DOACs, direct oral anticoagulants.
Eight patients with incidental and 11 patients with symptomatic PE had major bleeding; the respective 12-month cumulative incidences were 8.1% and 9.8% respectively and there was no significant difference (Figure 3; P = .62 from the log-rank test). The most frequent major bleeding locations were gastrointestinal (n = 12), intracranial (n = 3), and urogenital (n = 4); 2 (10.5%) were fatal. At the time of bleeding, 9 patients were treated with LMWH, 7 with DOACs, and 3 with Warfarin.
Cumulative incidence of major bleeding during the treatment period in patients with lung cancer with incidental versus symptomatic pulmonary embolism at 1-year follow-up.
During 1 year of follow-up, recurrent VTE was diagnosed in 23 patients (10.3%), including 10 patients (9.3%) in lung cancer patients with incidental PE and 13 patients (11.2%) with symptomatic PE. The 12-month cumulative recurrent VTE incidence was 9.6% for patients with incidental and 11.4% for patients with symptomatic PE (Figure 4; P = .61 from the log-rank test). None of these events were fatal. Of the total 23 patients with recurrent VTE, 10 patients developed recurrent PE, 4 patients in the group of IPE and 6 patients in the group of SPE. Six patients in each group developed subsequent lower-extremity DVT, and one patient in the SPE group developed thrombosis of the internal jugular vein. Among 10 patients with recurrent VTE after IPE, 3 patients were on anticoagulation at the time of recurrent VTE (DOACs in 2 and LMWH in 1), while 7 patients were off anticoagulation. Of these 7 patients, 3 patients had been on anticoagulant therapy for more than 6 months while 4 patients had less than 6 months. Of 13 patients with recurrent VTE after SPE, 4 patients developed recurrent VTE while on anticoagulation using DOACs, and 9 patients were off anticoagulation at the time of recurrent VTE. Of these 9 patients, 7 patients were off anticoagulation after continuing anticoagulation therapy for more than 6 months; 2 patients were on IVC filter without anticoagulation, including one patient developed recurrent VTE in the form of internal jugular venous thrombus.
Cumulative incidence of recurrent venous thromboembolism (VTE) in patients with lung cancer with incidental versus symptomatic pulmonary embolism at 1-year follow-up.
Prognosis
Overall, 72 patients died at the 1 year follow-up, which corresponds to mortality rates at 12 months of 32.3% considering the whole cohort. Thirty-seven patients (34.6%) with IPE and 35 patients (30.2%) with SPE died with a 1-year cumulative survival rate of 63.7% and 69.2% in lung cancer patients with IPE and SPE respectively, and the 1-year cumulative survival rate of SPE was significantly higher than that of IPE group (Figure 5; P = .03 from the log-rank test). In both groups, progressive cancer was the most frequent cause of death.
Cumulative survival curves in patients with lung cancer with incidental versus symptomatic pulmonary embolism at 1-year follow-up.
We performed a Cox proportional hazards model to identify the variables that effected survival in lung cancer patients complicated with PE. Univariate analysis found that the significant risk factors affecting the 1-year mortality included: male (hazard ratio (HR) 1.490; 95% CI: 1.221-1.693; P = .024), PS = 2-4 (HR 5.778; 95% CI: 4.267-8.998; P < .001), stage III/IV of lung cancer (HR 4.455; 95% CI: 2.632-7.813; P < .001), chronic respiratory disease (HR 2.174; 95% CI: 1.214-4.225; P = .022), recurrent VTE (HR 2.634; 95% CI: 0.634-3.438; P = .018), IPE (vs SPE) (HR 1.960; 95% CI: 2.259-3.433; P = .008) and proximal PE (vs distal PE) (HR 2.328; 95% CI: 1.551-4.797; P = .012) (Table 4). Finally, we performed a multivariable Cox analysis to see if IPE occurrence was an independent prognostic risk factor associated with 1-year mortality in lung cancer patients complicated with PE. This multivariable analysis showed that IPE occurrence was independently associated with 1-year mortality after adjusting for age and sex (HR 1.517; 95% CI: 1.366-1.684; P = .027). Other factors independently associated with 1-year mortality in lung cancer patients with PE were male (HR 1.175; 95% CI: 1.106-1.790; P = .039), PS = 2-4 (HR 2.984; 95% CI: 1.673-5.483; P = .001), stage III/IV of lung cancer (HR 2.253; 95% CI: 1.427-4.420; P<.001) and proximal PE (HR 1.717; 95% CI: 1.032-2.521; P = .031) (Table 4).
Univariate and Multivariate Analyses of Risk Factors Associated With the Mortality of Lung Cancer Patients With PE.
Abbreviations: IPE, incidental pulmonary embolism; SPE, symptomatic pulmonary embolism; BMI, body mass index; PS, performance status; VTE, venous thromboembolism; PE, pulmonary embolism; HR, hazard ratio; CI, confidence interval.
Discussion
This study aimed to evaluate the clinical outcome of lung cancer patients who were incidentally or suspected diagnosed with and treated for PE. We found that recurrent VTE and major bleeding rates were similar in both groups, but lung cancer patients with IPF had significantly higher 1-year cumulative mortality rates compared to those with SPE during 1 year follow-up. We also identified that the occurrence of IPE was an independent risk factor for poor prognosis in lung cancer patients.
Although it has long been known that pulmonary embolism can be incidental,21,22 broad practical interest concerning this issue has emerged in recent years in parallel to the development and widespread use of imaging tests, particularly in patients with malignancies. Overall, a remarkable 48% of our retrospectively assessed lung cancer patients were found to be incidental at pulmonary embolism presentation. We found that adenocarcinoma was more commonly noted in the incidental PE group while squamous cell carcinoma more prevalent in the suspected PE group. Lung cancer patients with IPE were more likely to have had recent chemotherapy and chronic respiratory disease than patients with symptomatic PE. O’Connell et al
23
found that a prior history of VTE was more common among patients with IPE, a finding confirmed by the present study. More common risk factors for PE, such as high BMI, recent surgery, concomitant VTE or high Hb were less often observed in patients with IPE than in patients with SPE. We noticed that symptomatic PE more frequently involve proximal pulmonary arteries, whereas incidental PE more commonly involves peripheral branches, but the difference did not meet the criteria for statistical significance. This is consistent with prior studies which have shown no significant difference in the location of SPE and IPE.16,24 However, these studies included patients of several different cancer types and did not focus on lung cancer alone. Patients with lung cancer are more prone to pulmonary symptoms, which may lead to a higher index of suspicion for PE by clinicians
As regards PE treatment, there is increasing evidence to support the treatment of incidental PE. In the current study, the majority (65.4%) of the IPE group received anticoagulant treatment initially, a similar treatment as the SPE group. There was no difference in the proportion of initially untreated patients between IPE and SPE groups. The incidental or suspected nature of PE had no bearing on treatment-related decisions. Despite receiving anticoagulant treatment, patients with lung cancer with IPE displayed a high risk of recurrence of VTE, which was comparable to those with SPE. These findings indirectly reinforce current guideline recommendations of optimal anticoagulant treatment in cancer patients with incidental PE as symptomatic PE. However, direct evidence regarding the treatment of IPE is scarce and treatment indications are largely derived from retrospective studies. Considering the similar outcomes that emerged from comparative studies on the recurrence of embolic events, bleeding complications and mortality in patients with incidental and symptomatic PE, the general consensus is to use the same treatment strategy for both sets of patients in the clinic.7,14,25
Primarily, on the basis of the results of the CLOT (randomized comparison of LMWH vs oral anticoagulant therapy for the prevention of recurrent VTE in patients with cancer) trial,15,26,27 current clinical guidelines recommend at least 3 to 6 months of anticoagulant treatment for patients with VTE and cancer, and that LMWH is preferable to warfarin-based treatment. However, previous reports showed that most patients receive less than 3 months of LMWH treatment and are notably more likely to discontinue treatment in the real world.28,29 This has been attributed to the burden of self-injection and the high cost of LMWH. The latest data showed that DOACs could emerge as an alternative to warfarin and LMWH for the treatment of cancer-associated VTE.30–33 These new agents may offer a significant improvement in the quality of life for these patients who need long-term anticoagulant therapy. In this present study, we found that most of the patients received DOACs for discharged treatment, which is consistent with previous publications.
In this study, the risk of 1-year mortality in lung cancer patients with incidental PE was significantly higher than symptomatic PE. This finding is consistent with a previous study which reported that the 3-year survival rates in patients with SPE and IPE were 60% and 42% respectively and patients with IPE have a worse prognosis than patients with SPE. 34 Similarly, another study indicated that the detection of unsuspected PE had a negative impact on the survival of patients with cancer compared with matched patients with cancer without VTE (HR, 1.5; 95% CI: 1.01-2.27). 23 However, Dentali et al, 35 found similar 6-month mortality rates for patients with cancer with asymptomatic and symptomatic VTE (51% and 48.6%, respectively), which were both significantly higher compared to the mortality rate of patients with cancer without VTE (27.1%). Further studies are needed to clarify the impact of SPE and IPE on patient's survival rates.
Several limitations also deserve acknowledgement. First, this was a single-center observational study; thus, our results might be subject to unrecognized confounding factors. Although we performed multivariate analysis and adjusted for several potential confounding factors, we could not correct for unmeasured or unobserved variables. Second, this study was retrospective. Limited by the retrospective design, information bias may have compromised the results. Third, the number of patients was relatively small for assessing risk factors in the multivariate statistical models.
Conclusions
In this study, we found that lung cancer patients with incidental PE had a similar rate of recurrent VTE, and incidence of hemorrhagic complications, but significantly higher 1-year cumulative mortality rate after PE compared to those with suspected PE. Despite being asymptomatic or clinically unsuspected, IPE occurrence was independently associated with poor prognosis in lung cancer patients with PE. Given the limitations of this retrospective analysis, these findings should be considered hypothesis-generating and need to be confirmed prospectively in larger studies.
Footnotes
Authors’ Contributions
Study design: Zhuanbo Luo and Kejing Ying. Data collection: Guofeng Ma, Yangfei Lu, and Jianchang Yao. Data analysis: Ning Xu. Writing: Zhuanbo Luo and Guofeng Ma.
Availability of Data and Materials
The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethics Statement
This study was approved by the Ethical Review Board of The First Affiliated Hospital of Ningbo University. Written informed consent was obtained from the patient.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China, TCM (traditional Chinese medicine) Science and Technology Plan of Zhejiang Province, Medical and Health technology Plan of Zhejing Province (grant numbers 81970049, 2020ZB218 and 2024KY1537) and Ningbo Youth technical backbone Program in Hygiene and health.
