Primary lung cancer is the second most prevalent malignancy worldwide but has the highest rate of mortality (1). Although the overall survival of patients with lung cancer substantially improved in the past decade with comprehensive and updated treatment strategies, including surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy, the risk of venous thromboembolism (VTE) in this class of patients has further increased recently (2). Venous thromboembolism can occur at any time in the course of the disease, and may at times constitute the presenting symptoms, triggering further investigations that lead to an eventual cancer diagnosis. Venous thromboembolism is the second most important risk factor contributing to mortality, after cancer itself (3). As expected, a similar trend is also observed in lung cancer (4, 5).

Venous thromboembolism can be classified into two major clinical conditions: deep vein thrombosis (DVT) and pulmonary embolism (PE). Large studies have shown that VTE is associated with worse outcomes in patients with cancer, including increased mortality. For instance, in one study, the one-year overall rate of survival in patients with lung cancer, who simultaneously had VTE, was 12%, compared to 36% in those without VTE (P < 0.001) (5). The mortality of those with VTE was 2.2-fold higher (95% confidence interval (CI) 2.05 to 2.40), while patients diagnosed with cancer within twelve months following a diagnosis of VTE had a one-year survival rate of 38%, compared to 47% percent in the control group without VTE (P <0.001) (6). The prevalence of cancer-related VTE varies according to patient-related factors, such as additional thrombogenic risk factors, including degree of mobility, performance status, presence of other comorbidities, past history of VTE, cancer-related factors, such as cancer location, stage, and grade, and treatment-related factors, such as whether the patient received surgery, chemotherapy, anti-angiogenic therapy, hormonal, and supportive therapy (7–9). Understanding and addressing the factors contributing to lung cancer-related VTE can significantly aid the prevention of VTE, which in turn reduces patient comorbidities and prevents reductions in performance status. This, in turn, helps to optimize the treatment schedules of cancer patients and is expected to benefit patient survival. Therefore, it is important to systematically analyze the characteristics of patients with VTE so that primary thromboprophylaxis with anticoagulant therapy and non-pharmacological interventions can be constituted appropriately.

At present, domestic and international guidelines for the prevention and management of VTE in cancer patients do not specifically outline the management of different VTE risk factors, nor do they suggest risk-factor specific or individualized management for VTE in patients suffering from different types of cancer. Therefore, assessment of the prevalence and characteristics of VTE in patients with lung cancer is of value toward optimizing the prevention and treatment of VTE in lung cancer. This may additionally aid in support of drafting updated guidelines to support these measures. The aim of this systematic review and meta-analysis is to determine the prevalence and patient-specific characteristics of VTE grouped by gender and regional characteristics of patients with lung cancer.

This review was conducted in accordance with the PRISMA 2020 statement for systematic reviews (9). The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO), registration number: CRD42022306400.

Overall, a total of 4087 articles were found through the initial literature search based on the aforementioned search criteria. Of these, 650 duplicate articles and 3356 irrelevant articles were excluded after initial abstract screening. Eighty-one additional articles were excluded after full text screening. Out of the literature excluded, 44 were conference abstracts and 2 were trials with non-related outcomes. Altogether, 35 studies (13–47) were found to be eligible for this systematic review. The literature selection process is outlined in Figure 1 .

This systematic review included 35 studies with 742,156 individuals. It demonstrated that the number of patients with VTE, as previously reported, is substantial in those suffering from lung cancer, with gender and regional variances. In evaluating the prevalence and characteristics of all VTE, DVT, and PE, we found the prevalence of VTE was the highest in Australasia and lowest in Europe. The prevalence of VTE was higher in male patients with lung cancer. DVT predominantly occurred in the distal lower extremities, while PE mostly occurred in segmental or subsegmental pulmonary arteries. This systematic review summarized the prevalence of VTE in patients with lung cancer, which provides a theoretical basis in constructing guidelines for the screening, prevention and management of thromboembolism in lung cancer.

VTE is one of the most important comorbidities leading to increased morbidity and mortality in cancer patients (7). Approximately 15% of patients are diagnosed with at least one VTE event in the course of their cancer (48). Primary lung cancer remains the leading cause of cancer death worldwide, which is further compounded by the high prevalence of VTE that both worsens the performance status of affected patients and complicates their cancer management. Understanding the characteristics of lung cancer-associated VTE is therefore of the utmost importance.

The association of race with VTE may reflect the different regional rates of VTE. It is widely understood that patients of Asian ethnicity have lower risks of VTE, where several ethnic comparative studies reported lower rates of thromboembolism affecting the venous system in patients of Asian descent in the United States when compared to Caucasians and African Americans (49). A study found at most a modest association of race with risk of VTE, particularly once comorbid conditions and socioeconomic status were accounted for in three large US cohort studies including 51,149 individuals and 916 VTE events. VTE rates were higher among black persons than white persons in the United States (risk ratio, 1.81; 95% confidence interval, 1.20–2.73) and significantly higher among black persons in the Southeast than black persons in the rest of the United States (risk ratio, 1.63; 95% confidence interval, 1.08–2.48), whereas they were not higher among white persons (risk ratio, 0.83; 95% confidence interval, 0.61–1.14) (50). A recent investigation found that the incidence of VTE varied across ethnic groups, with the highest incidence identified among African Americans (4.02%), followed by non-Hispanic Caucasians (2.98%), Hispanics (2.08%) and Chinese (0.79%) participants (51). The association between BMI and venous thromboembolism was strongest among non-White women with the higher incidence for obese compared with non-obese patients. Risk of venous thromboembolism increased with age for all race/ethnicities. Most of the above studies of geographic or racial incidence of VTE have used the Atherosclerosis Study Cohort, the Cardiovascular Health Study Cohort, and the Causes of Geographic and Racial Differences in Stroke Study Cohort, among others. Fewer lung cancer study cohorts are currently available. We used the existing literature to summarize the geographic and racial incidence of VTE associated with lung cancer. Our meta-analysis found that the overall prevalence of VTE in patients with lung was 5%, with a male predominance. The incidence of VTE varied significantly across regions and appeared to be the highest in Australasia, though only one study from Australia was included. Patients in North America and Asia had similar incidences of VTE, while Europeans had the lowest incidence of VTE. Interestingly, previous studies have not shown these meaningful conclusions. Reasons for such potential differences between different ethnicities are unclear. A few potential confounding factors may be the varying risk factors occurring in patients of different ethnicities, with obesity, diabetes mellitus, and elevated factor VIII being more common in African Americans. Similarly, genetic polymorphisms, such as factor V Leiden and mutations in the prothrombin gene 20210A are more common in Caucasians (52), which may explain the high incidence of VTE in Australia, with Caucasians being the largest ethnicity in this study. These findings may promote widespread adoption of risk assessment tools, and target prophylactic anticoagulation. Regional differences suggest the need to adapt prevention strategies to local epidemiological data and to increase medical resources, such as specialized training, equipment, and anticoagulants, in high-risk areas. In addition, raising patients’ awareness of VTE risk can help improve adherence to preventive measures.

DVT and PE are the most common types of VTE, with PE closely associated and often occurring secondary to DVT. In our study, 17 studies reported a low combined prevalence of 1% of DVT and PE, which was consistent with previous reports. DVT mostly occurred in the distal lower extremities, while PE mostly occurred in segmental or subsegmental pulmonary arteries. In one of our studies (41), 28 of 1471 patients with lung cancer were diagnosed with VTE, including five patients with PE alone (0.34%), nine with PE diagnosed following DVT (0.61%), and 14 patients with DVT alone (0.95%). The incidence of PE occurring following diagnoses of DVT was 44.7%, and patients with risk factors accounted for 88.3%. The biggest risk factors for VTE were prolonged bed rest, surgery, hyperlipidemia, hypertension, malignancy, increased hemoglobin, heart disease, trauma, and femoral vein puncture. The number of risk factors increases with age and patient comorbidities. The most common clinical manifestations of DVT were lower limb swelling (91.3%) and pain (58.3%). The femoral vein is the most commonly involved site of occlusion for DVT in lung cancer, which also has the highest association with secondary PE. Therefore, for this group of high-risk patients, we need to closely monitor these risk factors, implement stratified management, and take appropriate preventive and therapeutic measures. This will help reduce the risk of DVT and PE, which are of critical clinical importance.

The incidence of DVT in cancer ranges from 1% to 11%, and is commonly indicative of poor prognosis (53). Among cancer patients presenting with DVT, cancers of the lung, prostate, breast, and colorectum are the most common, which comprise approximately 10% to 15% of all patients diagnosed with DVT (54). In our study, the prevalence of DVT was 5%, with a prevalence of 7% and 4% in men and women, respectively. The prevalence of DVT is higher in men, with male gender being an independent risk factor for DVT (17). As demonstrated in another study, the cumulative incidence of PE was 2.2% among 8014 patients with lung cancer (55). PE is associated with increased mortality in lung cancer (5). In a large registry study, 3% of deaths in cancer patients were PE-related, versus 1% of deaths in patients not suffering from cancers (56). In our study, the prevalence of PE was 3%, with a higher prevalence in men than in women similar to that for DVT, which were 13% and 7%, respectively. Being male is an independent risk factor for PE, which has been found consistently in a number of observational studies (57). Increased hemoglobin is a known risk factor for VTE, with generally higher hemoglobin levels in men potentially being one of the reasons why men are more likely to develop VTE. In summary, VTE, encompassing DVT and PE, is a critical complication in cancer patients, especially lung cancer patients. Therefore, close clinical monitoring, accurate risk assessment, and appropriate prophylactic measures need to be taken in such patients. In addition, gender and hemoglobin level, as important risk factors, should not be ignored in clinical management.

This study has a number of limitations that need to be acknowledged. Although the qualities of our included studies were examined using the NOS scale, with an average score of 7.486 being obtained, indicating a high overall quality, the use of ICD-9 and ICD-10 codes were only used in five studies for diagnosing VTE. As most of the other 30 studies combined medical history, physical examination and imaging, the inconsistency observed in diagnosing VTE between different studies may have introduced significant bias. In addition, some of the studies dated back to the mid-2000s. As such, the observed prevalence of VTE in patients with lung cancer may not apply to patients undergoing more up-to-date contemporary individualized treatments, including targeted therapy and immunotherapy from the early 2010s onwards. Additionally, since the literature we included did not provide sufficient data to support an analysis of the incidence of VTE associated with different types of lung cancer, we did not proceed with graphical representation or further analysis of this aspect.

In conclusion, our meta-analysis demonstrates that the prevalence of lung cancer-related VTE is high and is gender- and region-specific. This study emphasizes the need to further explore the causes of regional differences and develop effective preventive strategies, provides an important basis for improving the recognition and management of VTE in lung cancer patients, and may lead to changes in clinical practice to reduce the risk of this serious complication.

In some of the literature we included, there may be instances where lung cancer patients have undergone surgery, radiotherapy, or chemotherapy, leading to a certain degree of heterogeneity in our analysis of the literature. Unfortunately, these studies did not provide sufficient data to allow for in-depth subgroup analysis, which is indeed regrettable. Therefore, risk factors related to VTE, such as surgery, radiotherapy, and chemotherapy, were not systematically analyzed in this study.