VTE is a common and life-threatening condition that occurs in cancer patients . Lung cancer is the leading cause of cancer-related death worldwide  and the incidence rate of VTE reaches 14% in lung cancer patients . VTE leads to a higher risk of death, higher cost of treatment, and lower quality of life in NSCLC patients [18, 29, 30]. Factors related to the formation of VTE include individual factors and tumor-related factors. A large prospective study showed that elder patients had a 10-fold higher incidence of VTE relative to young patients . Meanwhile, different gender can also be a risk factor for VTE [32, 33]. Additionally, a large retrospective study reported that  the highest rate of VTE (about 5%) was observed in African American patients, while the lowest rate (3%) was found in Asian/Pacific Islander patients. Surgery and chemotherapy have been shown to increase the risk of VTE as well. Cancer patients have a six- to seven-fold higher risk of developing chemotherapy-associated thrombosis . Chemotherapy-related VTE was first identified in patients treated with cisplatin, a platinum-based drug that has been widely used in many cancers . Other drugs such as tamoxifen, L-asparaginase, lenalidomide, immunosuppressive and cytotoxic drugs have also been reported to increase the risk of VTE . Recent evidence has indicated that some oncogenic driver mutations in NSCLC are related to VTE, such as anaplastic lymphoma kinase (ALK)  and ROS-1.
In this meta-analysis, 12 articles were included, involving 6,360 NSCLC and 120 SCLC patients. SCLC is a type of lung cancer with completely different pathological features and biological behavior, as well as different treatment strategies. We first performed a heterogeneity test based on the above-mentioned VTE-related factors and found that the heterogeneity of this meta-analysis was high (I2 = 81%, P < 0.01). The heterogeneity still existed after excluding the studies with SCLC patients. Also, there was still some heterogeneity in the Asian and non-Asian subgroups (data not shown). However, when studies with SCLC patients were removed, low heterogeneity was observed in the Asian subgroup. Since most of the studies included patients treated with chemotherapy, radiotherapy, and surgical treatment, we did not categorize them according to therapeutic regimens. Because of the high heterogeneity of the included studies, we used random-effects models for the analysis.
Our results showed that the OS of NSCLC patients with VTE was significantly shorter compared to those without VTE (HR = 1.71, 95% CI [1.39–2.10], P < 0.01). We deleted studies by Lee et al.  and Kourelis et a.l , which included patients with SCLC. The remaining studies were divided into two subgroups: Asian and non-Asian. The heterogeneity of the Asian subgroup significantly decreased (I2 = 35%, P = 0.20). Both subgroups showed that NSCLC patients with VTE had shorter OS than those without VTE. The sensitivity analysis showed that studies contributing to the heterogeneity did not significantly affect the pooled results, suggesting that our results were statistically robust.
A cohort study compared the survival of cancer patients with or without VTE and observed a higher mortality rate in those who experienced VTE (OR = 2.20, 95% CI [2.05–2.40]). The mortality ratio of patients who were diagnosed with cancer within one year after the diagnosis of VTE was 1.30 times (95%CI: 1.18–1.42) higher relative to those without VTE . Therefore, it is certain that VTE exerts a negative influence on the prognosis of cancer patients. A review involving 412,008 patients showed that 2.5% of them developed VTE and had a higher mortality compared to those without thrombotic events (HR = 1.38; 95% CI [1.28–1.49]). Lung cancer patients had a 1.29-fold greater risk of mortality (95% CI [1.12–1.48]) when complicated with VTE , which was slightly lower than our results. It has also been shown that lung cancer patients with PE had significantly shorter survival compared to the control group (243.5 vs. 327 days, p = 0.01), and a more significant difference was found in patients who were simultaneously diagnosed with PE and lung cancer .
Lung cancer is a very heterogeneous type of tumor disease, at a cellular and histological level. The treatment strategies and prognostic outcomes of different lung cancer pathological types are very different. Lung cancer patients in a hypercoagulable state are related to the primary disease. The understanding of lung cancer heterogeneity is crucial to the awareness of the VTE implications and future developments regarding this field. For risk assessment of lung cancer patients with VTE, more targeted risk prediction models based on the pathological types should be explored, and corresponding molecular biomarkers should also be investigated.
However, our study has some limitations. First, we only reviewed English articles, which may lead to language bias. Second, data were extracted from the forms and converted to HR values, which may not accurately describe the original results. However, despite limitations, the study provides a clear understanding of management of NSCLC with VTE in clinical practice.