ABSTRACT
Objective
Currently, immune checkpoint inhibitors (ICIs) therapy is one of the main methods of treatment in non-small cell lung cancer (NSCLC). This study aimed to explore the risk factors of VTE and evaluate the effect of ICIs on VTE in patients with NSCLC.
Research design and methods
We retrospectively studied patients with NSCLC who were divided into VTE group and without VTE (Non-VTE) group. We identified the risk factors of VTE in NSCLC patients and evaluated the effect of ICIs on VTE in NSCLC patients.
Results
We found that clinical stage III-IV (P = 0.015) and Khorana score (KS) ≥ 2 (P = 0.047) were independent risk factors for the occurrence of VTE in NSCLC, and treatment with ICIs reduced the risk of VTE occurrence (P = 0.028). There were no differences of survival rates in the 12-month (P = 0.449), 24-month (P = 0.412), or 36-month (P = 0.315) between the VTE and non-VTE groups. History of anti-angiogenic therapy (P = 0.033) and chronic obstructive pulmonary disease (COPD) (P = 0.046) were independent risk factors for VTE in NSCLC patients who were treated with ICIs.
Conclusion
This study suggests that we should strengthen anticoagulant therapy when using ICIs for NSCLC patients with a history of anti-angiogenic therapy and COPD.
1. Introduction
The risk of venous thromboembolism (VTE) in cancer patients is four-fold to seven-fold higher than that in non-cancer patients [Citation1–3]. VTE is prevalent among cancer patients and affects the overall prognosis [Citation4]. Lung cancer is the second most commonly diagnosed cancer and the first cause of cancer-related mortality [Citation5]. The incidence of VTE in lung cancer patients is as high as 8.0%~22.6% [Citation6–9]. Among different types of cancer, lung cancer is associated with a high incidence rate of VTE [Citation10]. In addition, it has been reported that different histological types, tumor stages, gene expression patterns, and treatment methods are closely related to the occurrence of VTE in lung cancer [Citation6–9].
In recent years, the widespread application of immune checkpoint inhibitors (ICIs) in clinical settings has revolutionized cancer treatment. The application of ICIs has significantly improved the prognosis of patients with melanoma, NSCLC, renal cell carcinoma, head and neck squamous cell carcinoma, and other cancers [Citation11–14]. ICIs promote the immune response to remove tumor cells [Citation15]. They are monoclonal antibodies against immune checkpoint proteins, including programmed death receptor 1 (PD-1), programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) [Citation15]. ICIs can cause a wide range of immune-related adverse events (irAEs), affecting the gastrointestinal tract, skin, thyroid, heart, and liver [Citation16]. Although VTE is a common complication of cancer treatment [Citation8,Citation9], whether ICIs are risk factors for VTE remains to be known.
In this study, we reviewed 730 patients who were initially diagnosed with NSCLC, and divided them into the VTE and non-VTE groups. Baseline clinical characteristics and possible risk factors of patients were collected. We aimed to explore the related risk factors of VTE, and prognosis of VTE in patients with NSCLC. We also hope to find out the effect of ICIs on VTE in patients with NSCLC, providing relevant data for clinical management of NSCLC.
2. Patients and methods
2.1. Study populations
We retrospectively recruited patients from the department of respiratory diseases of the Fourth Hospital of Hebei Medical University from 1 January 2019, to 31 October 2021. The inclusion criteria were as follows: (1) Patients aged 18–80 years; (2) Newly diagnosed NSCLC were confirmed by pathological examination; (3) According to the TNM stage of the Union for International Cancer Control (UICC), lung cancer was divided into stages I, II, III, and IV [Citation17]; (4) No history of other tumors. The exclusion criteria were as follows: (1) VTE history ≥3 months before the diagnosis of NSCLC; (2) Patients did not undergo VTE screening during follow-up. This study was approved by the Medical Ethics Committee of the Fourth Hospital of Hebei Medical University (ID: 2022KS022).
2.2. Data collection
The following clinical data were collected through an electronic medical record system: age, sex, smoking history, previous medical history (such as hypertension and chronic obstructive pulmonary disease (COPD)), time of diagnosing NSCLC, pathological type of tumor, clinical stage, history of a peripherally inserted central catheter (PICC), gene testing, contrast-enhanced computed tomography (CT), computed tomography pulmonary angiography (CTPA), deep vein ultrasound, VTE event, applied treatment (including surgery, platinum-based chemotherapy, radiotherapy, anti-angiogenic agents, and ICIs), and Khorana risk score (KS). For KS, each one of the following items received 1 point: pre-chemotherapy platelet count over 350 × 109/L, leukocyte count over 11 × 109/L, hemoglobin below 10 g/dL and/or use of erythropoiesis-stimulating agents and a body mass index (BMI) higher than 35 kg/m2. Patients with a total score of 0–1 points were categorized into the low-risk groups. Patients with a total score of ≥ 2 points were categorized into the medium and high-risk group [Citation18]. The patients were followed until 31 October 2022, through telephone calls, and outpatient and inpatient data. The OS was measured to analyze the prognosis of NSCLC. The steps of the study are shown in .
Figure 1. Flowchart of the study.
2.3. Assessment of VTE events
VTE events included deep vein thrombosis (DVT) and pulmonary embolism (PE). All patients had undergone lower extremity Doppler ultrasound to detect DVT. Contrast-enhanced chest CT was performed, and CTPA was performed to confirm PE in those who had clinical symptoms. Then, VTE events were consulted with an independent review committee, including experts in angiology and radiology. The adjudication committee confirmed or ruled out the diagnosis. In addition, patients without symptoms of VTE received a clinical examination every 8–12 weeks, depending on the treatment. VTE detected accidentally was considered an event, if the committee approved its clinical significance.
2.4. Statistical analysis
SPSS 26.0 software was used for statistical analysis. The relative composition of patients in the VTE and non-VTE groups was analyzed by constituent ratio. Chi-square test was used to compare the constituent ratio or rate between groups. Kaplan-Meier curve was drawn for OS. All risk factors were analyzed by single-factor analysis. Then, the factors with P < 0.2 were included in the binary logistic regression model to identify the independent risk factors affecting the occurrence of VTE. The Hosmer-Lemeshow statistical test was used to verify the goodness of fit. The differences were considered statistically significant if the P-value was < 0.05.
3. Results
3.1. Patients’ characteristics
Based on the inclusion criteria, we enrolled 730 patients with NSCLC. Among them, 475 patients (65.1%) were male, 336 (46.0%) were ≥65 years old, 397 (54.4%) were smokers, 514 (70.4%) had lung adenocarcinoma, 591 (81.0%) had clinical stage III-IV NSCLC, 231 (31.6%) had KS ≥ 2, 8.6% were PD-L1 positive (+, ≥1%), 170 (23.3%) underwent lung surgery, 392 (53.7%) received chemotherapy, 75 (10.3%) received radiotherapy, 211 (28.9%) received gene-targeted therapy, 166 (22.7%) received ICIs, and 331 (45.3%) underwent PICC. Among 730 patients, 132 (18.1%) patients experienced VTE and were included in the VTE group, and 598 (81.9%) patients did not experience VTE and were included in the non-VTE group. In the VTE group, 111 (84.1%) patients had DVT, 5 (3.8%) patients had PE, and 16 (12.1%) patients had DVT combined with PE. The clinical data of patients are shown in .
Table 1. The clinical characteristics of patients with NSCLC.
3.2. Risk factors of VTE in patients with NSCLC
We compared the VTE group with the non-VTE group to identify the risk factors of VTE. Single-factor analysis indicated that there were statistical differences between the VTE group and non-VTE group in sex (P = 0.003), adenocarcinoma (P = 0.001), smoking history (P = 0.005), clinical stage (P < 0.001), KS (P = 0.021), surgical history (P < 0.001), and ICIs therapy (P = 0.013). The risk factors with P < 0.2 were analyzed by binary logistic regression. The results showed that clinical stage III-IV (OR 3.120, 95% CI: 1.252–7.790, P = 0.015) and KS ≥ 2 (OR 1.508, 95% CI: 1.005–2.264, P = 0.047) were independent risk factors for VTE in patients with NSCLC. In contrast, the use of ICIs (OR 0.529, 95% CI: 0.300–0.934, P = 0.028) reduced the risk of VTE. The data are shown in and .
Figure 2. The risk factors for VTE in patients with NSCLC. X- axis represents the odds ratio (OR).Y-axis represents the risk factors.
Table 2. The risk factors of VTE in patients with NSCLC.
3.3. The timing of VTE during diagnosis and treatment
All patients were followed for 12 months to 46 months. In total, 132 patients experienced VTE before death or during the follow-up period. We recorded the specific timing of VTE for each patient. Among them, 28 (21.2%) patients were diagnosed with NSCLC and found VTE events at the same time, 39 (29.5%) patients experienced VTE within 3 months after diagnosing NSCLC, 17 (12.9%) patients experienced VTE within 3–6 months after diagnosing NSCLC, 5 (3.8%) patients experienced VTE within 6–9 months after diagnosing NSCLC, and 43 (32.5%) patients experienced VTE within 9–30 months after diagnosing NSCLC. There were no VTE events occurred within 31–46 months after diagnosing NSCLC. VTE is more likely to occur within 0–6 months after diagnosing NSCLC, and the timing of VTE in patients with NSCLC is shown in .
Figure 3. The timing of VTE during diagnosis and treatment in patients with NSCLC. X axis represents the occurrent time of VTE during diagnosis and treatment; Y-axis represents the number of NSCLC patients with VTE.
3.4. Effect of VTE on OS
In total, 730 (100%) patients completed 12 months of follow-up, 511 (70%) patients completed 24 months of follow-up, and 319 (43.7%) patients completed 36 months of follow-up. Up to the end of the follow-up period, 266 (36.4%) patients died, of which 58 patients were in the VTE group and 208 patients were in the non-VTE group. The survival curve was drawn by the Kaplan-Meier test, as shown in . The median OS (mOS) was not reached in the two groups, the Kaplan- Meier test predicted that the mOS of the VTE group was 33.0 months, and there were no significant differences between the two groups (HR 1.20, 95% CI: 0.882–1.630, P = 0.216). In addition, we conducted a statistical analysis of the number of patients of survival and death in NSCLC patients who were followed up for 12, 24, and 36 months. There were no differences in 12-month (P = 0.449), 24-month (P = 0.412), or 36-month (P = 0.315) survival rates between the VTE and non-VTE groups, respectively. The results are shown in .
Figure 4. The analyze of overall survival for NSCLC patients between VTE group and non-VTE group. X axis represents the occurrent time of VTE; Y-axis represents the survival rate.
Table 3. The analysis of the number of cases of survival and death in NSCLC patients between VTE group and non- VTE group at 12, 24 and 36 months.
3.5. Clinical characteristics of NSCLC patients treated with ICIs
Of 730 patients, 166 (22.7%) patients received ICIs treatment. The treatment of ICIs included first-line and multi-line ICIs treatment, as well as single ICIs treatment or ICIs treatment combined chemotherapy. Among the received ICIs treatment patients, 121 (72.9%) were male patients, 73 (44.0%) were ≥65 years old, 107 (64.6%) were smokers, 88 (53.0%) had lung adenocarcinoma, 148 (89.1%) had the clinical stage of III-IV, 52 (31.3%) had KS ≥ 2, PD-L1 test was done for 56 (33.7%) patients and was positive (+, ≥ 1%) in 45 (80.4%) of them. Furthermore, 8 (4.8%) patients had a history of COPD, 34 (20.5%) underwent lung surgery, 161 (97.0%) received chemotherapy, 33 (19.9%) received radiotherapy, 16 (9.7%) received gene-targeted therapy, and 42 (25.3%) received anti-angiogenesis agents. Based on the occurrence of VTE, patients were divided into the VTE and non-VTE groups. Among them, 19 (11.4%) patients were in the VTE group and 147 (88.6%) patients were in the non-VTE group. The clinical characteristics of 166 patients receiving ICIs therapy are shown in .
Table 4. The clinical characteristics of NSCLC patients who received ICIs treatment.
3.6. Risk factors of VTE in patients with NSCLC who received with ICIs
Of 166 NSCLC patients who received ICIs, 19 patients experienced VTE and were included in the VTE group, and 147 patients did not experience VTE and were included in the non-VTE group. Multivariate analysis indicated that there were statistical differences between the VTE group and the non-VTE group in the history of anti-angiogenic therapy (anti-angiogenic drugs included bevacizumab, apatinib, and anlotinib) (OR 3.133, 95% CI: 1.097–8.947, P = 0.033) and the history of COPD (OR 5.320, 95% CI: 1.029–27.507, P = 0.046). The data are shown in and .
Figure 5. The risk factors of VTE in patients with NSCLC who received ICIs treatment. X-axis represents the odds ratio (OR), Y-axis represents the risk factors.
Table 5. The risk factors of VTE in patients with NSCLC who received ICIs treatment.
3.7. The effect of different types of ICIs treatment on VTE in patients with NSCLC
Among 166 NSCLC patients who received ICIs treatment, 75 patients were treated with sintilimab, 43 with karelizumab, 31 with pembrolizumab, 8 with tirelizumab, and 6 with durvalumab. Among VTE patients, 6 patients were treated with sintilimab, 5 with karelizumab, 5 with pembrolizumab, 2 with tirelizumab, and 1 with durvalumab. There was no statistical difference in the effect of different types of ICIs treatment on VTE in NSCLC patients (P = 0.440), and the results are shown in .
Table 6. Correlation analysis between different types of ICI and VTE in NSCLC patients who received ICIs treatment.
4. Discussion
Consistent with previous studies, in this study, the cumulative incidence rate of VTE was 18.1% among patients with NSCLC [Citation9,Citation19]. We found that 70.4% of patients had lung adenocarcinoma, 81.0% of patients had the tumor stage of III-IV, suggesting that most patients had intermediate and advanced lung adenocarcinoma; therefore, they were mainly treated with chemotherapy, targeted therapy, ICIs therapy, and anti-angiogenic therapy. Univariate analysis revealed that sex, pathological type, cancer stage, KS, and ICIs therapy, all influenced the risk of VTE. However, in the multivariate analysis, only stage, KS, and ICIs therapy independently influenced the risk of VTE.
Many studies have confirmed that the risk of VTE is related to the pathological type of lung cancer. They illuminated that NSCLC imposes a higher risk of VTE compared with small cell lung cancer (SCLC) [Citation20–22], and the risk of VTE is higher in adenocarcinoma than in squamous cell carcinoma. That may be related to the production of mucus by adenocarcinoma cells, secretion of coagulation factors, activation of platelets, and formation of micro-thrombosis in capillary circulation [Citation23,Citation24]. The pathological types of the patients are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. In univariate analysis, the incidence of VTE was higher in adenocarcinoma. However, the results of multivariate analysis showed that there was no effect on the occurrence of VTE among different pathological types. This suggests that the occurrence of VTE is complex and influenced by multiple factors.
We conducted clinical staging for patients according to the TNM stage of the International Union against Cancer (UICC). Among patients, 19.0% were in stage I and II, and 81.0% were in stage III and IV. Of them, 6.5% of patients were complicated with VTE in stage I and II, 21.7% of patients were complicated with VTE in stage III and IV. The risk of VTE was significantly increased in stage III and IV (OR 3.120, 95% CI: 1.252–7.790, P = 0.015), which was an independent risk factor for VTE. Our results are consistent with some of the previous reports [Citation7,Citation25]. It is reported recently that lung adenocarcinoma complicated with DVT was associated with advanced stage, more severe myocardial injury, and a hypercoagulable state [Citation26].
The KS is a validated scoring tool used to predict VTE risk in ambulatory care settings before systemic therapy initiation. The scoring criteria include the type of tumor, white blood cell and platelet count, hemoglobin level, and BMI. The KS of patients was evaluated when patients were enrolled. Among them, 31.6% had KS ≥ 2 points with middle and high risks of VTE, and 22.9% of patients developed VTE with concomitant KS ≥ 2. It suggests that KS can be used to evaluate the risk of VTE in NSCLC. However, some studies suggest that KS is not sensitive enough to assess the risk of VTE in lung cancer [Citation20,Citation27]. Our study included more advanced NSCLC and more patients undergoing systemic therapy, which may improve the predictive power of KS for VTE [Citation18]. In addition, there were very few patients with KS ≥ 3 in our study, so we used KS ≥ 2 as the scoring threshold. The reason for the lower KS score may be related to the lack of enrolled patients with a BMI ≥ 35. Some reports have also found that Asian patients have a lower BMI and have started changing the cutoff to 25 kg/m2 improved the prediction of cancer-associated thrombosis [Citation28,Citation29]. In future studies, we can also use BMI ≥ 25 as the scoring standard for further research. The CASSINI trial assessed the use of rivaroxaban for KS ≥ 2 and high-risk ambulatory patients with cancer, and reported a lower incidence of VTE compared with placebo [Citation30]. The AVERT trial assessed the use of apixaban in high-risk patients, which significantly lowered the risk of VTE compared with placebo [Citation31]. Subsequently, NCCN updated practice guidelines and ASCO guidelines all recommended anticoagulation in cancer patients with a KS ≥ 2 [Citation32,Citation33]. In our study, patients had poor compliance. Patients with KS ≥ 2 received anticoagulant prophylaxis for VTE during hospitalization, but many patients stopped using anticoagulants on their own wish after discharge. Therefore, we did not include studies on anticoagulation for risk factor of VTE.
We found that 21.2% of VTE events were detected when NSCLC was diagnosed, 29.5% VTE events occurred within 3 months after diagnosis of NSCLC, and 12.9% VTE events occurred within 3–6 months after diagnosis of NSCLC, and the incidence of VTE gradually decreased after 6 months of diagnosis of NSCLC. It indicates that VTE events are more likely to occur during 0–6 months after diagnosis of NSCLC, and many studies reported that this period is the most common period of VTE [Citation34,Citation35]. It was suggested that patients with VTE must be screened for NSCLC in clinical practice, and VTE prevention should be considered at the initial stage of treatment. Especially, most patients have just taken corresponding treatments within 3 months after diagnosis, which also suggests that the treatment may be a risk factor for VTE.
We recorded the time of diagnosis, death or duration of follow-up for OS analysis. There were 266 (36.4%) died, of which 58 were in the VTE group and 208 were in the non-VTE group. The survival analysis curve showed that VTE had no significant impact on the OS of patients with NSCLC. In addition, there were no differences in 12-month, 24-month, or 36-month survival rates between the VTE and non-VTE groups, respectively. Moreover, most studies reported that there was no significant difference in OS between the VTE and non-VTE groups [Citation36,Citation37]. We assumed that VTE did not affect the prognosis of patients, which may be related to the patients did not reach mOS, and the difference between the VTE and non-VTE groups in survival may be observed with the extension of follow-up time.
It is well known that surgery, chemotherapy, radiotherapy, targeted therapy, ICIs, and anti-angiogenic agents are the main methods of treatment for NSCLC. In this study, 23.3% of patients underwent surgery, 50.7% received chemotherapy, 9.1% underwent radiotherapy, 28.9% received targeted therapy, 22.7% received immunotherapy, and 16.6% received anti-angiogenic drugs. Several studies suggested that different treatment plans can affect the occurrence of VTE [Citation34,Citation38]. In particular, chemotherapy and anti-angiogenesis treatment can cause VTE through vascular endothelial stimulation and/or injury [Citation7,Citation20]. In this study, most patients had advanced NSCLC. They received one group of anti-tumor drugs or combination therapy; thus, it was difficult to compare certain treatment methods. Therefore, we utilized a multifactorial analysis to find out the effect of treatment on VTE. We found that chemotherapy, anti-angiogenesis agents, and targeted treatment were not independent risk factors for VTE.
Currently, ICIs are the main treatment modality for NSCLC, but they cause various adverse reactions [Citation16]. The effect of ICIs on VTE among patients with NSCLC is not clear. Some studies suggested that ICIs compared with chemotherapy increase the risk of VTE [Citation39,Citation40], and another study reached the opposite conclusion [Citation41]. The incidence of VTE in patients receiving ICIs was 11.4% in our study, and multivariate regression analysis showed that the use of ICIs independently reduced the incidence of VTE in NSCLC (OR 0.529, 95% CI: 0.300–0.934, P = 0.028). We speculated that may be related to the reduced tumor size in patients treated with ICIs. In addition, there was no difference between different ICIs and the incidence of VTE in NSCLC. As ICIs are mostly used in combination with chemotherapy, it is not suitable to compare the effect of ICIs alone and ICIs combined with other drugs on patients complicated with VTE.
So far, no study has reported the risk factors of VTE in NSCLC patients treated with ICIs. Our study confirmed that the use of anti-angiogenic agents and the history of COPD were independent risk factors of VTE in NSCLC patients treated with ICIs. Anti-angiogenic agents mainly include small molecule tyrosine kinase inhibitors that can inhibit the downstream signal of vascular endothelial growth factor (VEGF) pathway, such as monoclonal antibodies targeting VEGF-A or its receptor VEGFR-2 [Citation42]. The anti-angiogenic agents used by the patients in this study were mainly bevacizumab, and few patients used anotinib and apatinib. Currently, the effect of bevacizumab on VTE in patients with NSCLC is not clear, but most studies believe that it can induce cancer-related thrombus [Citation43]. Our study confirmed that the use of anti-angiogenic agents was a risk factor for VTE in NSCLC patients who used ICIs, and the risk of VTE had increased three-fold by anti-angiogenic agents. COPD is associated with airway inflammation, increased CD8+T lymphocyte infiltration, and respiratory infection [Citation44]. About one-third of COPD patients are hospitalized due to illness, and the hospitalization is a predisposing factor for VTE [Citation45]. Some studies have found that the level of key coagulation factors is higher in patients with stable COPD, and their level of anti-thrombin is lower than that in non-COPD smokers [Citation46]. In patients with COPD, the levels of FII, FV, and FX are higher in patients with severe disease, which may be related to the higher incidence of VTE in patients with COPD [Citation46]. Our study found that the risk of VTE increased by five-fold in patients with concurrent NSCLC and COPD. Why patients with NSCLC and COPD are prone to VTE even after the use of ICIs is still unclear, and further research is needed.
Our study has some limitations. First, a fewer patients were enrolled in each group, but fewer patients were treated with ICIs and more patients need to be added. Second, the duration of follow-up was short. Better methods of treatment prolonged the survival of NSCLC, while we only followed patients for 1–3 years. Third, based on individualized treatment, the treatment plan of each patient is different from others, and patients with a long follow-up period have used various treatments. Fourth, many patients do not regularly apply preventive anticoagulant therapy due to poor patient compliance, which may affect the occurrence of VTE. Fifth, some biological predictors (such as P-Selectin, tissue factors, and tumor markers) may be risk factors of NSCLC combined with VTE, but we did not include them in our analysis. In our future study, we will pay more attention to the risk factors of VTE and conduct more in-depth clinical research.
5. Conclusions
We should strengthen anticoagulant therapy when using ICIs for NSCLC patients with a history of anti-angiogenic therapy and COPD.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.
Author contributions
P Wang, X He, S Wei designed the study, supervised all work, and helped write the manuscript. N Geng performed the researched the data. W Qin, B Li and S Song researched the data and/or helped design experiments. All authors contributed to the article and approved the submitted version.
Acknowledgments
We thank all the patients involved in the study for their participation. We thank the doctors and nurses from the department of the Fourth Hospital of Hebei Medical University for assistance with follow-up.
Additional information
Funding
References
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