ABSTRACT
Background
Lung cancer is associated with a high risk of thromboembolism. The incidence and mortality of lung cancer increased in the population over 60 years old. Our research aimed to reveal the risk factors and prognosis of thromboembolism in elderly patients with stage IV lung cancer.
Methods
Metastatic lung cancer patients over 60 years of age at the Affiliated Jiangyin Hospital of Nantong University between 1 January 2011 and 30 June 2019 were screened. Univariable and multivariable analyses were conducted to reveal the risk factors for thromboembolism. Log‐rank test and multivariate Cox regression analysis were performed to determine the prognosis of this cohort.
Results
Four hundred and fourteen‐patients included in this study, 33 developed venous thromboembolism (VTE), and 39 developed arterial thromboembolism (ATE), respectively. Body mass index (BMI) and D‐dimer level were independent risk factors associated with VTE. History of hypertension was an independent risk factor related to ATE. Older patients with ATE were associated with shorter overall survival (OS) of 7 months.
Conclusions
Higher levels of BMI and D‐dimer were related to VTE, while hypertension was related to ATE. ATE was associated with a poorer prognosis. In clinical practice, appropriate prevention and treatment of thromboembolism should be conducted in this cohort.
Keywords: arterial thromboembolism, elderly patients with stage IV lung cancer, prognosis, risk factor, venous thromboembolism
1. Introduction
The relationship between potential cancer and thromboembolism was first described by Trousseau in 1865 [1]. Patients with cancer are more prone to develop thromboembolism because of a hypercoagulable state [2]. Thromboembolism consists of venous and arterial thromboembolism (VTE/ATE). VTE mainly includes deep vein thrombosis (DVT), pulmonary embolism (PE), and splanchnic vein thrombosis (SVT), which is a common complication of cancer with the second leading cause of mortality in cancer patients [3, 4]. ATE includes ischemic stroke, acute coronary syndrome (ACS), and acute peripheral artery occlusion. Compared with VTE, ATE is relatively uncommon among people living with cancer [5]. According to previous studies in cancer patients, the 2‐year cumulative incidences of VTE and ATE were 8.7% and 2.6%, respectively [5, 6].
In western countries, the number of new cases of advanced lung cancer has decreased in the past few years, while localized‐stage lung cancer incidence increased suddenly by 4.5% annually [7]. However, the incidence is still on the rise in China [8]. Nowadays, nearly one‐third of lung cancer cases and cancer‐related deaths worldwide occurred in China [9, 10]. Compared with the improved survival rates for all cancers, the lung cancer survival rate remains lower [8]. There are significant differences in the incidence and mortality between younger and older lung cancer patients in China [11]. A previous study from China reported that the incidence and mortality increased in lung cancer patients over 60 years old [12]. It means that elderly lung cancer patients should be taken seriously in China.
The morbidity and mortality from thromboembolism are higher in patients with lung cancer [13]. It was reported that compared with the general population, the risk of VTE in lung cancer cases was 20‐fold higher [14]. Lung cancer patients with VTE have a 50% higher risk of mortality compared to those without VTE [15]. Patients with cancer seem to be at a higher risk of ATE, especially lung and pancreatic cancers [16, 17]. Navi et al. reported that patients over 67 years of age diagnosed with lung and colorectal cancers were more prone to develop ATE events [18]. Our previous study on patients with metastatic lung cancer showed that older age was a significant risk factor of ATE and ATE had a poorer survival [19].
Given the severe situation of lung cancer patients over 60 years old in China and few research on thromboembolism, we explored the clinical characteristics and prognosis of VTE and ATE in this cohort in this study.
2. Materials and Methods
2.1. Study Design and Patients
A single‐center retrospective study of metastatic lung cancer patients over 60 years of age at the Affiliated Jiangyin Hospital of Nantong University between 1 January 2011 and 30 June 2019 was conducted. The institutional Ethics Committee approved this protocol (number: 2023031).
Patients were included if they (1) were ≥ 60 years old; (2) were histopathologically diagnosed with metastatic lung cancer. Patients were excluded if they (1) had a history of other malignancy or thromboembolism; (2) had a history of surgery unrelated to lung cancer within the past 3 months; (3) had any severe infection within the past 6 weeks; (4) received continuous anti‐platelet or anti‐coagulation therapy; (5) had incomplete medical records or lost to follow‐up.
2.2. Data Collection
The electronic record system collected basic clinical data including patient demographics, histology, baseline laboratory results (e.g., leukocyte, hemoglobin, platelet, and D‐dimer), and imaging results (e.g., Doppler ultrasonography, electrocardiography, echocardiography, coronary angiography, computed tomography [CT], computed tomography angiography [CTA], and magnetic‐resonance‐imaging [MRI]). The follow‐up data including treatment of malignancy and thromboembolic events were mainly from the hospital information system and follow‐up calls. Follow‐up for VTE/ATE ended on 30 June 2021.
2.3. Assessment of VTE/ATE Events
VTE/ATE events were mainly diagnosed by laboratory and imaging results (e.g., cardiac biomarkers, Doppler ultrasonography, electrocardiography, echocardiography, coronary angiography, CT, CTA, and MRI).
2.4. Statistical Analysis
The Reverse Kaplan–Meier method was used to calculate the median follow‐up time. The patients included in the study were divided into two groups: the VTE group and non‐VTE group, ATE group and non‐ATE group. Since continuous variables do not follow a normal distribution within the groups, Mann–Whitney U test was conducted as univariable analysis to identify the risk factors for thromboembolism. Continuous variables (age, body mass index [BMI], and laboratory results) were presented as median/interquartile range (IQR) and categorical data were presented as frequencies and percentages. Variables at p < 0.2 in the univariable analysis were entered into the subsequent multivariable analysis. The predictive ability of continuous variables screened out by multivariate analysis for thrombotic events was evaluated by receiver operating characteristic (ROC) curve and area under the ROC curve (AUC). The maximum Youden's index was used to determine the optimal cutoff value. Cumulative incidences of VTE and ATE were calculated by R package cmprsk. The Kaplan–Meier method was used to calculate the median occurrence time of VTE and ATE. Log‐rank test was conducted to compare the survival curves of three groups and identify prognostic factors related to overall survival (OS). Multivariate Cox regression analysis was used for further verification. Time‐dependent ROC was used for mortality prediction. In survival analysis, age and BMI were converted into binary variables based on the median of all patients. The D‐dimer threshold of 0.55 mg/L was determined by Siemens test thrombin reagent, leukocyte count threshold of 10 * 109/L and platelet count threshold of 300 * 109/L applied in this study were determined by Hematology analyzer (Sysmex Corporation). Because the cutoff of hemoglobin for men and women are different, the threshold of hemoglobin was set at 100 g/L after referring to previous studies [20, 21]. The statistical analyses above were performed using IBM SPSS software 26.0 for Mac (IBM Corp, Armonk, NY, USA) and R software version 4.3.3 (R Foundation for Statistical Computing, Vienna, Austria). Pictures were drawn by GraphPad Prism 9.0 (GraphPad Software, San Diego, CA, USA) for mac and R software. Statistical significance was set at p < 0.05 (two‐sided).
3. Results
3.1. Clinical Characteristics
The clinical characteristics of patients were shown in Table 1. A total of 414 metastatic lung cancer patients over 60 years of age were included in this study. Median age was 68 years (IQR: 64–73) and 67.6% (280/414) were males. The median BMI was 21.895 kg/m2 with IQR of 18.295–23.530 kg/m2, 33.8% (140/414) had a certain history of smoking, 85.3% (353/414) had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.39.6% of patients had a history of hypertension and 6.3% with diabetes mellitus. Non‐small cell lung cancer (NSCLC) was the main pathological type (84.3%, 349/414). The median leukocyte was 7.205 * 109/L (IQR: 6.028–9.108 * 109/L). The median platelet was 231.500 * 109/L (IQR: 178.000–285.000 * 109/L). The median hemoglobin was 125.000 g/L (IQR: 114.775–136.000 g/L). The median D‐dimer was 1.370 mg/L (IQR: 0.608–2.950 mg/L). Most patients (n = 297, 71.7%) were treated with chemotherapy, 35.3% (146/414) and 44.0% (182/414) of the patients received radiotherapy and targeted therapy, respectively. During a median follow‐up of 13 months, 33 VTE and 39 ATE events were observed. No patient had both clinical VTE and ATE.
TABLE 1.
Demographic and clinical characteristics between patients with and without VTE.
| Variables | Total (n = 414) | VTE (n = 33) | Non‐VTE (n = 381) | χ 2 (Z) | p |
|---|---|---|---|---|---|
| Age (years), median (IQR) | 68 (64–73) | 67 (63.5–71.5) | 68 (64–74) | −0.950 | 0.342 |
| Sex | 0.262 | 0.609 | |||
| Male | 280 (67.6) | 21 (63.6) | 259 (68.0) | ||
| Female | 134 (32.4) | 12 (36.4) | 122 (32.0) | ||
| BMI (kg/m2), median (IQR) | 21.895 (18.295–23.530) | 22.860 (21.300–24.630) | 21.730 (18.085–23.530) | −2.518 | 0.012* |
| Smoking history | 0.004 | 0.951 | |||
| No/unknown | 274 (66.2) | 22 (66.7) | 252 (66.1) | ||
| Yes | 140 (33.8) | 11 (33.3) | 129 (33.9) | ||
| ECOG PS | — | 1.000 | |||
| 0–1 | 353 (85.3) | 28 (84.8) | 325 (85.3) | ||
| 2–4 | 61 (14.7) | 5 (15.2) | 56 (14.7) | ||
| Comorbidities | |||||
| Hypertension | 0.158 | 0.691 | |||
| No | 250 (60.4) | 21 (63.6) | 229 (60.1) | ||
| Yes | 164 (39.6) | 12 (36.4) | 152 (39.9) | ||
| Diabetes mellitus | — | 1.000 | |||
| No | 388 (93.7) | 31 (93.9) | 357 (93.7) | ||
| Yes | 26 (6.3) | 2 (6.1) | 24 (6.3) | ||
| Histology | 0.347 | 0.556 | |||
| NSCLC | 349 (84.3) | 29 (87.9) | 320 (84.0) | ||
| SCLC | 65 (15.7) | 4 (12.1) | 61 (16.0) | ||
| Baseline laboratory data | |||||
| Leukocyte count (*109/L), median (IQR) | 7.205 (6.028–9.108) | 7.000 (5.695–8.665) | 7.220 (6.075–9.130) | −0.905 | 0.365 |
| Platelet count (*109/L), median (IQR) | 231.500 (178.000–285.000) | 222.000 (190.500–287.500) | 232.000 (177.500–284.500) | −0.027 | 0.979 |
| Hemoglobin (g/L), median (IQR) | 125.000 (114.775–136.000) | 126.000 (114.500–142.800) | 125.000 (114.550–135.600) | −1.072 | 0.284 |
| D‐dimer (mg/L), median (IQR) | 1.370 (0.608–2.950) | 2.850 (1.265–13.140) | 1.310 (0.555–2.605) | −3.780 | < 0.001* |
| History of chemotherapy | 1.797 | 0.180 | |||
| No | 117 (28.3) | 6 (18.2) | 111 (29.1) | ||
| Yes | 297 (71.7) | 27 (81.8) | 270 (70.9) | ||
| History of radiotherapy | 0.268 | 0.605 | |||
| No | 268 (64.7) | 20 (60.6) | 248 (65.1) | ||
| Yes | 146 (35.3) | 13 (39.4) | 133 (34.9) | ||
| History of targeted therapy | 0.831 | 0.362 | |||
| No | 232 (56.0) | 16 (48.5) | 216 (56.7) | ||
| Yes | 182 (44.0) | 17 (51.5) | 165 (43.3) |
Abbreviations: BMI: body mass index; ECOG PS: Eastern Cooperative Oncology Group performance status; IQR: interquartile range; NSCLC: non‐small cell lung cancer; SCLC: small cell lung cancer; VTE: venous thromboembolism.
p < 0.05 was statistically significant.
3.2. Risk Factors Related to VTE
The univariate analysis revealed that VTE was associated with BMI and D‐dimer level. However, no association between age, sex, smoking history, ECOG PS, hypertension, diabetes mellitus, histology, leukocyte, platelet, hemoglobin, history of chemotherapy, radiotherapy, and targeted therapy with VTE was found. Details were shown in Table 1.
Table 2 showed the multivariable logistic regression analysis results. BMI (OR, 1.134; 95% CI, 1.003–1.282; p = 0.045) and D‐dimer (OR, 1.128; 95% CI, 1.069–1.189; p < 0.001) were independent risk factors related to VTE in geriatric metastatic lung cancer patients.
TABLE 2.
Multivariable logistic regression analysis for VTE.
| Variable | OR (95% CI) | p |
|---|---|---|
| BMI | 1.134 (1.003–1.282) | 0.045* |
| D‐dimer | 1.128 (1.069–1.189) | < 0.001* |
| History of chemotherapy | 0.198 | |
| No | 1 (Reference) | |
| Yes | 1.943 (0.706–5.346) |
Abbreviations: BMI: body mass index; CI: confidence interval; OR: odds ratio; VTE: venous thromboembolism.
p < 0.05 was statistically significant.
The AUC of BMI to predict VTE events was 0.632 (95% CI, 0.541–0.723), the best cutoff value was 19.54 kg/m2 with the sensitivity of 87.9% and the specificity of 37.3%. The AUC of D‐dimer was 0.698 (95% CI, 0.604–0.793); when the best cutoff value was 6.94 mg/L, the sensitivity was 39.4%, and the specificity was 92.1%, respectively (Figure 1).
FIGURE 1.
ROC curves for predicting VTE and mortality. (a) ROC curve of BMI for predicting VTE; (b) ROC curve of D‐dimer for predicting VTE; (c) time‐dependent ROC of leukocyte for predicting mortality; (d) time‐dependent ROC of hemoglobin for predicting mortality. Abbreviations: AUC, area under the ROC curve; BMI, body mass index; ROC, receiver operating characteristic; VTE, venous thromboembolism.
3.3. Risk Factors Related to ATE
The univariate analysis revealed that age and history of hypertension were significant risk factors of ATE (Table 3).
TABLE 3.
Univariable analysis for ATE.
| Variables | ATE (n = 39) | Non‐ATE (n = 375) | χ 2 (Z) | p |
|---|---|---|---|---|
| Age (years), median (IQR) | 70 (66–75) | 68 (64–73) | −2.030 | 0.042* |
| Sex | 0.890 | 0.346 | ||
| Male | 29 (74.4) | 251 (66.9) | ||
| Female | 10 (25.6) | 124 (33.1) | ||
| BMI (kg/m2), median (IQR) | 21.720 (18.810–22.960) | 21.910 (18.250–23.630) | −0.618 | 0.537 |
| Smoking history | 0.415 | 0.519 | ||
| No/unknown | 24 (61.5) | 250 (66.7) | ||
| Yes | 15 (38.5) | 125 (33.3) | ||
| ECOG PS | 1.144 | 0.285 | ||
| 0–1 | 31 (79.5) | 322 (85.9) | ||
| 2–4 | 8 (20.5) | 53 (14.1) | ||
| Comorbidities | ||||
| Hypertension | 6.747 | 0.009* | ||
| No | 16 (41.0) | 234 (62.4) | ||
| Yes | 23 (59.0) | 141 (37.6) | ||
| Diabetes mellitus | — | 1.000 | ||
| No | 37 (94.9) | 351 (93.6) | ||
| Yes | 2 (5.1) | 24 (6.4) | ||
| Histology | 1.770 | 0.183 | ||
| NSCLC | 30 (76.9) | 319 (85.1) | ||
| SCLC | 9 (23.1) | 56 (14.9) | ||
| Baseline laboratory data | ||||
| Leukocyte count (*109/L), median (IQR) | 7.400 (5.950–7.400) | 7.180 (6.050–9.100) | −0.551 | 0.581 |
| Platelet count (*109/L), median (IQR) | 239.000 (166.000–305.000) | 231.000 (181.000–284.000) | −0.233 | 0.815 |
| Hemoglobin (g/L), median (IQR) | 126.000 (112.000–139.000) | 125.000 (115.000–136.000) | −0.039 | 0.969 |
| D‐dimer (mg/L), median (IQR) | 1.510 (0.710–4.200) | 1.370 (0.560–2.770) | −0.830 | 0.406 |
| History of chemotherapy | 0.000 | 0.994 | ||
| No | 11 (28.2) | 106 (28.3) | ||
| Yes | 28 (71.8) | 269 (71.7) | ||
| History of radiotherapy | 0.008 | 0.931 | ||
| No | 25 (64.1) | 243 (64.8) | ||
| Yes | 14 (35.9) | 132 (35.2) | ||
| History of targeted therapy | 3.042 | 0.081 | ||
| No | 27 (69.2) | 205 (54.7) | ||
| Yes | 12 (30.8) | 170 (45.3) |
Abbreviations: ATE: arterial thromboembolism; BMI: body mass index; ECOG PS: Eastern Cooperative Oncology Group performance status; IQR: interquartile range; NSCLC: non‐small cell lung cancer; SCLC: small cell lung cancer.
p < 0.05 was statistically significant.
The subsequent multivariable analysis further confirmed that hypertension (OR, 2.229; 95% CI, 1.123–4.423; p = 0.022) had a significant association with ATE (Table 4).
TABLE 4.
Multivariable logistic regression analysis for ATE.
| Variable | OR (95% CI) | p |
|---|---|---|
| Age | 1.030 (0.979–1.085) | 0.256 |
| Hypertension | 0.022* | |
| No | 1 (Reference) | |
| Yes | 2.229 (1.123–4.423) | |
| Histology | 0.579 | |
| NSCLC | 1 (Reference) | |
| SCLC | 1.269 (0.546–2.948) | |
| History of targeted therapy | 0.164 | |
| No | 1 (Reference) | |
| Yes | 0.588 (0.278–1.242) |
Abbreviations: ATE: arterial thromboembolism; CI: confidence interval; NSCLC: non‐small cell lung cancer; OR: odds ratio; SCLC: small cell lung cancer.
p < 0.05 was statistically significant.
3.4. Prognostic Factors Associated With OS
Three hundred and eighty‐seven‐deaths were observed during the follow‐up period. The median OS of 414 patients was 11 (95% CI: 9.534–12.466) months. Univariable analysis showed that sex, BMI, ECOG PS, leukocyte, hemoglobin, history of radiotherapy, history of targeted therapy, and ATE were statistically significant with OS, while VTE was not correlated with OS (p = 0.988). Multivariable Cox regression analysis demonstrated that sex, leukocyte, hemoglobin, history of radiotherapy, history of targeted therapy, and ATE were independent prognostic factors for OS. Table 5 showed the details. Leukocyte count ≥ 10 * 109/L (vs. leukocyte count < 10 * 109/L; HR, 1.326; 95% CI, 1.006–1.746; p = 0.045) and ATE (vs. non‐ATE; HR, 1.582; 95% CI, 1.127–2.221; p = 0.008) were associated with shorter OS. Female (vs. male; HR, 0.637; 95% CI, 0.509–0.799; p < 0.001), hemoglobin ≥ 100 g/L (vs. hemoglobin < 100 g/L; HR, 0.593; 95% CI, 0.375–0.939; p = 0.026), with radiotherapy (vs. without radiotherapy; HR, 0.764; 95% CI, 0.615–0.949; p = 0.015), and with targeted therapy (vs. without targeted therapy; HR, 0.691; 95% CI, 0.554–0.862; p = 0.001) were protective factors related to better OS.
TABLE 5.
Univariable and multivariable factors associated with OS.
| Variables | Total (n = 414) | Univariable analysis | Multivariable Cox regression | ||
|---|---|---|---|---|---|
| Median OS (mo) | p | HR (95% CI) | p | ||
| Age (years) | 0.066 | ||||
| < 68 | 197 (47.6) | 12 | 1 (Reference) | ||
| ≥ 68 | 217 (52.4) | 11 | 1.154 (0.939–1.419) | 0.173 | |
| Sex | < 0.001* | ||||
| Male | 280 (67.6) | 9 | 1 (Reference) | ||
| Female | 134 (32.4) | 16 | 0.637 (0.509–0.799) | < 0.001* | |
| BMI (kg/m2) | 0.003* | ||||
| < 22 | 213 (51.4) | 9 | 1 (Reference) | ||
| ≥ 22 | 201 (48.6) | 13 | 0.820 (0.665–1.010) | 0.062 | |
| Smoking history | 0.380 | — | — | ||
| No/unknown | 274 (66.2) | 12 | |||
| Yes | 140 (33.8) | 9 | |||
| ECOG PS | 0.031* | ||||
| 0–1 | 353 (85.3) | 12 | 1 (Reference) | ||
| 2–4 | 61 (14.7) | 9 | 1.227 (0.920–1.638) | 0.164 | |
| Comorbidities | |||||
| Hypertension | 0.271 | — | — | ||
| No | 250 (60.4) | 11 | |||
| Yes | 164 (39.6) | 11 | |||
| Diabetes mellitus | 0.183 | ||||
| No | 388 (93.7) | 11 | 1 (Reference) | ||
| Yes | 26 (6.3) | 8 | 1.216 (0.808–1.831) | 0.348 | |
| Histology | 0.153 | ||||
| NSCLC | 349 (84.3) | 12 | 1 (Reference) | ||
| SCLC | 65 (15.7) | 10 | 0.975 (0.726–1.308) | 0.865 | |
| Baseline laboratory data | |||||
| Leukocyte count (*109/L) | 0.012* | ||||
| < 10 | 342 (82.6) | 12 | 1 (Reference) | ||
| ≥ 10 | 72 (17.4) | 8 | 1.326 (1.006–1.746) | 0.045* | |
| Platelet count (*109/L) | 0.377 | — | — | ||
| < 300 | 337 (81.4) | 11 | |||
| ≥ 300 | 77 (18.6) | 12 | |||
| Hemoglobin (g/L) | 0.007* | ||||
| < 100 | 21 (5.1) | 6 | 1 (Reference) | ||
| ≥ 100 | 393 (94.9) | 12 | 0.593 (0.375–0.939) | 0.026* | |
| D‐dimer (mg/L) | 0.205 | — | — | ||
| < 0.55 | 94 (22.7) | 15 | |||
| ≥ 0.55 | 320 (77.3) | 10 | |||
| History of chemotherapy | 0.723 | — | — | ||
| No | 117 (28.3) | 9 | |||
| Yes | 297 (71.7) | 12 | |||
| History of radiotherapy | 0.020* | ||||
| No | 268 (64.7) | 9 | 1 (Reference) | ||
| Yes | 146 (35.3) | 15 | 0.764 (0.615–0.949) | 0.015* | |
| History of targeted therapy | < 0.001* | ||||
| No | 232 (56.0) | 8 | 1 (Reference) | ||
| Yes | 182 (44.0) | 16 | 0.691 (0.554–0.862) | 0.001* | |
| VTE | 0.988 | — | — | ||
| No | 381 (92.0) | 12 | |||
| Yes | 33 (8.0) | 8 | |||
| ATE | 0.009* | 0.008* | |||
| No | 375 (90.6) | 12 | 1 (Reference) | ||
| Yes | 39 (9.4) | 7 | 1.582 (1.127–2.221) | ||
Abbreviations: ATE: arterial thromboembolism; BMI: body mass index; CI: confidence interval; ECOG PS: Eastern Cooperative Oncology Group performance status; HR: hazard ratio; NSCLC: non‐small cell lung cancer; OS: overall survival; SCLC: small cell lung cancer; VTE: venous thromboembolism.
p < 0.05 was statistically significant.
To further evaluate the predictive accuracy of the independent prognostic factors identified in the multivariable Cox model, we performed time‐dependent ROC analysis for 1‐ and 2‐year OS. The time‐dependent AUC for leukocyte count was 0.587 (95% CI, 0.532–0.642) for 1‐year survival and 0.560 (95% CI, 0.494–0.626) for 2‐year survival. The optimal cutoff value was 7.53 and 8.89 * 109/L for predicting mortality risk at 1‐ and 2‐year. The ROC analysis for the protective factor hemoglobin yielded an AUC of 0.454 (95% CI, 0.464–0.536) for 1‐year survival and 0.469 (95% CI, 0.222–0.778) for 2‐year survival, which was below 0.5. This confirmed that the relationship between hemoglobin and death was inverse. A lower level of hemoglobin was predictive of this event, which was consistent with its definition as a protective factor. The optimal cutoff value of hemoglobin was 118.0 and 129.7 g/L for predicting mortality risk at 1‐ and 2‐year (Figure 1).
3.5. Comparisons of VTE and ATE in Occurrence and Survival Time
The median occurrence times of VTE and ATE were 2 and 1 month, respectively. However, there was no statistical significance in the occurrence time between VTE and ATE in this cohort (p = 0.099).
The cumulative 3‐, 6‐, 12‐, and 24‐month incidences of VTE were 4.15% (95% CI: 2.22–6.09), 5.77% (95% CI: 3.48–8.07), 6.94% (95% CI: 4.32–9.57), and 8.79% (95% CI: 5.46–12.12), respectively. 3‐, 6‐, 12‐, and 24‐month cumulative incidences of ATE were 6.34% (95% CI: 3.98–8.70), 7.48% (95% CI: 4.90–10.07), 9.63% (95% CI: 6.58–12.68), and 10.70% (95% CI: 7.35–14.06), respectively (Figure 2).
FIGURE 2.
Cumulative incidence curves of VTE and ATE. Abbreviations: ATE, arterial thromboembolism; VTE, venous thromboembolism.
Median OS of the three groups including without VTE or ATE, with VTE and with ATE were then calculated. Median OS of patients was 12 (95% CI: 10.224–13.776) months for those without VTE or ATE, 8 (95% CI: 5.774–10.226) months for those with VTE, and 7 (95% CI: 4.378–9.622) months for those with ATE. The difference of OS among the three groups was statistically significant (p = 0.033) (Figure 3). In a subsequent pairwise comparison, p value was adjusted to 0.0167 after Bonferroni correction. Older patients with ATE had a poorer prognosis than those without VTE/ATE (p = 0.008). No statistical differences were observed between patients with ATE and VTE, or between patients with VTE and without VTE/ATE, with p values of 0.174 and 0.837, respectively.
FIGURE 3.
Comparison of survival for elderly stage IV lung cancer patients. Abbreviations: ATE, arterial thromboembolism; VTE, venous thromboembolism.
3.6. Comparison of Thromboembolic Risk Factors and Clinical Outcomes Between Elderly and General Cohorts
In our prior study, we explored the current status of VTE and ATE in patients over 18 years old with metastatic lung cancer [19]. In this study, we focused on patients over 60 years old. Here, we have made a comparison between the elderly and the general population in terms of the risk factors for thromboembolism and survival.
3.6.1. Differential Risk Factors for VTE and ATE
In the general cohort of 587 patients, univariate and multivariate logistic regression analyses showed only D‐dimer level (OR, 1.866; 95% CI, 1.045–3.334; p = 0.035) was associated with VTE. In the geriatric cohort, BMI emerged as an independent risk factor for VTE, which was not significant in the general population.
For ATE, age and hypertension were risk factors in the general cohort. Age was related to ATE only in the general population but not in the elderly.
3.6.2. Clinical Outcomes Comparison Between the Two Groups
In the general cohort, univariable analysis and multivariable Cox regression analysis were conducted to identify prognostic factors associated with OS. Results showed that female (vs. male; HR, 0.699; 95% CI, 0.580–0.842; p < 0.001), hemoglobin ≥ 100 g/L (vs. hemoglobin < 100 g/L; HR, 0.617; 95% CI, 0.421–0.904; p = 0.013), ATE (vs. non‐ATE; HR, 1.635; 95% CI, 1.201–2.228; p = 0.002), with targeted therapy (vs. without targeted therapy; HR, 0.591; 95% CI, 0.490–0.712; p < 0.001) were predictors for OS. Leukocyte level and history of radiotherapy were prognostic factors for OS in the elderly group, but not in the general group. In both elderly and general cohorts, ATE was independently associated with worse OS, while VTE was not related to OS.
In the overall population, the median occurrence times of ATE and VTE were 2 and 4 months, respectively, while in the elderly population, they were 1 and 2 months, respectively. ATE occurred earlier than VTE in the general group (p = 0.012), but there was no statistical difference in this among the elderly. The median OS for the overall population was 12 months, and for the elderly, it was 11 months.
4. Discussion
The morbidity of lung cancer is expected to rise among developing countries, including China [22]. Lung cancer is also the leading cause of cancer death worldwide [23]. Thanks to advances in targeted therapy, lung cancer‐specific survival increased from 26% in 2001 to 35% in 2014 [24]. Nowadays in China, with the rapid development of treatment in lung cancer, there are quite plenty of metastatic lung cancer patients alive. Patients with lung cancer confer a higher risk of VTE and ATE [25, 26]. Moreover, advanced‐stage cancer is associated with an increase in VTE and ATE [27]. The incidence and mortality of lung cancer increased in patients over 60 years of age [12]. However, few studies have been conducted on VTE and ATE in this cohort. In this study, we mainly investigated the clinical characteristics and prognosis of thromboembolism in this population.
In our study, the incidence of VTE in metastatic lung cancer patients over 60 years old was 7.97%. Lung cancer has been reported to be more prone to develop VTE among solid tumors, with an incidence ranging from 4% to 13% in previous studies [28, 29, 30, 31, 32]. Few researchers have studied the incidence of VTE in metastatic lung cancer. Su et al. reported that 12.2% of the enrolled patients with newly diagnosed metastatic NSCLC developed VTE during 6 months follow‐up period [33]. A prospective study observed the cumulative incidence of VTE was 22.6% after 24 weeks [34]. The cumulative 6‐ and 24‐month incidences of VTE in our research were 5.77% and 8.79%, respectively. The incidence seemed to be lower in older patients. A large population‐based study confirmed that younger age was associated with a higher risk of VTE among patients with lung cancer, which may explain the result of our study [35]. The overall incidence of ATE in the present study was 9.42%. Compared with VTE, ATE is a less common complication in patients with malignancy [5]. However, ATE proportion was higher in patients with respiratory system cancer [36]. A previous retrospective study showed that the incidence of ATE at 6 months in patients with lung, gastric, and pancreatic cancers was 8.3%, 6.5%, and 5.9%, respectively [27]. A large study reported that the risk of ATE was higher in more advanced cancers at first diagnosis [26]. As researchers on ATE in metastatic lung cancer are scarce, we previously conducted a study to explore ATE in this cohort, and the incidence of ATE was 8.18%, lower than that of elderly patients. Our recent study found that older age was an independent risk factor for ATE, which was consistent with previous studies [5, 17, 19]. It may be the reason why the incidence increased in the elderly group.
It is worth noting that during the follow‐up period, we did not observe any patients experiencing both VTE and ATE. In the past, due to the finding that VTE consisted of red blood cells and fibrin, while ATE was mainly made up of platelets, these two types of thrombi were regarded as two separate diseases [37, 38]. However, in recent years, some scholars have speculated that there may be a correlation between VTE and ATE based on the fact that patients with VTE were associated with an increased risk of atherosclerosis and ATE, and patients with ATE were at a higher risk of VTE [39, 40, 41]. A 20‐year population‐based cohort study showed that for patients with DVT, the relative risk of myocardial infarction was 1.6, and that of stroke was 2.19. For PE patients over 70 years old, the risk of myocardial infarction or stroke was 3.96% in the first year [40]. Keller et al. found that VTE and atherosclerosis share common risk factors including hypercoagulable state, hyperlipidemia, inflammation, and endothelial injury [42]. Our study was a single‐center one with a small sample size and patients included were at stage IV who had shorter survival time. Furthermore, as it was a retrospective study, the true incidence of thrombotic events may be underestimated. Although it is well known that VTE is treated with anticoagulant therapy and ATE is treated with antiplatelet therapy, studies have reported that direct oral anticoagulants could prevent the progression of coronary atherosclerosis [43, 44]. Intervention for patients who have developed thrombosis may reduce their risk of subsequent thrombosis. Moreover, VTE and ATE were not found to share the same risk factors in our research. The above reasons might explain why there was no concurrent thrombosis observed during the follow‐up period in this study.
Comparison of the VTE risk factors between the elderly and the overall population from the same cohort was conducted. Results showed D‐dimer was an independent risk factor in these two groups, while BMI was not related to VTE in the general population. Previous studies on the risk factors of VTE in lung cancer have yielded inconsistent results. For the entire population with lung cancer, some studies have found that BMI was associated with the occurrence of VTE, while others have not obtained such results [45, 46, 47, 48, 49]. Few studies have explored the risk factors for VTE in geriatric cancer patients, especially those with lung cancer. A previous study has shown that among elderly patients undergoing total hip arthroplasty, BMI > 25 kg/m2 was an independent predictor of development of VTE [50]. Obesity may cause thromboembolism by activating adipocytokines including adiponectin and leptin, decreasing the fibrinolytic cascade and increasing inflammation and the activity of coagulation [51]. Visceral obesity is related to an increased risk of metabolic disorders, and the occurrence of metabolic syndrome may increase the risk of thromboembolism by 1.7 times [52]. Visceral obesity is more common among the elderly, which might serve as an explanation [53]. In our study, we calculated the optimal cutoff value of BMI for predicting the risk of VTE in an older population of metastatic lung cancer was 19.54 kg/m2. A study from the United States confirmed that BMI ≥ 30 kg/m2 was associated with unprovoked VTE [54]. The result of a study on the VTE risk of Japanese lung cancer patients showed that the cut‐off value of BMI was 25.4 kg/m2 [46]. Due to differences in genes and diet, the cut‐off values of BMI vary among ethnic groups [55, 56]. Moreover, because of diseases and aging, the elderly are more prone to be underweight [57]. Although it is generally accepted that the normal range of BMI is 18.5 to 24.9 kg/m2, there is controversy among the older population [58]. Therefore, for the elderly group of lung cancer patients, even if they do not reach the traditional standard of obesity, the risk of VTE may still increase, which may provide important significance for prevention strategies. D‐dimer is a degradation product of cross‐linked fibrin, reflecting the activation of the fibrinolytic and hemostatic system [59]. Many studies have confirmed that D‐dimer was an independent risk factor for VTE in lung cancer cases, the cutoff value varied between 1.14 and 3.3 mg/L [46, 47, 60, 61, 62, 63]. A study from Europe classified the D‐dimer levels in the new risk prediction model for VTE into four grades: < 500 ng/mL, 500–1500 ng/mL, > 1500–4000 ng/mL, and > 4000 ng/mL, with points of 0, 1, 2, and 3, respectively [63]. The cutoff value of D‐dimer in our study was 6.94 mg/L, which was higher than that of these studies. The level of D‐dimer increases with age [64]. The population in our study was over 60 years old, which was different from these studies. This might explain this result. It is worth noting that the AUC of BMI and D‐dimer in our study for predicting VTE was 0.632 and 0.698 respectively, indicating poorer predictive abilities. This suggested the insufficiency of a single factor in predicting VTE. In the future, we hope to establish a thrombosis prediction model through a prospective study to enhance the predictive ability. Our research confirmed that in the overall cohort, both advanced age and hypertension were independent risk factors for ATE. However, in the elderly subgroup, only hypertension was a risk factor, and the effect of age in this subgroup was no longer significant. Previous pan‐cancer studies also revealed that patients with higher age and hypertension had an increased risk of ATE [5, 17]. ATE mainly consists of ischemic stroke and ACS, which belongs to cardiovascular and cerebrovascular diseases. Hypertension is undoubtedly a risk factor for cardiovascular diseases, which may be the reason hypertension was independently associated with ATE. Few studies have explored deeply into the risk factors of ATE within the geriatric lung cancer subgroup. Our research revealed that in the higher risk group with age homogenization, the impact of hypertension on ATE seemed more important.
The application of time‐dependent ROC analysis has achieved dynamic evaluation, providing a more detailed understanding of how the predictive power of these routine clinical biomarkers evolved over time, particularly for 1‐year and 2‐year survival. It is well known that inflammation can promote the occurrence, metastasis and progression of tumors [65]. White blood cells, comprising neutrophils, lymphocytes, monocytes, and so on, serve as important indicators of inflammatory processes. Tomita et al. reported that elevated preoperative white blood cells were associated with poorer survival in NSCLC [66]. Recent studies have found that the systemic immune inflammation index based on neutrophil, lymphocyte, and platelet could predict poor prognosis in NSCLC and small cell lung cancer (SCLC) [67]. The optimal cutoff value of leukocyte was 7.53 and 8.89 * 109/L for predicting mortality risk at 1‐ and 2‐year, providing a clinically important threshold for risk stratification, potentially identifying patients who might benefit from more aggressive management or anti‐inflammatory therapies. Anemia can aggravate hypoxia in tumors, leading to resistance of tumors to chemotherapy and radiotherapy, thereby affecting survival of patients with cancer [68, 69, 70]. Our research found a higher level of hemoglobin was a protective factor related to better OS, which was consistent with some previous studies. Our data suggested that a hemoglobin level below 118.0 and 129.7 g/L at 1‐ and 2‐year served as an important warning, identifying a patient subgroup with consequent tumor hypoxia, which may contribute to treatment resistance and disease progression. It is worth noting that the AUCs for leukocyte and hemoglobin in predicting 1‐ and 2‐year survival in our study were lower, indicating a limited ability as a single predictor. It is consistent with the understanding that cancer prognosis is determined by multiple factors. Nevertheless, leukocyte and hemoglobin were independent prognostic factors in the multivariable analysis, confirming their associations with OS, despite their classification limitations. In the future research, we will attempt to establish a predictive model that incorporates multiple factors.
Our study showed that the risk of VTE or ATE increased in the first few months after diagnosis of metastatic lung cancer in elderly patients, although there was no statistical significance in the occurrence time between these two types of thromboembolism. In this study for VTE, median occurrence time was 2 months, and for ATE was 1 month, respectively. Su et al. observed that VTE events were most noticeable within the first 60 days in patients with newly diagnosed metastatic NSCLC in a prospective research [33]. Previous studies in cancer of diverse types also revealed that the rate of VTE was highest in the first 6 months or even in the first 3 months after cancer diagnosis [5, 71]. Similar results were found in some previous studies on ATE. Wang et al. reported the risk of ATE was most significant within 30 days after cancer diagnosis [17]. Another study showed the number of cancer patients who developed ATE events was more than twice that of the control group within 6 months of cancer diagnosis. Our prior study in the overall population from the same cohort reported the median occurrence times of ATE and VTE were 2 and 4 months, respectively. The elderly cohort developed VTE or ATE events earlier after diagnosis of cancer, seriously affecting quality of life and subsequent anti‐tumor therapy. Therefore, early diagnosis and intervention of thromboembolism seems necessary to this subgroup.
In this study, we found poorer prognosis of ATE than those without VTE/ATE. However, there were no statistical differences between patients with ATE and VTE, or between patients with VTE and without VTE/ATE. This result was consistent with our previous study of metastatic lung cancer patients over 18 years of age [19]. Our research confirmed that in both elderly and general cohorts, ATE was independently associated with worse OS, while VTE was not related to OS. There have been few studies on the prognosis of ATE in metastatic lung cancer patients, especially the elderly population. A study from a public database showed that cancer patients with ATE had a 3.1‐fold increase in mortality rate [26]. Suzuki et al. reported that there was no significant difference in median OS from lung cancer diagnosis between the VTE and non‐VTE groups, supporting our result [48]. It has been suggested that tumor remission with antitumor therapy and regular anticoagulant therapy could reduce the incidence of VTE, which was important for prognosis [72].
Our study has some limitations. First of all, it was a retrospective study from a single center; the sample size was small, may not be representative, and may not be applicable to other patient cohorts. In addition, since the study was retrospective, the actual incidence of thrombotic events may have been underestimated, which may affect the results. Last but not least, we explored the impact of treatment methods including chemotherapy, targeted therapy, and radiotherapy on thrombosis occurrence and survival. However, most patients received multiple lines of treatment, and the treatment approach was rather complex. Since in our study we simply divided the treatment methods into two groups, these might affect the results of the research. Therefore, in the future, it is necessary to conduct a prospective study to verify our findings.
Author Contributions
Y.Q.: substantial contribution to design, data acquisition, statistical analysis, manuscript drafting. X.L. and X.S.: data collection, statistical analysis. S.Y. and N.W.: acquisition and interpretation of data. Q.W. and D.W.: substantial contribution to the conception of this research and critical manuscript revision. All authors read and approved the final manuscript.
Funding
This study was sponsored by grants from the Youth Project of Jiangyin Municipal Health Commission (No. Q202305).
Ethics Statement
This study was approved by the Ethics Committee of the Affiliated Jiangyin Hospital of Nantong University (No. 2023031).
Consent
Verbal informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgments
The authors have nothing to report.
Qin Y., Liang X., Sun X., et al., “Clinical Characteristics and Prognosis of Thromboembolism in Elderly Patients With Stage IV Lung Cancer,” Geriatrics & Gerontology International 26, no. 1 (2026): e70325, 10.1111/ggi.70325.
Contributor Information
Qiong Wang, Email: wangqiong55@hotmail.com.
Dan Wu, Email: wudan96121@163.com.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.