Cisplatin-associated arterial and venous thromboembolic events (TEEs) are becoming an increasing concern. In patients with small-cell lung cancer (SCLC) who are treated using cisplatin-based chemotherapy, we assume that the overall risk of TEEs is high. However, cisplatin-associated vascular toxicity in patients with SCLC has been overlooked to date. The aim of this study was to determine the incidence of TEEs in patients with SCLC and to analyze the predictors for TEE occurrence.
We retrospectively analyzed 277 patients who received chemotherapy for SCLC between 2006 and 2012. As the influence of chemotherapy on TEE occurrence developed after its initiation, a time-dependent Cox regression analysis was used to estimate the significant predictors for TEE.
Among the 277 patients, 30 patients (11%) developed a TEE. The 3-month, 6-month, and 1-year cumulative incidences of TEEs were 5.0%, 9.1%, and 10.2%, respectively. Of 30 total TEEs, 22 (73%) occurred between the time of initiation and 4 weeks after the last dose of platinum-based chemotherapy. Approximately 218 patients (79%) received cisplatin-based chemotherapy. In multivariate analysis, cisplatin-based chemotherapy was an independent risk factor for TEE occurrence (hazard ratio [HR], 4.36; p=0.05). Variables including smoking status (common HR, 2.14; p=0.01) and comorbidity index (common HR, 1.60; p=0.05) also showed significant association with TEE occurrence.
The 1-year cumulative incidence of TEE is 10.2% in Asian patients with SCLC. Cisplatin-based chemotherapy in SCLC might be a strong predictor for the risk of TEE.
Patients with malignancy have a 4- to 8-fold increased risk of venous thromboembolism compared to those without malignancy [
Among chemotherapeutic agents, cisplatin in particular has been associated with an increased risk of a thromboembolic event (TEE) [
The aim of the current study was to investigate the incidence and characteristics of TEE in patients with SCLC who received platinum-based chemotherapy.
All patients who received chemotherapy for SCLC and underwent at least 4 weeks of follow-up after their initial chemotherapy session between January 2006 and June 2012 were analyzed retrospectively. This study was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. H-1102-013-349).
Comorbidity was assessed using the Adult Comorbidity Evaluation 27 (ACE-27), a validated comorbidity instrument used for assessment of patients with cancer [
We defined TEE to include arterial thrombosis, deep vein thrombosis (DVT), pulmonary embolism (PE), and thrombosis in other vascular territories except for superficial vein. All reports of radiological (computerized tomography [CT], CT angiography, Doppler ultrasonography, and conventional angiography) or nuclear medicine (ventilation/perfusion scans) studies were reviewed in order to identify a venous or arterial TEE. Two independent investigators (Y.-G.L. and E.L.) double-checked and confirmed the occurrence of TEE by retrospective review of electrical medical records and results of imaging studies. Two or more TEEs occurring either simultaneously or at different times were counted as one event.
The primary study objective was to determine the cumulative incidence and characteristics of TEEs in patients with SCLC. The time-to-TEE was calculated by taking the difference in time from the date of cancer diagnosis to the first identified date of TEE occurrence. The cumulative hazard estimates for TEE were calculated using the Nelson-Aalen method and compared between groups using log-rank tests. The secondary study objective was to investigate the predictive risk factors for the occurrence of a TEE, which was analyzed using Cox time-dependent covariate regression analysis. When a linear effect of a categorical variable was suspected, we calculated the common hazard ratio (HR) from one group to the next. Variables that were found to be significant with p ≤ 0.05 using a stepwise backward-selection method were entered into a final multivariate model. All analyses were performed using Stata ver. 12.0 (StataCorp, College Station, TX).
Overall, 306 patients were diagnosed with SCLC during the study period; 277 received chemotherapy and were included in the current study. Twenty-nine patients were excluded; 26 patients did not receive chemotherapy due to old age and/or poor performance status, and three patients were found to have a TEE at the time of cancer diagnosis.
Patients’ baseline and treatment characteristics are summarized in
Among the 277 patients included in this study, 30 patients (11%) developed a TEE. The 3-month, 6-month, and 1-year cumulative incidences of TEEs were 5.0%, 9.1%, and 10.2%, respectively. Of a total of 30 TEEs, all TEEs occurred in patients who had received a platinum-based chemotherapy; 22 (73%) occurred between the time of initiation and four weeks after the last dose of platinum-based chemotherapy and the remaining eight (27%) occurred during best supportive care after the end of chemotherapy. Among 22 TEEs associated with platinum-based chemotherapy, 20 (91%) occurred during cisplatin-based chemotherapy and two (9%) occurred during carboplatin-based chemotherapy. Among 20 TEEs related to the cisplatin-based chemotherapy, the majority (90%) occurred during the first-line cisplatin chemotherapy (between the time of initial dose of chemotherapy and 4 weeks after the last dose) and the other 10% occurred thereafter.
The majority of events were the occurrence of only PE (n=15), followed by arterial thrombosis (cerebrovascular accidents+central arterial thrombosis, n=7), DVT combined with PE (n=4), and only DVT (n=4).
In univariate analyses, the smoking status (current vs. non-smoker), stage of SCLC, and invasion of the superior vena cava showed association with a significant increase in the risk of TEE (
In multivariate analysis that included treatment variables as time-dependent covariates, cisplatin-based chemotherapy was an independent risk factor for TEE occurrence (HR, 4.36; 95% CI, 1.00 to 18.97; p=0.05). Variables including the smoking status (common HR, 2.14; 95% CI, 1.16 to 3.95; p=0.01) and ACE-27 comorbidity (common HR, 1.60; 95% CI, 1.00 to 2.58; p=0.05) also showed significant association with TEE occurrence (
This is the first study to focus primarily on SCLC and to evaluate the risk of TEE in patients with SCLC. In our retrospective analysis of 277 patients treated with platinum-based chemotherapy for SCLC, the 3-month, 6-month, and 1-year cumulative incidences of TEEs were 5.0%, 9.1%, and 10.2%, respectively. In multivariate analysis, the current smoking status, higher comorbidity index, and cisplatin-based chemotherapy were independent predictors for increased risk of TEE. Compared to patients receiving non-cisplatin based chemotherapy, risk of TEE was 4.4 times higher for patients receiving cisplatin-based chemotherapy.
In a population-based study including 13,542 patients with SCLC conducted in California between 1993 and 1999, the 2-year incidence of venous thromboembolism in patients with SCLC was 2.5% [
Despite clinical evidence of cisplatin-induced hypercoagulability, the pathophysiology remains unclear. Several studies have suggested that cisplatin may cause the following actions: endothelial damage via induction of procoagulant microparticles, an increase in the procoagulant activity of red blood cells, and modulation of tissue factor on human monocytes. These characteristics may contribute to cisplatin-induced hypercoagulability [
In terms of dose-response relationship, according to our data, the cumulative dose of cisplatin did not show correlation with TEE occurrence. This finding is consistent with results from a previous large retrospective study by Moore et al. [
In contrast to the well-known risk factors (smoking status, comorbidity index, and cisplatin-based chemotherapy) for thrombosis in our study, the Khorana score was not predictive of development of TEE. This finding may be explained by the fact that the overall risks for TEE in patients receiving cisplatin-containing chemotherapy were much higher compared to those in the study population included in the Khorana study [
Our results are limited by selection bias due to the retrospective nature of the study. The exclusion of patients who did not receive chemotherapy because of poor performance status and/or severe organ decompensation may lead to an underestimation of the real burden of TEE in patients with SCLC. Since the total number of patients with SCLC and TEE is low due to their rare incidence, our analyses were most likely underpowered for detection of statistical significance. Therefore, conduct of additional studies with large sample sizes will be necessary in order to confirm our findings.
In conclusion, in the current study, the 3-month, 6-month, and 1-year cumulative incidences of TEEs in Asian patients with SCLC were 5.0%, 9.1%, and 10.2%, respectively. Cisplatin-based chemotherapy in SCLC might be a strong predictor for the risk of TEE.
Conflict of interest relevant to this article was not reported.
This study was supported by grant No. 0720142084 from the National Research Foundation of Korea and by a grant of Seoul National University College of Medicine (800-20140171). The authors wish to thank Leo Song (University College Dublin School of Medicine, Dublin, Ireland) for the assistance in data collection.
Cumulative incidence of thromboembolic events (TEEs) according to chemotherapeutic regimen. HR, hazard ratio.
Baseline characteristics and univariate analysis for development of thromboembolic events (TEEs)
Characteristic | Patient | TEE case | Hazard ratio | p-value |
---|---|---|---|---|
Total patients | 277 (100) | 3010.8) | - | - |
Age group (yr) | ||||
< 65 | 123 (44.4) | 15 (12.2) | 1 | |
≥ 65 | 154 (55.6) | 15 (9.7) | 0.97 (0.47-1.99) | 0.94 |
Gender | ||||
Male | 247 (89.2) | 26 (10.5) | 1 | |
Female | 30 (10.8) | 4 (13.3) | 1.27 (0.44-3.64) | 0.66 |
ECOG performance status | ||||
0-1 | 250 (90.3) | 26 (10.4) | 1 | |
2-3 | 27 (9.7) | 4 (14.8) | 2.33 (0.81-6.75) | 0.12 |
Smoking status | ||||
Never smoker | 80 (28.9) | 2 (2.5) | 1 | |
Ex-smoker | 43 (15.5) | 4 (9.3) | 3.77 (0.69-20.63) | 0.13 |
Current smoker | 154 (55.6) | 24 (15.6) | 6.03 (1.43-25.54) | 0.02 |
ACE-27 comorbidity index | ||||
No comorbidity | 124 (44.8) | 14 (11.3) | 1 | |
Mild decompensation | 117 (42.2) | 119.4) | 0.95 (0.43-2.10) | 0.9 |
Moderate decompensation | 27 (9.8) | 3 (11.1) | 1.44 (0.41-5.03) | 0.57 |
Severe decompensation | 9 (3.3) | 2 (22.2) | 3.09 (0.70-13.61) | 0.14 |
Khorana variable | 42 (15.2) | 2 (4.8) | 0.45 (0.11-1.91) | 0.28 |
Prechemotherapy platelet count (≥ 350×109/L) | ||||
Prechemotherapy hemoglobin (< 10 g/dL or use of ESA) | 6 (2.2) | 0 | - | - |
Prechemotherapy leukocyte count (> 11×109/L) | 36 (13) | 2 (5.6) | 0.65 (0.15-2.74) | 0.56 |
BMI ≥ 35 kg/m2 | 1(0.4) | 0 | - | - |
Khorana risk score | ||||
1 | 205 (74) | 27 (13.2) | 1 | |
2 | 60 (21.7) | 2 (3.3) | 0.30 (0.07-1.25) | 0.1 |
3 | 11 (4) | 19.1) | 0.96 (0.13-7.11) | 0.97 |
4 | 1 (0.4) | 0 | - | - |
Khorana risk group | ||||
Intermediate | 265 (95.7) | 29 (10.9) | 1 | |
High | 12 (4.3) | 18.3) | 1.04 (0.14-7.68) | 0.97 |
Stage | ||||
Limited | 103 (37.2) | 9 (8.7) | 1 | |
Extensive | 174 (62.8) | 2112.1) | 2.20 (0.99-4.90) | 0.05 |
Superior vena cava invasion | ||||
No | 252 (91) | 24 (9.5) | 1 | |
Yes | 25 (9) | 6 (24) | 2.75 (1.12-6.74) | 0.03 |
ECOG, Eastern Cooperative Oncology Group; ACE, Adult Comorbidity Evaluation; ESA, erythropoiesis-stimulating agent; BMI, body mass index.
Treatment outcomesl
Characteristic | No. (%) |
---|---|
Initial treatment | |
Chemotherapy | 211 (76.2) |
Chemotherapy+radiation therapy | 38 (13.7) |
Radiation followed by chemotherapy | 28 (10.1) |
First-line chemotherapy (n=277) | |
Cisplatin+etoposide | 169 (61.0) |
Carboplatin+etoposide | 70 (25.3) |
Cisplatin+irinotecan | 37 (13.4) |
Carboplatin+irinotecan | 1 (0.4) |
Second-line chemotherapy (n=155) | |
Cisplatin+irinotecan | 60 (38.7) |
Cisplatin+etoposide | 21 (13.6) |
Irinotecan | 19 (12.3) |
Topotecan or belotecan | 17 (11.0) |
Carboplatin+etoposide | 15 (9.7) |
Carboplatin+irinotecan | 12 (7.7) |
Others | 11 (7.1) |
Exposure to cisplatin | |
No | 59 (21.3) |
Yes | 218 (78.7) |
No. of cisplatin cycles | |
Median (interquartile range) | 6 (5-7) |
Cumulative cisplatin dose (mg/m2) | |
Median (interquartile range) | 420 (350-490) |
Multivariate analysis of risk factors for development of thromboembolic events after start of chemotherapy
Variable | Hazard ratio | 95% Confidence interval | p-value |
---|---|---|---|
Smoking status |
2.14 | 1.16-3.95 | 0.01 |
ACE-27 comorbidity |
1.60 | 1.00-2.58 | 0.05 |
Superior vena cava invasion | 2.25 | 0.91-5.57 | 0.08 |
Stage | |||
Limited | 1 | - | - |
Extensive | 2.19 1 | 0.97-4.95 | 0.06 |
Chemotherapy | |||
Non-cisplatin-based | 1 | - | - |
Cisplatin-based | 4.36 | 1.00-18.97 | 0.05 |
ACE, Adult Comorbidity Evaluation.
As the separate effects of ‘Smoking’ and ‘ACE-27 comorbidity’ (