Patients with cancer are at increased risk of thromboembolic events 1. The prevalence of cancer among patients with deep venous thrombosis or pulmonary embolism reportedly ranges between 4 and 20% 2,3 and thromboses are found on autopsy in 50% of patients with cancer 4. Venous thromboembolic events (VTEs) portend a poor prognosis; only 12% of patients with cancer who have a VTE survive beyond 1 year 5.
Studies have shown several risk factors for the development of thromboembolic events in patients with cancer 3,6, with chemotherapy being a well-known risk factor. In particular, studies have shown that cisplatin (CDDP) is significantly associated with an increased risk of VTEs in patients with cancer, including lung cancer 7–10. One of the several suggested mechanisms is an increase in von Willebrand factor concentration after CDDP-based chemotherapy, which may indicate stimulation of and/or damage to endothelial cells by chemotherapy 11. Carboplatin (CBDCA) and nedaplatin (CDGP) are believed to be much safer platinum-based agents, including inducing less renal-related and gastrointestinal tract-related adverse effects. Previous studies have not identified a difference in risk of developing VTEs between CDDP and CBDCA 12,13. However, these findings are limited by small sample sizes.
The aim of this study was to evaluate the relative risk of VTEs in patients with lung cancer who had received CDDP-based chemotherapy versus CBDCA/CDGP-based chemotherapy; the relevant data having been drawn from a national inpatient database in Japan.
Materials and methods
The Diagnosis Procedure Combination database 14, a national inpatient database covering ∼50% of acute care inpatients in Japan, includes the following data: age, sex, body height and weight (BMI), primary diagnoses, comorbidities at admission and complications after admission coded according to the International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10) activities of daily living (ADL) on admission, chemotherapy drugs, thoracentesis, radiotherapy, and discharge status. ADL was represented as Barthel index, which is a scale that measures disability or dependence in 10 ADL such as feeding, bathing, and mobility. Total possible scores range from 0 to 100, with lower scores indicating expanded disability.
This study was approved by the Institutional Review Board of the University of Tokyo. The board waived the requirement for patient informed consent because of the anonymous nature of the data.
We retrospectively collected data of patients with primary lung cancer (ICD-10 code, C34) who had undergone platinum-based doublet chemotherapy between April 2012 and March 2015 and were aged 20 years or older.
The primary outcome of this study was the occurrence of VTEs during hospitalization. VTEs included pulmonary embolism (ICD-10 code, I26), deep venous thrombosis (I80), and other VTEs (I82).
We used the χ2-test to compare rates of patient’s characteristics between the two groups, the Mann–Whitney test to compare median values between the groups, and multivariable logistic regression analysis to assess associations between patient-level factors and VTE after adjustment for within-hospital clustering by means of a generalized estimation equation. The threshold for significance was set at P less than 0.05. We performed all statistical analyses using SPSS version 22.0 (IBM SPSS; IBM, Armonk, New York, USA).
Clinical background of patients
A total of 239 840 patients with lung cancer (aged ≥20 years) who had been treated with platinum-based chemotherapy were included. We excluded patients if they had received more than one type of platinum compound (n=1351) or nonstandard chemotherapy regimen such as platinum monotherapy and doublets with nonspecific immunomodulators (n=3385), which left 235 104 patients for analysis.
A total of 86 316 patients had received CDDP-based chemotherapy and 148 788 CBDCA-based or CDGP-based chemotherapy. Their clinical characteristics are shown in Table 1. The patients who received CBDCA/CDGP-based chemotherapy were significantly older and had lower BMIs and Barthel indexes than those who had received CDDP-based chemotherapy. A significantly higher proportion of patients in the CDDP group had received radiotherapy or had central vein catheters inserted than in the CBDCA/CDGP group, whereas a significantly higher proportion had undergone thoracic drainage and/or thoracentesis in the CBDCA/CDGP group. Hypertension, diabetes, and hyperlipidemia were major comorbidities on admission, and a small percentage of patients had cardiovascular comorbidities, including atrial fibrillation, valvular disorder, and varices. The percentages of all comorbidities (except for varices) on admission were higher in the CBDCA/CDGP group than in the CDDP group. The proportion of patients receiving prehospital antithrombotic medication was also higher in the CBDCA/CDGP group.
Venous thromboembolic events
VTE was detected in 675 (0.29%) patients, including 433 with deep venous thrombosis and 186 with pulmonary embolism. Rates of VTE according to treatment group are shown in Table 2; these events occurred significantly more frequently in the CDDP group than in the CBDCA/CDGP group (0.35 vs. 0.25%, respectively). Patients who received CDDP-based chemotherapy had shorter lengths of hospital stay and lower in-hospital mortality.
The clinical characteristics of patients with in-hospital VTE are listed in Table 3. VTE predominantly occurred in younger patients, women, never-smokers, and patients with lower Barthel indexes. Invasive medical procedures such as radiotherapy, insertion of central vein catheters, thoracic drainage, and thoracentesis were performed significantly more frequently in the VTE group. Furthermore, a lower proportion of patients with VTE had diabetes and higher proportions of them had varices or were receiving antithromboembolic therapy on admission. Patients who developed VTE had longer hospital stays [median (interquartile range): 24 (15–46) vs. 15 (8–24) days; P<0.001] and higher mortality (8.1 vs. 2.2%; P<0.001) compared with patients without VTE.
Multivariable logistic regression analysis
The results of multivariable logistic regression analysis are shown in Table 4. A higher rate of occurrence of VTE was associated with younger age, female sex, never smoking, and lower Barthel index. Prehospital antithromboembolic therapy and invasive medical procedures including radiotherapy, insertion of central vein catheter, and thoracic drainage were also associated with higher rate of VTE; however, the comorbidity of diabetes was associated with a lower rate. CDDP-based chemotherapy was more strongly associated with VTE than CBDCA/CDGP-based chemotherapy (adjusted odds ratio: 1.35; 95% confidence interval: 1.08–1.68; P=0.008).
In this study, we used data drawn from a nationwide large database to compare rates of VTE between patients with lung cancer who had received CDDP versus those who had received CBDCA/CDGP.
Previous studies have shown that CDDP is a significant risk factor for VTE. However, it has remained unclear whether CDDP is associated with a higher risk than CBDCA. Our study showed that patients who received CBDCA/CDGP-based chemotherapy were older, had lower BMIs and Barthel indexes, were more likely to have pleural effusions and various comorbidities, stayed longer in hospital, and had a higher in-hospital mortality rate. That is, the overall condition of patients in the CBDCA/CDGP group was worse than that of patients in the CDDP group. Multivariable logistic regression analysis showed that CDDP-based chemotherapy was significantly associated with a higher rate of VTEs than CBDCA/CDGP-based chemotherapy after adjustment for these conditions.
CDGP is a cisplatin derivative developed in Japan to decrease the toxic effects induced by CDDP. Similar to CBDCA, hydration for renal protection is not required, and therefore, CDGP is considered as a safer alternative for CDDP. In this study, we combined the patients who received CBDCA and CDGP. However, CDGP is a relatively minor drug even in Japan, and the patients treated with CDGP account for a small proportion (4.4%) of the CBDCA/CDGP group. Even after exclusion of the CDGP group (Supplementary Tables 1–3, Supplemental digital content 1; http://links.lww.com/ACD/A254), the CDDP group was associated with significantly increased risk of VTE (adjusted odds ratio: 1.50; 95% confidence interval: 1.16–1.94; P=0.002).
The rate of occurrence of VTEs was relatively low in this study compared with rates reported in previous studies (8.4–12.9%) 7,10,15,16. This may be partly because of differences in duration of follow-up between these studies. We counted only VTEs during hospitalization, whereas previous studies reported the cumulative incidence over longer periods (mostly ≤1 year). The rate of VTE may have been affected by length of hospitalization. However, in the present study, although patients with CDDP-based chemotherapy had shorter hospital stays, CDDP-based chemotherapy was associated with a higher rate of VTEs during hospitalization.
Previous studies have identified various risk factors for VTE, including immobilization 17,18, radiotherapy 19, central venous catheter 20, and surgery 21. The results of the present study were consistent with these previous data, and Barthel’s ADL score, radiation, central venous device, and thoracentesis were independent risk factors for VTE with higher adjusted odds ratio compared with that for CDDP. Close follow-up is needed also for the patients with these risk factors. However, our findings concerning age were paradoxical: older patients are known to be at high risk of VTE 22,23, whereas in our cohort, patients older than 70 years were at the lowest risk. This may be explained by differences in dose and duration of chemotherapy between younger and older patients.
Platinum-containing chemotherapy is widely used for the treatment of various cancers. In theory, our results of CDDP-related VTEs in patients with lung cancer may be applicable to other cancers. However, incidence rates of VTE vary among primary sites of cancers, and lung cancer is one of the most common cancers related to VTEs 24. Furthermore, a certain kind of platinum-containing drug is predominantly used in some cancers. For example, CBDCA is preferred in a standard platinum-based therapy for relapsed ovarian cancer 25,26. Further investigation is needed.
We acknowledge that our study has several limitations. First, because it was a retrospective observational study, recoded diagnoses of VTE may have been less reliable than diagnoses in planned prospective studies. Second, our cohort had a relatively low rate of VTE because we lacked data on VTE events after discharge. Third, there may be bias in the form of unmeasured confounders, such as the cancer staging, which is not included in Diagnosis Procedure Combination database.
In conclusion, in our study of patients with lung cancer, CDDP-based chemotherapy was associated with a higher rate of VTE than was seen in CBDCA/CDGP-based chemotherapy. Care should be taken to prevent VTE in patients with lung cancer, especially those receiving CDDP-based chemotherapy.
Akihisa Mitani, Taisuke Jo, and Hideo Yasunaga contributed to conception and design; analysis and interpretation is done by Akihisa Mitani and Taisuke Jo; and drafting the manuscript for important intellectual content was done by Akihisa Mitani, Taisuke Jo, Hideo Yasunaga, Yukiyo Sakamoto, Wakae Hasegawa, Hirokazu Urushiyama, Yasuhiro Yamauchi, Hiroki Matsui, Kiyohide Fushimi, and Takahide Na.
This work was supported by grants from the Ministry of Health, Labour and Welfare, Japan (H29-Policy-Designated-009 and H29-ICT-Genral-004); Ministry of Education, Culture, Sports, Science and Technology, Japan (17H04141); and the Japan Agency for Medical Research and Development (AMED).
Conflicts of interest
There are no conflicts of interest.
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