VTE is a common complication of pancreatic cancer. However, data regarding the incidence, characteristics, or survival of patients with metastatic pancreatic cancer with VTE who receive palliative chemotherapy are limited. In the present study, the incidence of VTE was 23.6%, which was similar to that of previous reports. A randomized controlled study of patients with pancreatic cancer receiving chemotherapy performed to assess the value of simultaneous thromboprophylaxis with chemotherapy found that VTE incidence during the trial in the no thromboprophylaxis group was 28% [10]. In another retrospective study, the incidence of VTE in patients with pancreatic cancer receiving chemotherapy was 35.7% [11]. In the present study, we found that VTE occurrence itself did not affect the survival of patients with metastatic pancreatic cancer receiving palliative chemotherapy. In general, VTE occurrence is known to lead to poor survival outcomes in patients with cancer. In contrast, some studies have reported that VTE occurrence in patients with pancreatic cancer was not associated with poor survival, which is similar to the results of our study [12, 13]. Furthermore, the most important VTE related prognostic factor in the present analysis was the time of VTE diagnosis, rather than the occurrence of VTE. Patients diagnosed with VTE around the initiation of cancer chemotherapy, defined as early VTE, showed significantly poor survival in this study. The prognosis was even worse in patients with early VTE among the subgroup of patients with VTE, resulting in an almost 4-fold increased risk of death. Nonetheless, most previous studies regarding VTE focused on all VTE events during treatment courses; only one study investigated early VTE in patients with pancreatic cancer receiving chemotherapy. In the study by Mandala et al. comprising 227 patients with nonresectable pancreatic cancer, the incidence of early VTE was 12.3%, [14], which was similar to 10.6% of the 216 included patients in our study. Although early VTE did not affect the PFS or OS on multivariate analysis in the study of Mandala et al., it was associated with poor response to chemotherapy.
VTE development in patients with cancer results from multifactorial mechanisms. The main pathogenesis is associated with the generation of both intrinsic and extrinsic hypercoagulable status owing to cancer cells. Cancer cells stimulate the coagulation cascade by increasing the production of procoagulant activators such as tissue factor (TF) [15]. The upregulated coagulation cascade affects not only systemic coagulation but also tumor growth and metastasis through activation of angiogenesis signaling pathways [16]. This stimulation of tumor angiogenesis leads to more aggressive tumor progression. A study on pancreatic cancer found that TF is also expressed in pancreatic cancer cells and its expression was associated with poor histologic grade and worse prognosis [17]. Moreover, the expression of TF on tumor cells resulted in increased mitogenic activity through enhanced vascular permeability and synthesis of vascular endothelial cell growth factor [18]. Therefore, our analysis suggests that the occurrence of early VTE at the time of cancer diagnosis indicates an enhanced angiogenic condition of the tumor that implies biologically more aggressive characteristics at baseline, thus possibly resulting in poor OS. In addition, a hypercoagulable status has been associated with poor response to chemotherapy [19]. Moreover, additive morbidity owing to VTE and interruption or delay of chemotherapy due to VTE management or anticoagulation treatment may also be associated with poor survival in patients with early VTE.
In addition, a higher number of metastatic organs were also a significant poor prognostic factor among patients with VTE in the present study. High numbers of metastatic organs are associated with a relatively large tumor burden and advanced tumor status, factors that cause poor survival outcome. In previous analyses that included patients with pancreatic cancer from resectable stage to advanced disease, patients with metastatic disease showed a higher risk of death compared to other patients, when they were diagnosed with VTE [12]. Even in the present study, which included only patients with advanced stage pancreatic cancer, patients with a higher number of metastatic organs showed significantly worse prognosis among patients with VTE. Therefore, we should focus on this subgroup of patients with poor prognostic factors to improve survival outcomes. For example, further investigation on the effectiveness of anticoagulation treatment in patients with a higher tumor burden and/or who experience early VTE are necessary. VTE-related prognostic factors in this study might be helpful to select patients for future clinical trials.
Prediction of VTE is important because it encourages greater attention to the occurrence of VTE in patients presenting significant risk factors. In the present study, we focused on investigating the predictors of early VTE because it was a significant poor prognostic VTE-related factor. Among all patients, those with a PLT count > 350,000/μL, which is a factor included in Khorana’s model, showed a higher incidence of VTE. Increased PLT count is associated with hyperviscosity and has been associated with increased risk of VTE in a previous study [20]. Unexpectedly, a serum Na level < 135/mmol was a significant risk factor for occurrence of early VTE in this study. Hyponatremia is not a well-known predictive factor for VTE, but some studies have reported the association of VTE and hyponatremia. In a study of Chinese non-small cell lung cancer patients, the risk of VTE was increased in patients with hyponatremia (< 130/mmol) [21]. In addition, in a study of pediatric patients who underwent orthopedic surgery, hyponatremia was reported as a risk factor for VTE [22]. Nevertheless, the mechanism underlying the association between hyponatremia and early VTE is difficult to explain; however, hyponatremia prior to chemotherapy may reflect poor oral intake or a poor general medical status of the patient, and this state may be associated with a thrombosis-prone condition. Further studies are needed to investigate the mechanisms involved.
In the present study, classification into the high-risk group defined using Khorana’s model was also an important predictive marker of early VTE. No difference was observed in the incidence of all VTE between the intermediate- and high-risk groups defined according to Khorana’s model; however, a significant difference for the risk of early VTE occurrence was observed. The initial study used to define Khorana’s prediction model included patients with various types of cancer [4]. Only 54 (2.0%) gastric and 19 (1.4%) pancreatic cancer patients were included in the derivation cohort and the validation cohort of that study. Even in other studies for external validation, the number of patients with pancreatic cancer was small [23, 24]. In addition, according to previous studies, which included only patients with pancreatic cancer, conflicting findings were observed regarding the predictive role of the model. Munoz Martin et al. compared the incidence of VTE detected within 6 months after diagnosis between high- and intermediate-risk groups according to Khorana’s model in 84 patients with pancreatic cancer receiving chemotherapy. VTE incidence was higher in the high-risk group (37.5%) than in the intermediate-risk group (33.3%) [11]. Conversely, van Es et al. reported that Khorana’s model did not discriminate between intermediate risk and high risk of VTE because VTE incidence did not differ between the two groups in their study that included 178 patients with pancreatic cancer receiving chemotherapy [25]. However, we can suggest that Khorana’s model has a predictive role particularly for early VTE in patients with pancreatic cancer receiving chemotherapy and our study has value in the validation of the model that included 216 patients, which is by far the greatest number of patients with same disease status included in comparable studies.
In the present study, symptomatic VTE occurred in 6.9% of patients. In general, symptomatic VTE has received greater attention because it can negatively impact on quality of life, delay cancer treatment, and result in additive anticoagulation treatment. In contrast, asymptomatic VTE has not been a subject of common interest in this field. Nevertheless, symptomatic VTE did not affect OS in the present study. Moreover, two-thirds of patients with early VTE exhibited asymptomatic VTE. Therefore, we suggest that the occurrence and detection time of VTE is more important, regardless of the presence of symptoms; VTE screening at the start of palliative chemotherapy should be performed even in patients with no VTE-related symptoms. Some VTEs, such as PE or VVT, can be detected despite the absence of symptoms because patients are required to undergo imaging analysis including chest and abdominopelvic CT to assess their cancer status prior to the initiation of chemotherapy. In addition, laboratory analysis using D-dimer, which is a fibrin degradation product and reflects the activation of hemostasis and fibrinolysis, would be helpful because D-dimer is a well-known and widely available biomarker for screening of VTE in the general population and in some cancer patients [26]. However, the potential use of D-dimer as a predictive factor for VTE in patients with pancreatic cancer receiving palliative chemotherapy has not been reported and further investigation is necessary. Because concordant markers are yet to be confirmed in clinical practice, focusing on the Khorana score, which has been shown to have meaningful significance in predicting the occurrence of VTE, could be helpful, particularly in predicting synchronous VTE, as in our study. Further research regarding the use of coagulation-related markers and clinical factors would be helpful for screening for VTE located outside of the routine CT imaging field or for those with microcoagulable status barely detectable using imaging modalities.
This study is limited by its single institution retrospective design. We could not analyze the association or role of clinical factors with VTE-related or coagulation-related laboratory tests because of insufficient data. We only determined an association of clinical factors and VTE. However, this study has value because of the higher number of patients included compared to other previous studies with a similar objective. The present study should provide the basis for further investigations, such as studies into the role of anticoagulation therapy for patients with pancreatic cancer and early VTE.