Six hundred sixty-one patients with pancreatic cancer who visited the Daegu Catholic University Medical Center from January 2011 to December 2020 were eligible (Fig. 1). All cases were retrieved using the diagnostic code for pancreatic cancer (C250, C251, C252, C253, C257, and C259) based on the Korean Standard Classification of Diseases, 8th edition. The exclusion criteria were as follows: patients who did not receive palliative chemotherapy, those with resectable disease, those with other malignancies, the presence of VTE at diagnosis, follow-up period <three months, those transferred to other hospitals, those with a neuroendocrine tumor, and a lack of medical records. The medical records were reviewed, and the following data were collected: demographics, laboratory findings, comorbidities, and radiologic findings.

This study was a retrospective, observational cohort study. The primary outcome was the incidence of VTE in patients with advanced PDAC who received palliative chemotherapy. The secondary outcomes were the risk factors associated with VTE and OS. The study protocol was reviewed and approved by the Institutional Review Board of Daegu Catholic University Medical Center (IRB number: CR-22-069-L). The need for informed consent was waived because this study was performed retrospectively.

Advanced PDAC included locally advanced and metastatic disease, defined according to National Comprehensive Cancer Network Guideline (Version 1. 2022).¹⁷ Metastatic disease was defined as a distant metastasis, including non-regional lymph node metastasis; locally advanced disease was defined as solid tumor contact of >180申 with the superior mesenteric artery or celiac axis, or unreconstructible superior mesenteric vein or portal vein due to tumor involvement.¹⁷ The OS was defined as the time from the diagnosis to the date of death from any causes. Alcohol consumption was confirmed by the medical records at the time of the PDAC diagnosis. A patient was considered a drinker if their drinking history was marked ‘yes’ on the medical records. A former drinker was defined as a patient who did not consume alcohol in the last 12 months.

VTE included deep vein thrombosis (DVT), pulmonary thromboembolism (PTE), and visceral venous thrombosis (VVT). DVT was detected through ultrasonography or CT. It was performed when patients were diagnosed with PTE or had lower leg pain, swelling, or both. DVT of the upper extremity was not included in this study. PTE was diagnosed via chest CT performed for the response evaluation according to the chemotherapy schedule or when patients had symptoms, such as dyspnea and chest discomfort. VVT was defined as thrombosis in the abdominal veins, such as the portal vein, mesenteric vein, splenic vein, and inferior vena cava. The condition was detected through abdomen and pelvis CT. The Khorana score was calculated from the results of laboratory tests at the diagnosis of PDAC.¹⁸

Statistical analysis was performed using IBM SPSS statistics for Windows version 26.0 (IBP Corp., Armonk, NY, USA). The continuous variables were described as the median with interquartile ranges. A student t-test or a Mann–Whitney U-test was used for them. The chi-square test or Fisher’s exact test was used to compare the categorical variables. The Wilcoxon signed-rank test and McNemar’s test were used to compare the changes in the variables in patients with VTE. The cumulative incidence of VTE was estimated using the Kaplan–Meier method. OS was also evaluated using the Kaplan–Meier method. A log-rank test was used to compare the OS between VTE and non-VTE group. The Cox-proportional hazard model was used to identify the risk factors associated with VTE and OS. The variables with p<0.2 were used in multivariate analysis. The results are presented as the hazard ratio (HR) and the 95% confidence interval (CI). The designated level of statistical significance was p<0.05 (two-tailed).

Of 170 patients with advanced PDAC, 24 (14.1%) developed VTE during the median follow-up period of 341 days. Table 1 lists the baseline characteristics of the patients according to the occurrence of VTE. The median age of the patients was 64 years. The proportion of males was 58.2%, and the median BMI was 21.9 kg/m². The most common tumor location was the head (n=83, 48.8%), followed by the body (n=63, 37.1%) and tail (n=19, 11.2%). One hundred and one patients (59.4%) had metastatic disease, and 69 (40.6%) had locally advanced disease. One hundred and seven patients (62.9%) were diagnosed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and endoscopic ultrasound-guided fine needle biopsy (EUS-FNB); ERCP and liver biopsy were used in 28 (16.5%) and 12 (7.1%) patients, respectively. The tumor differentiation was unknown in most of the patients (n=108, 63.5%). Twenty-seven patients (15.9%) had moderately differentiated cancer, and 11 (6.5%) had poorly differentiated cancer. Only four patients (2.4%) had a well-differentiated cancer. Fifty-six (32.9%), 61 (35.9%) 12 (7.1%) patients had hypertension, diabetes mellitus, and hypercholesterolemia, respectively. One hundred and thirty-six patients (80.0%) received gemcitabine-based chemotherapy, and 31 patients (18.2%) had 5-FU-based chemotherapy. The median level of the carbohydrate antigen 19-9 (CA 19-9) was 369 U/mL, and that of CEA was 5.45 ng/mL at the diagnosis of PDAC. The proportion of patients with a Khorana score over 2 was 18.8%. Patients with VTE were older than those without VTE (68 years vs. 62 years, p=0.039). Other than age, there was no significant difference between the two groups with respect to demographics, clinical features, and laboratory findings.

Of 24 patients with VTE, 17 (70.8%) had metastatic disease, and seven (29.2%) had locally advanced disease at the time of the VTE diagnosis. Table 2 lists the clinical features of the patients with VTE. Eleven patients (45.8%) had progressive disease, while 10 (41.7%) had stable disease. Twenty patients (83.3%) were treated with direct oral anticoagulants, and four patients (16.7%) were not treated. The median time from PDAC diagnosis to death was 164 days, and there was no immediate death from VTE. The hemoglobin level was lower at the time of the VTE diagnosis than at the PDAC diagnosis (9.6 g/L vs. 12.6 g/L, p<0.001). The PT was prolonged at the time of VTE diagnosis than that at the time of PDAC diagnosis (INR 1.15 vs. 1.05, p<0.001).

The median period from PDAC diagnosis to the occurrence of VTE was 152 days. Fig. 2 shows the cumulative incidence. The cumulative incidence of VTE was 4.7% (95% CI, 2.39-9.22) at 90 days, 9.9% (95% CI, 6.14-15.59) at 180 days, and 16.9% (95% CI, 11.50-24.36) at 360 days. Table 3 lists the risk factors for VTE. In univariate analysis, age over 65 (HR, 2.413; 95% CI, 1.070-5.443) was the only significant factor. On the other hand, in multivariate analysis, CA 19-9 level over 1,000 U/mL (HR, 2.666; 95% CI, 1.112-6.389; p=0.028) and a history of alcohol consumption (HR, 0.327; 95% CI, 0.109-0.981; p=0.046) were statistically significant factors associated with VTE.

Of the 24 patients with VTE, 12 (50.0%) were symptomatic, and 12 (50.0%) were asymptomatic. Table 4 lists the types of VTE. More than half of patients with PTE or DVT had symptoms, whereas none of the patients with VVT had symptoms. The patients with VTE showed shorter median survival than those without VTE (347 vs. 556 days, p=0.041), as shown in Fig. 3. On the other hand, there was no significant difference in OS according to the presence or absence of symptoms (Fig. 4).

Table 5 lists the risk factors associated with OS. Univariate analysis revealed metastatic disease (HR, 1.781; 95% CI, 1.140-2.780; p=0.011), pancreatic tail cancer (HR, 1.951; 95% CI, 1.111-3.428; p=0.030), CA 19-9 level over 1,000 U/mL (HR, 2.191; 95% CI, 1.352-3.548; p=0.001), and VTE (HR, 1.786; 95% CI, 1.017-3.135; p=0.044) to be statistically significant factors associated with OS. Multivariate analysis showed that a CA 19-9 level over 1,000 U/mL (HR, 1.843; 95% CI, 1.113-3.052; p=0.017) and VTE (HR, 1.850; 95% CI, 1.049-3.263; p=0.033) were significant factors. Metastatic disease (HR, 1.591; 95% CI, 0.996-2.541; p=0.052) was an important factor, but it was not statistically significant.