Research ArticleClinical Studies

High Preoperative Serum D-dimer Predicts Unfavorable Survival Outcomes for Pancreatic Cancer Patients

TOMOHISA OTSU, MASAMICHI HAYASHI, HIDEKI TAKAMI, YOSHIKUNI INOKAWA, NOBUTAKE TANAKA, KEISUKE KURIMOTO, KOKI NAKANISHI, SHINICHI UMEDA, DAI SHIMIZU, NORIFUMI HATTORI, MITSURO KANDA, CHIE TANAKA, GORO NAKAYAMA and YASUHIRO KODERA
Anticancer Research July 2023, 43 (7) 3173-3181; DOI: https://doi.org/10.21873/anticanres.16491

Abstract

Background/Aim: Pancreatic cancer cells release certain tissue factors into the bloodstream. It is well known that pancreatic cancer progresses with thrombus formation. Because we routinely measure serum D-dimer levels in preoperative patients as a screening marker of deep venous thrombosis, we examined its association with high serum D-dimer in our cohort of pancreatic cancer resected cases. Patients and Methods: We examined 315 patients with pancreatic ductal adenocarcinoma who underwent surgical resection in our department from January 2012 to July 2021. All cases were divided into high D-dimer cases (n=118) and low D-dimer cases (n=197) using the cut-off value of 1.0 μg/ml, an institutional upper limit. Clinicohistological characteristics and postoperative survival outcomes were evaluated. Results: Preoperative high D-dimer cases showed significantly worse progression-free survival (PFS) (p=0.021) and overall survival (OS) (p=0.027) than low D-dimer cases; median PFS was 13.9 months versus 21.4 months, and that of OS was 33.4 months versus 68.0 months. Clinicohistological characteristics of high D-dimer cases were age over 70 years (p<0.001), pathological portal vein invasion (p=0.003), and initially borderline resectable or unresectable cases (p=0.027). Multivariate analysis indicated that preoperative high D-dimer was a significant prognostic factor of PFS (hazard ratio=1.42, p=0.025) and OS (hazard ratio=1.51, p=0.036). Conclusion: Preoperative high serum D-dimer over 1.0 μg/ml was associated with pathological portal vein invasion and could be an unfavorable prognostic marker of PFS and OS after surgery, typically due to distant metastasis.

Key Words:

Despite significant advances in diagnostic technologies and multidisciplinary treatments, the prognosis of pancreatic cancer remains dire. An association between cancer and hemostasis has been reported in various studies (1, 2). Venous thromboembolism (VTE) is a frequent complication in patients with cancer, and is the second leading cause of death in patients with cancer (3). A tendency of systemic blood coagulation as well as procoagulant changes are frequently observed in patients with cancer (4). Among all solid tumor malignancies, patients with pancreatic cancer have the highest incidence of cancer-associated VTE, reaching 36% (5).

Pancreatic ductal adenocarcinoma (PDAC) cells are known to release high levels of tissue factor (TF) into the bloodstream (6). TF is a transmembrane glycoprotein that binds the coagulation serine protease factor and functions as the initiator of coagulation in vivo (7). Recent studies suggested that the coagulation proteases and receptors promote PDAC tumor progression and dissemination (2); thus, TF release and PDAC progression seem to synergize. Furthermore, the elevation of protease-activated receptor-1 (PAR1) expression is known to activate PDAC progression by thrombus formation through TF–thrombin–PAR1 signaling (2).

To monitor coagulation status or to evaluate the VTE risk by blood examination, the Khorana score is conventionally used, which consists of parameters based on primary tumor site, thrombocytosis, leukocytosis, anemia, and obesity (8). Recently, the Vienna scoring system, which includes D-dimer (>1.44 μg/ml) and soluble P-selectin (sP-selectin), was reported to show increased sensitivity and specificity for VTE detection (9). D-dimer originates from once-coagulated fibrin only, while the fibrin/fibrinogen degradation products are also elevated after primary fibrinolysis of non-coagulated fibrinogen during the secondary fibrinolysis process. This is why D-dimer elevation could be an indicator of systemic thrombotic status (10). On the other hand, sP-selectin is a platelet-activating factor. These factors are usually up-regulated in hypertension and diabetes.

As for the surgically resected cohort, Zhang et al. reported in 2021 that high preoperative D-dimer (>0.53 μg/ml) and fibrinogen concentrations were associated with short overall survival (OS) in patients with PDAC undergoing radical R0 resection by upfront surgery (11). However, their cohort did not include cases that underwent preoperative treatment. Chemotherapy is also a well-known risk factor of thrombosis, and our cohort consisted of both pre-operative-treated cases and those that received upfront surgery. Therefore, this study re-evaluated the impact of D-dimer levels and the Khorana score as indicators of poor prognosis among patients with surgically resected pancreatic cancer with or without preoperative treatment. We followed the definition of the Khorana score as described in the previous paper (8). We did not apply the Vienna scoring system to our cohort because of the lack of sP-selectin data.

Patients and Methods

Patient selection. We examined patients with pancreatic ductal adenocarcinoma who underwent surgical resection in the Department of Gastroenterological Surgery of Nagoya University Hospital (Nagoya, Japan) from January 2012 to July 2021. All resected specimens were histologically diagnosed as PDAC. Resectability of all cases had been classified as either resectable (R), borderline resectable (BR), or unresectable (UR) according to the National Comprehensive Cancer Network guidelines. For R patients, we conduct two courses of neoadjuvant chemotherapy with gemcitabine and S-1 according to the Japan Pancreas Society guideline. However, for BR or UR patients, there is no recommendation for regimen and duration of neoadjuvant chemotherapy. Accordingly, we decide on regimens and duration of NAC by each patient, which tends to be more intensive and prolonged treatment. The criteria for conducting surgery for UR patients are a decrease of tumor markers and no growth of tumor evaluated by computed tomography after more than half a year of neoadjuvant therapy. The Review Board of Nagoya University approved the clinical data collection protocol, and written informed consent was obtained from all patients included in this study. The clinicohistological characteristics of 315 patients are summarized in Table I.

View this table:
Table I.

Patients’ cohort (n=315).

D-dimer classification. D-dimer levels had been measured within 30 days before pancreatectomy as a VTE screening examination for cases with planned general anesthesia. We set the cut-off value to the upper limit of the normal range of our hospital (1.0 μg/ml). All patients were grouped into high D-dimer cases (≥1.0 μg/ml) and standard cases (<1.0 μg/ml).

Subgroup patients with pretreatment and preoperative D-dimers. Among the total cohort (n=315), patients with measured D-dimer at the pretreatment time point, mainly due to the screening test for staging laparotomy, and preoperative treatment followed by pancreaticoduodenectomy were extracted (n=56). They were classified into R and BR/UR cases and examined separately.

Statistical analysis. Continuous variables were compared using Student’s t-test or Mann–Whitney U-test. Categorical valuables were compared using the χ2 test or Fisher’s exact test, where appropriate. Because D-dimer was measured just before surgery, progression-free survival (PFS) was defined as the duration from surgery to the first documentation of disease progression. OS was defined as the duration from surgery to the date of death from any cause. Associations of D-dimer value and other histopathological factors with PFS/OS were evaluated using the log-rank test or Cox proportional hazards model with hazard ratios (HRs) and 95% confidence intervals (95%CIs). p-Values of <0.05 were considered statistically significant. Statistical analyses were performed using the JMP Pro software program, version 16 (SAS Institute, Cary, NC, USA).

Results

Preoperative serum D-dimer level or Khorana score and clinicohistological findings. Totally 315 patients were included in this study. Among them, 118 were assigned into the high D-dimer group and 197 into the low D-dimer group. The clinicohistological characteristics of each group are presented in Table II. High D-dimer cases tended to be older (>70 years) (p<0.001), have BR or UR statuses (p=0.027), and have pathological portal vein invasion (p=0.003). Preoperative Khorana score high-risk status was not significantly associated with the D-dimer status.

View this table:
Table II.

Clinicohistological characteristics by D-dimer status.

Similarly, Khorana score high-risk cases and intermediate-risk cases were compared in Table III. BR/UR NCCN resectability was solely associated with high-risk cases (p<0.001).

View this table:
Table III.

Clinicohistological characteristics by Khorana score status.

Preoperative high D-dimer patients or Khorana score high-risk patients and survival outcomes. Figure 1 shows the Kaplan–Meier curves of the high and low D-dimer cases. PFS of high D-dimer patients was significantly shorter than that of low D-dimer patients [median survival time (MST): 13.9 months vs. 21.4 months; p=0.021]. OS of high D-dimer patients was also significantly shorter than that of low D-dimer patients (MST: 33.4 months vs. 68.0 months; p=0.027). The difference was outstanding among the subgroup of BR or UR cases (MST: 29.6 months vs. not reached; p=0.013), whereas not statistically different in the R cases (Figure 2). Clinicohistological characteristics of BR and UR cases classified by D-dimer status are shown in Table IV. No difference was seen in oncological factors except for patients’ age.

Figure 1.
Figure 1.

The Kaplan–Meier curves for overall survival (OS) and progression-free survival (PFS) of 315 resected pancreatic adenocarcinoma cases with high and low D-dimer levels.

Figure 2.
Figure 2.

The Kaplan–Meier curves of the high and low D-dimer cases among unresectable (UR) and borderline resectable (BR) pancreatic adenocarcinoma (PDAC) cases (A), and resectable (R) PDAC cases (B).

View this table:
Table IV.

Clinicohistological characteristics by D-dimer status for BR and UR cases.

In addition, Khorana score high-risk cases did not show survival difference when compared with intermediate-risk cases (data not shown).

Univariate and multivariate analysis of PFS and OS. Risk factors of PFS were evaluated by multivariate analysis using the proportional hazard model. Significant preoperative prognostic factors of PFS were high preoperative D-dimer (HR=1.42, 95%CI=1.05-1.93; p=0.025), high preoperative CA19-9 (HR=1.70, 95%CI=1.19-2.43; p=0.003), and histologically proven positive lymph node metastasis (HR=2.36, 95%CI=1.73-3.24; p<0.001). The multivariate analysis of OS also identified high preoperative D-dimer (HR=1.51, 95%CI=1.03-2.23; p=0.036), high CA19-9 (HR=1.98, 95%CI=1.25-3.12; p=0.003), histologically proven positive lymph node metastasis (HR=2.09, 95%CI=1.41-3.08; p<0.001), and no adjuvant chemotherapy (HR=2.69, 95%CI=1.65-4.37; p<0.001) as significant prognostic factors (Table V and Table VI).

View this table:
Table V.

Postoperative progression-free survival.

View this table:
Table VI.

Postoperative overall survival.

Characteristics of high D-dimer cases. We also evaluated the correlation between preoperative D-dimer levels and postoperative first recurrence pattern. Among 261 cases that achieved histological R0 resection, 107 distant metastatic recurrences and 27 local recurrences were documented on average during 26.9 months of follow-up after surgery (Figure 3A). Interestingly, distant metastatic cases showed relatively high D-dimer levels compared with local recurrence-only cases (p=0.048).

Figure 3.
Figure 3.

D-dimer levels and recurrence patterns or preoperative treatment. (A) Dot plots of D-dimer levels in cases with histologically R0 resection according to postoperative recurrence patterns (distant metastasis vs. local recurrence only). (B) Dot plots of paired D-dimers before and after preoperative treatment of 23 R PDAC cases and 33 borderline resectable/unresectable (BR/UR) cases.

Additionally, we collected D-dimer levels before and after preoperative treatment for 56 available pancreaticoduodenectomy cases. Although there was no difference in resectable cases (n=23), D-dimer levels after preoperative treatment were significantly higher than those before the treatment in BR or UR cases (n=33), all of whom received longer preoperative treatment than R cases (Figure 3B). This implies that long-term chemotherapy presents a risk of elevated D-dimers.

Discussion

Instead of the Khorana score, preoperative high D-dimer levels were associated with poor OS and PFS for BR or UR PDAC cases. At the same time, no significant difference was found in resectable PDAC cases. These results imply that D-dimer elevation typically occurs in advanced PDAC cases, invading the portal vein system and requiring long-term preoperative treatment before surgical resection. In particular, chemotherapy with an intravenous catheter is reported to be a significant risk factor for VTE formation (12).

Similarly, several reports indicated that serum high D-dimer levels increase the risk of cancer death in patients with other malignancies (4), such as non-small cell lung (13), gastric (14), cervical, (15) and ovarian (16) cancers. In addition, in breast cancer cases, plasma D-dimer level is a valuable marker of early tumor metastasis and is associated with lymphovascular invasion, clinical stage, and lymph node involvement (17). As for pancreatic cancers, both portal vein system invasion and high serum D-dimer levels were reported to be associated with distant metastasis (18). Even in our high D-dimer cohort, histological portal vein invasion-positive cases demonstrated significantly worse RFS (p=0.031), whereas no difference was observed in the low D-dimer cohort (p=0.318) (Figure 4). From this viewpoint, the hypercoagulation status might facilitate distant metastasis (19). For example, Li et al. reported that a high D-dimer level was a significant risk factor for bone metastasis occurrence from non-small cell lung cancer (20). Tsuyuki et al. demonstrated that hypercoagulation status results in a poor prognosis of patients with cancer using a D-dimer level of 6 μg/ml or higher as a cut-off value (21).

Figure 4.
Figure 4.

The Kaplan–Meier curves of progression-free survival (PFS) by pathological portal vein invasion in positive and negative cases among preoperative high D-dimer cases (A) and low D-dimer cases (B).

Kuderer et al. summarized hemostatic system changes in cancer growth and progression (22). These mainly consist of tissue factor-derived thrombin and fibrin matrix formation, tumor-educated platelets, and P- and L-selectins, which play a role in the interaction of cancer cells with endothelial cells, platelets, and leukocytes. In particular, P-selectin was highly expressed in metastatic pancreatic tumor cells (23). Furthermore, MUC16 was reported to be a functional L-selectin ligand, and up-regulation of sialofucosylated MUC16 enhances the ability of circulating tumor cells to adhere to host tissues that express L-selectin ligands. These mechanisms may induce cancer cell metastasis (24). Moreover, both P- and L-selectin knockout mice marked the attenuation of metastasis (25). Although we could not perform further examination due to the lack of P-selectin and MUC16 data, D-dimer could be an indirect monitoring marker of cancer metastatic potential because of hypercoagulation induced by cancer-generated TF.

Several reports have shown that anticoagulant drugs, such as thrombosis treatments, improve the prognosis of cancer patients by preventing life-threatening coagulation disease and tumor progression. For example, Aki et al. reported in their systematic review that heparin affects cancer cell proliferation, migration, and invasion, and interferes with adherence to vascular endothelium (26, 27). Low-molecular-weight heparins or warfarin are also reported to have the same effects (28). However, regarding PDAC, direct evidence of the advantages of primary thromboprophylaxis is still lacking (29).

This study has several limitations. First, this was a single-center retrospective study. Therefore, a larger-size multicenter study is required to confirm these results. Second, D-dimer levels were examined before surgery only as a screening test for VTE and were not examined during the follow-up period. Thus, this study could not clarify whether it could be used as a monitoring marker.

In our surgically resected pancreatic cancer single-center cohort, preoperative D-dimer levels over 1.0 μg/ml were associated with portal vein system invasion. The existence of both factors predicts poor survival outcomes, typically due to the occurrence of distant metastases.

Acknowledgements

The Authors thank H. Nikki March, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Footnotes

  • Authors’ Contributions

    M.H. designed the project. M.H. and T.O. analyzed clinical and blood examination data. M.H., H.T., Y.I., N.T. and K.K. performed pancreatectomy, followed up with the patients and collected blood examination data. M.H. and T.O. wrote the manuscript. Y.I., K.N., S.U., D.S., N.H. M.K., C.T., G.N., and Y.K. revised the manuscript.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare in relation to this study.

  • Received April 14, 2023.
  • Revision received May 11, 2023.
  • Accepted May 12, 2023.

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High Preoperative Serum D-dimer Predicts Unfavorable Survival Outcomes for Pancreatic Cancer Patients
TOMOHISA OTSU, MASAMICHI HAYASHI, HIDEKI TAKAMI, YOSHIKUNI INOKAWA, NOBUTAKE TANAKA, KEISUKE KURIMOTO, KOKI NAKANISHI, SHINICHI UMEDA, DAI SHIMIZU, NORIFUMI HATTORI, MITSURO KANDA, CHIE TANAKA, GORO NAKAYAMA, YASUHIRO KODERA
Anticancer Research Jul 2023, 43 (7) 3173-3181; DOI: 10.21873/anticanres.16491
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