|Year : 2014 | Volume
| Issue : 8 | Page : 246-251
High levels of D-dimer correlated with disease status and poor prognosis of inoperable metastatic colorectal cancer patients treated with bevacizumab
Liming Zhu1, Bixia Liu1, Yazhen Zhao1, Luying Liu2, Chen Yang3, Yunshan Yang1, Haijun Zhong1
1 Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
2 Department of Radiotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
3 Department of Ultrasonography, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China
|Date of Web Publication||17-Feb-2015|
Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang
Source of Support: Public welfare technological research and social development projects in Zhejiang province: 2013C33206, Conflict of Interest: None
Purpose: To assess the levels of D-dimer baseline levels in inoperable metastatic colorectal cancer (mCRC) patients treated with bevacizumab and its relationship with prognosis.
Materials and Methods: From June 1, 2011 to December 31, 2013, a total of 121 patients with mCRC received beacizumab combined with chemotherapy and 74 of them were included in the present study. A nonparametric statistical test was performed to analyze the relationship between plasma D-dimer levels and clinical pathological factors. The Cox proportional model was used to analyze the effects of D-dimer on progression-free survival (PFS) time and overall survival (OS).
Results: Of the 74 cases, 40 were men and 34 women (aged 31-74 years), with a median age of 55.5 years. The median of PFS and OS were 6.3 and 17.8 months respectively. High levels of baseline plasma D-dimer were correlated with high scoring of Eastern Cooperative Oncology Group-Performance Status (P = 0.001), IV phase of disease at the first visit (P = 0.001), unremoval primary focal (P = 0.006), the number of metastatic organs ≥ 2 (P = 0.034), abdominal cavity effusion (P = 0.004) and no history of adjuvant chemotherapy (P = 0.003). It was found by single factor analysis that plasma baseline D-dimer levels ≥ 1.9 μg/mL were closely related with a short PFS (hazard ratio [HR] 2.14, 95% confidence interval [CI] 1.04-4.40, P = 0.038) and OS (HR 5.22, 95% CI 2.05-13.28, P = 0.001). After adjustment for other factors, plasma baseline D-dimer levels ≥ 1.9 μg/mL were still closely correlated with a short OS (HR 3.52, 95% CI 1.28-9.67, P = 0.015).
Conclusion: High levels of plasma baseline D-dimer correlated with high tumor load, advanced disease status and poor prognosis of inoperable mCRC patients treated with bevacizumab. However, clinical research on a much larger cohort of patients will be required to verify these findings.
Keywords: Bevacizumab, colorectal cancer, D-dimer, metastases, prognostic
|How to cite this article:|
Zhu L, Liu B, Zhao Y, Liu L, Yang C, Yang Y, Zhong H. High levels of D-dimer correlated with disease status and poor prognosis of inoperable metastatic colorectal cancer patients treated with bevacizumab. J Can Res Ther 2014;10, Suppl S4:246-51
|How to cite this URL:|
Zhu L, Liu B, Zhao Y, Liu L, Yang C, Yang Y, Zhong H. High levels of D-dimer correlated with disease status and poor prognosis of inoperable metastatic colorectal cancer patients treated with bevacizumab. J Can Res Ther [serial online] 2014 [cited 2021 Sep 16];10:246-51. Available from: https://www.cancerjournal.net/text.asp?2014/10/8/246/151451
| > Introduction|| |
D-dimer is a specific degradation product of cross-linked fibrin (so named because it contains two cross-linked D fragments of the fibrin protein) that is produced when the fibrinolytic system acts on the fibrin matrix present in blood clots.  It is normally present at very low concentrations in normal human plasma and increased levels reflect the activation of the blood coagulation and fibrinolysis system. Its main use is to exclude thromboembolic disease. Several important applications include the exclusion of a diagnosis of venous thrombosis, diagnosis of disseminated intravascular coagulation and evaluation of the therapeutic effects of thrombolysis.
Malignant tumor patients are often in a high coagulation state, and it has been demonstrated that venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and arterial embolism are the second leading cause of death in cancer patients.  As a marker of high coagulation and fibrinolytic states, an increase in plasma D-dimer levels is closely correlated with a shortened survival time and increased risk of death in some cancer patients, but its relationship with prognosis is independent of thrombotic events. ,,
Colorectal cancer is the third most common malignant tumor worldwide, and multiple studies have shown that preoperative plasma D-dimer levels can predict lymph node metastasis, staging and prognosis of resectable colorectal cancer patients. However, the application level of plasma D-dimer in inoperable metastatic colorectal cancer (mCRC) patients remains unclear. Chemotherapy combined with beacizumab is the standard treatment regimen for first-and second-line mCRC. In the present study, we measured the plasma D-dimer levels in a set of consecutive inoperable mCRC patients before they were treated with beacizumab. The aim was to analyze factors that could influence D-dimer baseline levels and its relationship with prognosis in inoperable mCRC patients treated with bevacizumab.
| > Materials and methods|| |
Selection criteria of patients
In this retrospective observational study, subjects were mCRC patients in the tumor hospital of Zhejiang province who were treated with beacizumab combined with chemotherapy. The inclusion criteria were: Histologically diagnosed metastatic colorectal adenocarcinoma; plasma D-dimer detected <7 days before treatment; no R0 surgery opportunity; age ≥ 18 years; life expectancy >3 months; 0-2 points on the Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) score; sufficient reserves of bone marrow and liver and kidney function; patients had received at least one cycle of beacizumab treatment combined with chemotherapy; basic chemotherapy regimens were capecitabine and oxaliplatin or modified 5-fluorouracil (5-FU), leucovorin (LV) and oxaliplatin or fluorouracil, leucovorin, and irinotecan first-, second-line treatment; informed consent forms before treatment were signed. The exclusion criteria were: There was definite thrombotic disease before treatment commenced; medical treatment started within 4 weeks of palliative surgery in a hospital; metastases present in the central nervous system; uncontrollable hypertension; clinical evidence of infection or other inflammatory disease; blood coagulation dysfunction or patients treated with anticoagulation and thrombolysis medications; bleeding which needed hemostatic treatment; unhealed larger wound or had severe peptic ulcer; intestinal obstruction; pregnant and lactating women. The Ethics Committee of the tumor hospital in the Zhejiang province approved this study.
Detection of plasma D-dimer
Plasma D-dimer was detected by latex immunoturbidimetry using a Stago Revolution fully automated blood coagulation analyzer. The Liatest D-dimer kit was obtained from Diagnostica Stago S.A.S (Stago). Processing and analysis of all the blood samples closely followed the manufacturer's instructions. The measurable plasma D-dimer levels ranged from 0 to 20 μg/mL, with the upper normal value limit being 0.5 μg/mL.
Evaluation of progressive-free survival and overall survival
All of the patients received a chest, abdomen and pelvic baseline imaging (including enhanced computed tomography [CT], magnetic resonance imaging or positron emission tomography-CT) examination within 4 weeks of treatment, and were re-examined every 6-8 weeks during therapy and every 8-12 weeks after treatment. In the present study, progression-free survival (PFS) was defined as the period from the start of treatment to disease progression or death for any reason; overall survival (OS) was defined as the period from the start of treatment to the death of patients for any reason.
Statistical Package for the Social Sciences version 17.0 (SPSS, IBM, Armonk, NY, USA) software package was used for statistical analysis. Nonparametric tests were performed for the analysis of the relationship between plasma D-dimer levels and clinical pathological findings. The data were grouped by quartile of testing value and the Kaplan-Meier method used to estimate survival time and produce a survival curve. The Cox proportional model was employed for single factor analysis and variables of P < 0.05 and D-dimer levels were selected to enter the multi-factor model based on the results of single factor analysis. A backward stepwise regression method in a multi-factor Cox proportional hazards model was employed to analyze the effect of high levels of D-dimer on PFS and OS. P < 0.05 was considered to be a statistically significant difference.
| > Results|| |
From June 1, 2011 to December 31, 2013, a total of 121 mCRC patients was treated with beacizumab combined with chemotherapy. Of the 121 patients, 74 were included in our study, and their baseline characteristics are listed in [Table 1]. There were 40 men and 34 female (age range 31-74 years), with a median age of 55.5 years. They received beacizumab treatment on 1-28 occasions with a median of 6 times. The median of the follow-up time, PFS and OS were 18.4 months (6.3-30.4 months), 6.3 months (95% confidence interval [CI] 4.8-7.8 months) and 17.8 months (95% CI 12.1-23.5 months) respectively, by the end of follow-up in June 30, 2014.
|Table 1: Nonparametric test of the relationship between plasma D-dimer baseline levels and clinical pathological features|
Click here to view
Plasma D-dimer values in these 74 patients ranged from 0.19 to 16 μg/L with a median value of 0.94 μg/L. The first, second and third quartile levels were 0.56 μg/mL, 0.94 μg/mL and 1.9 μg/L respectively, with the levels in 14 cases within the upper limit of the normal range. Brachial vein and left renal vein thrombosis occurred in two patients after the second and fifth beacizumab treatment, and the baseline plasma D-dimer levels in these two patients were less than the median value. Nonparametric testing showed that the high level of baseline plasma D-dimer was closely correlated with the ECOG-PS score (P = 0.001), IV phase disease at the first visit (P = 0.001), an unremoved primary focus (P = 0.006), the number of metastatic organs ≥ 2 (P = 0.034), abdominal cavity effusion (P = 0.004) and no history of adjuvant chemotherapy (P = 0.003) [Table 1].
D-dimer was grouped according to its quartile, and the PFS and OS curve of each group are shown in [Figure 1]. We used the Cox proportional model for single factor analysis of D-dimer subgroups and other factors, and found that the baseline plasma D-dimer levels ≥ 1.9 μg/mL were closely correlated with short PFS (hazard ratio [HR] 2.14, 95% CI 1.04-4.40, P = 0.038) and OS (HR 5.22, 95% CI 2.05-13.28, P = 0.001) [Table 2]. Based on the results of single factor analysis, variables of P < 0.05 were selected to process in the multi-factor model. After the later analysis, baseline plasma D-dimer levels ≥ 1.9 μg/mL were still closely related with a short OS (HR 3.52, 95% CI 1.28-9.67, P = 0.015) after adjustment for the ECOG-PS score, whether the primary cancer focus was removed or the number of metastatic organs and therapeutic qualities considered [Table 3].
|Figure 1: Progression-free survival and overall survival curve of plasma D-dimer quartile subgroups|
Click here to view
|Table 2: Single factor analysis of the relationship between plasma D - dimer and clinical pathological features, PFS and OS|
Click here to view
|Table 3: Multi - factor analysis of relationship between plasma D - dimer and clinical pathological features, PFS and OS|
Click here to view
| > Discussion|| |
Malignant tumors have the characteristics of invasion and metastasis and may influence the exogenous coagulation system by activating it through cancer procoagulation, tissue factor, plasminogen activator inhibitor 1 and human fibrinogen-like protein 2. Locally produced fibrinolytic enzyme could degrade the extracellular matrix barrier and thereby facilitate local invasion and distant metastasis. ,,, Many articles have reported that plasma D-dimer levels can be used to judge the disease stage, prognosis of many solid tumors and predict the incidence of thrombotic events in cancer patients. ,,,,,,,
Research on the application value of plasma D-dimer in colorectal cancer was carried out in the 1990s. Edwards et al. reported a correlation between higher plasma D-dimer level in patients with advanced but operable colorectal cancer, especially in those patients in Dukes' stage C.  Oya et al. found that preoperative plasma D-dimer levels in colorectal cancer patients were related to tumor size, invasion depth, lymph node metastasis, vascular invasion, and liver metastasis. It is noteworthy that the postoperative survival time of these patients could be predicted based on D-dimer levels. , Subsequent studies have confirmed these findings. , Because the formation of deep vein thrombosis may affect the prognosis of patients, Stender et al. further designed a prospective cohort study to eliminate the effect of this factor.  The results suggested that for colorectal cancer patients without deep vein thrombosis pre- or post-operatively, the 1-year survival rate of patients with preoperative plasma D-dimer levels above 0.3 mg/L was 78.1%. It was 93.6% in patients with preoperative plasma D-dimer levels lower than this cut-off value, and the difference was statistically significant (HR = 3.6, 95% CI 3.6-3.6). Therefore, one can conclude that the relationship between D-dimer levels and the prognosis of operable colorectal cancer patients is independent of venous thrombosis events.
However, the prognostic value of plasma D-dimer levels in patients with inoperable mCRC was not clear. In a prospective Stage II clinical study that compared therapy with beacizumab combined with 5-FU/LV with simple 5-FU/LV for mCRC, Blackwell et al. reported that baseline plasma D-dimer levels had no detectable association with PFS, but was significantly correlated with some factors that reflect the more advanced state of the cancer such as carcinoembryonic antigen and albumin levels, distant metastasis, tumor load and the number of metastatic organs. The D-dimer levels were also an independent predictor of OS, and the authors concluded that D-dimer may be a useful marker for antiangiogenic therapy and should be included in the prognosis model of mCRC.  Yamamoto et al. measured the plasma D-dimer levels of 42 patients with progressive or recurrent inoperable mCRC before chemotherapy and found that the levels were closely correlated with the modified Glasgow prognostic factor score (mGPS). Single factor analysis suggested that age, progression or progression-free disease, plasma D-dimer levels, and mGPS were associated with prognosis, but only the plasma D-dimer level was an independent prognostic factor after multiple factor analysis. 
Currently, beacizumab has been widely used in the treatment of inoperable mCRC patients, but not all patients treated with beacizumab were analyzed in Blackwell et al. and Yamamoto's et al. investigation. As far as we are aware, to date no study on the relationship of plasma D-dimer levels with prognosis of inoperable mCRC patients treated with bevacizumab has been published.
The plasma D-dimer levels of patients in our study were detected before treatment with beacizumab combined with chemotherapy, and the results suggest that a high baseline plasma D-dimer level is closely correlated with a high ECOG-PS score, IV phase disease at the first visit, unremoval primary cancer focus, metastatic organs ≥2, abdominal cavity effusion and no history of adjuvant chemotherapy. These results are similar to those of Blackwell et al. and Tellioglu et al., ,, and suggest that high levels of baseline plasma D-dimer are a good marker for a higher tumor load and more advanced disease status.
D-dimer was grouped by quartile and incorporated into the Cox proportional model for analysis. Single factor analysis found that a baseline plasma D-dimer level ≥1.9 μg/mL was closely related to short PFS and OS, but it was only closely related to the OS after multiple factor analysis. Thus, baseline plasma D-dimer levels ≥1.9 μg/mL in this group of patients were an independent prognostic factor for OS. In the report of the relationship between D-dimer and prognosis of patients with various types of cancer by Ay et al., the survival rate of patients was declined significantly with an increase in D-dimer levels in the quartile subgroup,  but our data only reached statistical significance in the third quartile group. In multiple factor analysis, the risk ratio of OS in the two subgroups after the first quartile and before the third quartile was 1.58 and 0.80 respectively. The data did not reflect the consistent trend reported in Ay's study, which may be due to a larger sampling error or that D-dimer <1.9 μg/mL was not a reliable marker of patient survival time. But considering that sample size of Ay's study was up to 1178 patients, and survival difference among D-dimer subgroups was obvious, the reason for failing to present the trend of D-dimer levels with survival is most likely attributable to a larger sampling error.
| > Conclusion|| |
Our study shows unequivocally that high levels of baseline plasma D-dimer are closely correlated with a more advanced disease status and poor prognosis of inoperable mCRC patients who have been treated with beacizumab. Our study was unable to follow the trend of D-dimer levels with prognosis due to the small sample size, and also failed to detect sufficient thrombotic events after the therapy. Thus, the influence of thrombotic events on prognosis could not be evaluated, and a study using a larger cohort of patients will be necessary to confirm our conclusions.
| > References|| |
Adam SS, Key NS, Greenberg CS. D-dimer antigen: Current concepts and future prospects. Blood 2009;113:2878-87.
Farge D, Durant C, Villiers S, Long A, Mahr A, Marty M, et al.
Lessons from French National Guidelines on the treatment of venous thrombosis and central venous catheter thrombosis in cancer patients. Thromb Res 2010;125 Suppl 2:S108-16.
Stender MT, Larsen TB, Sørensen HT, Thorlacius-Ussing O. Preoperative plasma D-dimer predicts 1-year survival in colorectal cancer patients with absence of venous thromboembolism (VTE): A prospective clinical cohort study. J Thromb Haemost 2012;10:2027-31.
Ay C, Dunkler D, Pirker R, Thaler J, Quehenberger P, Wagner O, et al.
High D-dimer levels are associated with poor prognosis in cancer patients. Haematologica 2012;97:1158-64.
Zhang PP, Sun JW, Wang XY, Liu XM, Li K. Preoperative plasma D-dimer levels predict survival in patients with operable non-small cell lung cancer independently of venous thromboembolism. Eur J Surg Oncol 2013;39:951-6.
Kvolik S, Jukic M, Matijevic M, Marjanovic K, Glavas-Obrovac L. An overview of coagulation disorders in cancer patients. Surg Oncol 2010;19:e33-46.
Hernández C, Orbe J, Roncal C, Alvarez-Hernandez M, Martinez de Lizarrondo S, Alves MT, et al.
Tissue factor expressed by microparticles is associated with mortality but not with thrombosis in cancer patients. Thromb Haemost 2013;110:598-608.
Ramer R, Rohde A, Merkord J, Rohde H, Hinz B. Decrease of plasminogen activator inhibitor-1 may contribute to the anti-invasive action of cannabidiol on human lung cancer cells. Pharm Res 2010;27:2162-74.
Su K, Chen F, Yan WM, Zeng QL, Xu L, Xi D, et al.
Fibrinogen-like protein 2/fibroleukin prothrombinase contributes to tumor hypercoagulability via IL-2 and IFN-gamma. World J Gastroenterol 2008;14:5980-9.
Suega K, Bakta IM. Correlation between clinical stage of solid tumor and D dimer as a marker of coagulation activation. Acta Med Indones 2011;43:162-7.
Mytnik M, Stasko J. D-dimer, plasminogen activator inhibitor-1, prothrombin fragments and protein C - Role in prothrombotic state of colorectal cancer. Neoplasma 2011;58:235-8.
Diao D, Zhu K, Wang Z, Cheng Y, Li K, Pei L, et al.
Prognostic value of the D-dimer test in oesophageal cancer during the perioperative period. J Surg Oncol 2013;108:34-41.
Kodama J, Seki N, Fukushima C, Kusumoto T, Nakamura K, Hongo A, et al.
Elevated preoperative plasma D-dimer levels and the incidence of venous thromboembolism in Japanese females with gynecological cancer. Oncol Lett 2013;5:299-304.
Roselli M, Ferroni P, Portarena I, Riondino S, La Farina F, Formica V, et al.
Predictive value of high-sensitive D-dimer determination for chemotherapy-associated venous thromboembolism in gastrointestinal cancer patients. Thromb Haemost 2012;108:1243-5.
Edwards CM, Warren J, Armstrong L, Donnelly PK. D-dimer: A useful marker of disease stage in surgery for colorectal cancer. Br J Surg 1993;80:1404-5.
Oya M, Akiyama Y, Yanagida T, Akao S, Ishikawa H. Plasma D-dimer level in patients with colorectal cancer: Its role as a tumor marker. Surg Today 1998;28:373-8.
Oya M, Akiyama Y, Okuyama T, Ishikawa H. High preoperative plasma D-dimer level is associated with advanced tumor stage and short survival after curative resection in patients with colorectal cancer. Jpn J Clin Oncol 2001;31:388-94.
Xu G, Zhang YL, Huang W. Relationship between plasma D-dimer levels and clinicopathologic parameters in resectable colorectal cancer patients. World J Gastroenterol 2004;10:922-3.
Kilic M, Yoldas O, Keskek M, Ertan T, Tez M, Gocmen E, et al.
Prognostic value of plasma D-dimer levels in patients with colorectal cancer. Colorectal Dis 2008;10:238-41.
Blackwell K, Hurwitz H, Liebérman G, Novotny W, Snyder S, Dewhirst M, et al
. Circulating D-dimer levels are better predictors of overall survival and disease progression than carcinoembryonic antigen levels in patients with metastatic colorectal carcinoma. Cancer 2004;101:77-82.
Yamamoto M, Yoshinaga K, Matsuyama A, Iwasa T, Osoegawa A, Tsujita E, et al.
Plasma D-dimer level as a mortality predictor in patients with advanced or recurrent colorectal cancer. Oncology 2012;83:10-5.
Tellioglu G, Agcaoglu O, Siperstein A, Berber E. Serum D-dimer as a prognostic marker in patients undergoing radiofrequency ablation of colorectal liver metastasis. J Invest Surg 2012;25:295-300.
[Table 1], [Table 2], [Table 3]