Elsevier

Clinical Oncology

Volume 19, Issue 7, September 2007, Pages 494-498
Clinical Oncology

Original article
High Plasma d-dimer Level is Associated with Decreased Survival in Patients with Lung Cancer

https://doi.org/10.1016/j.clon.2007.04.002Get rights and content

Abstract

Aims

An elevated plasma d-dimer level indicates the activation of coagulation and fibrinolysis. In the present study, we investigated the association of pre-treatment haemostatic parameters (d-dimer, fibrinogen and prothrombin fragment 1+2) with clinicopathological parameters and outcome in patients with lung cancer.

Materials and methods

Plasma levels of d-dimer and other parameters were measured in 78 evaluable patients with lung cancer (60 non-small cell lung cancers, 18 small cell lung cancers). At diagnosis, 35 patients (44.9%) were locally advanced stage (IIIA/B) and 43 patients (55.1%) had metastatic disease (IV). Multivariate statistical analysis was carried out using Cox's proportional hazards model. The receiver operating characteristic curve was used to determine the cut-off values for d-dimer, fibrinogen and prothrombin fragment 1+2.

Results

The median survival for all patients was 264 days (95% confidence interval 200–328 days). A significant association between the plasma levels of d-dimer and the response to chemotherapy was observed (P = 0.03). With the univariate analysis, tumour stage, pre-treatment plasma levels of d-dimer, fibrinogen, platelet count, lactate dehydrogenase concentration and Karnofsky performance status were predictive for survival. With the multivariate analysis (P  0.1), the plasma level of d-dimer (P < 0.001), tumour stage (P = 0.01) and Karnofsky performance status (P = 0.02) were identified as independent predictive factors. The median survival times were 405 days (95% confidence interval 165–644 days) and 207 days (95% confidence interval 146–267 days, P < 0.001), respectively, for patients with a low d-dimer level (≤0.65 μg/ml) and a high d-dimer level (>0.65 μg/ml).

Conclusions

Elevated plasma levels of d-dimer in patients with lung cancer are associated with decreased survival and a poor response to treatment. Pre-treatment for the d-dimer level may be useful in the prediction of survival and the response to treatment.

Introduction

The activation of coagulation and fibrinolysis is frequently associated with malignancy, although the mechanism involved is not completely understood. About 90% of cancer patients with metastatic disease and one-half of patients with cancer have abnormal coagulation parameters [1]. The extent of such activation has been reported to correlate with tumour stage and prognosis in some malignancies, such as lung, breast and colorectal cancer 2, 3, 4, 5, 6, 7, 8.

Tumour cells can produce procoagulant molecules that activate coagulation either directly or indirectly by initiating an inflammatory response. Oncogenic events in cancer cells (e.g. the expression of mutant K-ras, epidermal growth factor receptor (EGFR), phosphatase and tensin homologue (PTEN) or p53) lead to an increase in procoagulant molecule levels and activity, and thereby promote tumour aggressiveness, angiogenesis and hypercoagulability [9]. Several biologically active plasmin and/or thrombin cleavage fragments of fibrinogen and/or cross-linked fibrin elicit pro-angiogenic or anti-angiogenic effects that may contribute to wound healing and tumorigenesis. Fibrinogen or fibrin fragment E, for example, can stimulate angiogenesis in some in vitro and in vivo assay systems 10, 11.

d-dimer is a stable end product of fibrin degradation and levels of d-dimer are elevated by enhanced fibrin formation and fibrinolysis [12]. Elevated plasma d-dimer levels have been reported to be associated with poor prognosis in patients with lung cancer 2, 7, 8. Fibrinogen is recognised by multiple integrin and non-integrin receptors found on tumour cells, stromal cells and inflammatory cells [13]. In one study, the poorer prognosis was noted in 286 lung cancer patients who had elevated fibrinogen, d-dimers and a prolonged prothrombin time [14]. Prothrombin fragment (F1+2) is generated during the conversion of prothrombin to thrombin by activated factor X. The upward trend in plasma levels of F1+2 has been correlated with an increased risk of death [15].

The aim of the present study was to analyse the association between pre-treatment plasma levels of d-dimer, fibrinogen and F1+2 and clinicopathological parameters, the response to chemotherapy and outcome in patients with lung cancer.

Section snippets

Materials and Methods

This study included 78 patients with histologically proven carcinoma of the lung (stage III–IV). The pre-treatment evaluation included a complete history, a physical examination with evaluation of the Karnofsky performance status (PS) score, a complete blood cell count and a serum chemistry analysis. All patients were classified according to the 1997 staging system [16]. All patients gave informed consent before entering this study.

Results

Between September 2004 and September 2005, 128 consecutive patients with lung cancer were admitted to the Trakya University Hospital. Eighty-four patients who had the inclusion criteria were prospectively enrolled into this study. Six of the 84 were not evaluated due to no follow-up. Therefore, 78 were included in the analysis. Patients had a median age of 61 years (range 37–82). The patients' characteristics are shown in Table 1.

The results of comparisons between the haemostatic parameters and

Discussion

The biological significance of the haemostatic abnormalities in cancer is not clear. There is some evidence to suggest that the capacity of neoplastic cells to activate the coagulation system and to express increased fibrinolytic activity facilitates their growth and contributes to their invasive and metastatic behaviour [6]. In lung cancer tissues, fibrin deposits may promote cell proliferation and neovascularisation of the growing tumour; they may protect tumour cells from immune or

References (22)

  • O. Taguchi et al.

    Prognostic significance of plasma D-dimer levels in patient with lung cancer

    Thorax

    (1997)
  • Cited by (109)

    View all citing articles on Scopus
    View full text