Fibrinogen is one of the important parameters concerning the relationship between malignancy and coagulation disorders. A link between hyperfibrinogenemia and malignant diseases has previously been revealed. It is increasingly recognized that fibrinogen levels have prognostic significance in several cancers. In our study, we assessed the effect of plasma fibrinogen levels on advanced NSCLC in 160 patients.
To our knowledge, previous studies related to fibrinogen in tumors were mainly focused on its prognostic value [16
], while there have been few studies where the fibrinogen level has been used for evaluating response to chemotherapy [23
]. There are two studies in which the relationship between fibrinogen level and therapeutic response have been assessed in SCCL. The first study was carried out on 37 patients, and revealed that patients not responding to chemotherapy had higher fibrinopeptide A levels than those who responded to chemotherapy. In contrast, patients with a prolonged CR did not exhibit evidence of abnormal thrombin activity [28
]. In the second study carried out on 119 patients, higher pre-treatment fibrinogen levels at diagnosis reflected a more advanced stage of disease, and were also associated with a reduced likelihood of a positive response to chemotherapy and a lower OS. This effect was more apparent in SCCL patients with limited stage disease [29
]. In NSCLC, a small study including 49 patients with unresectable locally advanced or metastatic lung cancer has been carried out. The data showed that the average basal levels of fibrinogen were high but remained constant after chemotherapy in these 49 NSCLC patients [30
]. Our study analyzed the relationship between the basal level of fibrinogen and chemotherapy-induced changes in fibrinogen, and chemotherapy response. The results showed that fibrinogen levels decreased significantly in 98 patients with pre-chemotherapy hyperfibrinogenemia, but the decrease was not significant in the 160 patients. This was, in part, in accordance with findings for other malignancies. The potential reasons for this where that the pre-chemotherapy fibrinogen level in some of the patients that responded to chemotherapy was normal, and may not have significantly decreased after chemotherapy. In addition, the sample size was small. Therefore, these findings should encourage the initiation of further large scale trials to confirm the hypothesis that elevated fibrinogen can represent poor responsiveness to chemotherapy in advanced NSCLC.
In previous large multicenter studies involving patients with epithelial ovarian cancer and endometrial cancer, it was reported that pre-therapeutic plasma fibrinogen levels could be used as an independent prognostic parameter for disease-free and overall survival [24
]. Tang et al. found that high pre-operative plasma fibrinogen levels were associated with distant metastases and impaired prognosis, after curative resection in patients with colorectal cancer [22
]. Yamashita et al. suggested that the pre-operative plasma fibrinogen level could be a useful predictor of lymphatic metastasis in intestinal-type gastric cancer [20
]. A study involving 93 patients with NSCLC who underwent surgical resection demonstrated that high plasma fibrinogen levels were correlated with increasing tumor size, advanced pathological T stage, squamous cell carcinoma and a poor prognosis. Another study that enrolled patients with advanced NSCLC demonstrated that reduced survival was associated with higher fibrinogen levels [18
]. In our study, similar results raise the possibility that the pre-chemotherapy plasma fibrinogen level was associated with OS in NSCLC. This is in accordance with previously published data in patients with other malignancies, reflecting the fact that fibrinogen can be used as an independent prognostic parameter for survival.
The proliferative characteristics of tumor cells and the interaction with different stromal cells and supportive tissue govern how the tumors grow. It has been determined that most solid tumors contain a substantial amount of fibrinogen and fibrin, the fibrous protein into which fibrinogen is transformed. This is frequently deposited around solid tumors, suggesting that fibrinogen may promote the formation of tumor stroma. Along with other adhesive glycoproteins, fibrinogen forms a coating on the surfaces of tumor cells, and serves as a scaffold to support the binding of growth factors and to promote tumor cell dispersion in a manner analogous to wound repair. Simultaneously, the coating of fibrinogen could also protect tumor cells from immune surveillance and prolong malignant cell survival [31
It is a general opinion that advanced cancer and anorexia-cachexia syndrome are often associated with an inflammatory response [32
]. Increasing age is linked to a higher state of subclinical inflammation and an increased production of proinflammatory cytokines [26
]. Patients enrolled in the present study were all diagnosed with advanced NSCLC. Elderly patients and those with weaker performance status seem to have higher levels of plasma fibrinogen. Fibrinogen level was significantly correlated with WBC and platelet counts in our study. This is probably evidence that high fibrinogen levels are indicative of, not only a coagulation factor but also an acute-phase reactant protein that is greatly enhanced in response to infection and other inflammatory disorders. However, the precise mechanisms involved have not been fully clarified. Interleukin-6 (IL-6), which is believed to be the key cytokine, is capable of stimulating hepatocyte fibrinogen synthesis [34
]. In contrast, another important inflammatory cytokine, IL-1, has been shown to inhibit fibrinogen synthesis [35
]. Higher fibrinogen levels have often been observed to be significantly associated with reduced hemoglobin levels, indicating that hypoxia might induce an increase in fibrinogen levels. Thus, the regulation of fibrinogen synthesis during inflammation appears to be quite complicated.
The role of the serum tumor markers in advanced NSCLC is controversial [36
]. Several reports have been published concerning the prognostic value of CEA; there have been fewer reports on CA-125[38
]. CEA is a serum tumor marker that is expressed in numerous solid tumors. There are discordant findings with regard to the accuracy of pretreatment levels of CEA in predicting prognosis in advanced NSCLC patients. In a study by Jin et al. involving 111 advanced NSCLC patients, CEA level was found to be useful in evaluating chemotherapy response, and baseline CEA level was shown to be a significant predictive factor for OS [40
]. Susana et al. reported on 277 advanced NSCLC patients where high baseline levels of CEA were found to be a significant negative prognostic factor [38
]. Similar results have been reported by other authors [41
]. However, the results of other studies have indicated that CEA level was not useful in the prognostic evaluation of NSCLC patients [43
]. Similarly, in the studies of Kulpa et al. and Ardizzoni et al. involving 107 patients with advanced-stage squamous cell lung cancer and 200 patients with stage I-IV non small cell lung cancer, respectively, CEA was not found to be a prognostic factor for survival [36
]. In our current study, the change in CEA levels before and after chemotherapy was correlated with therapeutic response (DCR group) and we did not find that it was a significant prognostic factor for OS.
The role of CA125 in NSCLC is not well known. Trapé et al. reported that CA125 could be a predictive factor for response to treatment and a prognostic factor for survival in patients with NSCLC treated with chemotherapy [39
]. In a study by Susana et al., CA125 level was found to have increased in approximately half of the population and this marker had a significant prognostic value [38
]. In our study, CA125 levels decreased significantly after chemotherapy in the DCR group and had prognostic value for OS.