Serum fibrinogen levels are positively correlated with advanced tumor stage and poor survival in patients with gastric cancer undergoing gastrectomy: a large cohort retrospective study

Gastric cancer (GC) is one of the most common malignancies and the third leading cause of cancer related death worldwide [1]. Early diagnosis of GC is very difficult, and the majority of GC cases are diagnosed during advanced stages with distant metastasis [2]. GC incidence and mortality are particularly high in Asia [2]. According to the 2012 estimations of the World Health Organization’s GLOBOCAN project, the age standardized rates (ASR) of GC incidence and mortality in Asia were 15.8 and 11.7 per 100,000, respectively [2].

Although advancements have been made in GC chemotherapy and local control, patient prognosis remains poor. The overall 5-year survival rate of patients with GC is estimated to be between 10 and 30 % in US and Europe. However, large regional differences exist between eastern and western nations. For instance, survival rates in Japan have been reported to range from 50 to 70 % [3]. The most prominent prognostic factors affecting the outcome and survival of GC patients are tumor related factors, including tumor size, lymph node metastasis, the degree of tumor cell differentiation, the extent of tumor invasion and the presence of distant metastasis [4‐9]. Studies suggest that increasing tumor size, advanced TNM stages and poor differentiation are all important indicators of aggressive GC and predict worse outcome [10, 11].

It is increasingly being recognized that, in addition to tumor related factors, GC patient prognosis is also affected by operation and patient related factors [12]. For example, intraoperative blood loss and transfusion delay are associated with worse post-surgical patient outcomes [12]. Additionally, age, sex, inflammatory response, abnormal blood coagulation and comorbidity have also been correlated with poor survival and prognosis [13, 14].

Platelet and blood coagulation abnormalities occur frequently in cancer patients. Thrombocytosis is considered an important risk factor, and it is associated with poor GC prognosis [14]. Fibrinogen is a 340-kDa glycoprotein that is primarily produced by hepatic cells, and is an important clotting factor that helps regulate the hemostatic pathway [15]. Fibrinogen is converted into fibrin, a final product of hemostatic system, through the proteolytic effect of thrombin [15]. Fibrinogen plays important roles in blood coagulation, cell-cell adhesion and the inflammatory response [15]. Elevated fibrinogen is a well-known predictor of cardiovascular events and an independent predictor of mortality in patients with chronic kidney disease [16]. Additionally, recent studies have suggested that elevated fibrinogen promotes cancer cell growth, progression and metastasis [17‐21]. Furthermore, plasma fibrinogen levels have been associated with tumor size, tumor invasion and lymph node metastasis in patients with various cancers [15]. In advanced GC, elevated fibrinogen levels have been associated with metastasis and tumor progression [15, 22]. Moreover, it has been reported that preoperative plasma fibrinogen levels are a useful predictor of lymphatic and hematogenous metastasis in GC [22, 23].

Hyperfibrinogenemia is increasingly being recognized as an important risk factor influencing cancer development and outcome. However, few reports have investigated the use of fibrinogen as a prognostic biomarker for GC patient survival. The primary aim of this study was to evaluate the usefulness of preoperative serum fibrinogen (FBG) as a biomarker for predicating tumor progression and survival of patients with GC. Additionally, we investigated the effects of multiple risk factors on the survival of GC patients.

In this comprehensive retrospective study of the risk factors influencing GC patient survival after gastrectomy, we analyzed patient-related, tumor-related and operation-related demographic and clinicopathological data from 1196 patients who were treated for operable GC in Harbin Medical University Cancer Hospital between 2005 and 2007. The results of our study indicate that many factors influence the survival rates and survival time of post-surgical GC patients. However, the most important finding reported by this study is that serum FBG levels are positively correlated with the progression and metastasis of GC. Thus, our results indicate that FBG is an independent risk factor that can be used to predict GC patient survival. Additionally, our results confirm the importance of other well-known tumor-related and operation-related factors.

FBG is an acute-phase protein that regulates clotting and fibrinolysis, and hyperfibrinogenemia has frequently been linked with a number of malignancies [20, 21, 25]. It is thought that the link between hyperfibrinogenemia and cancer may be related to the systemic activation of the clotting system observed in many cancer patients [26]. Two possible mechanisms underlying this relationship include cancer cell driven stimulation of FBG levels by direct activation of the clotting response to produce procoagulant factors (including FBG), and indirect stimulation of mononuclear cells to secrete these factors [27]. A strong correlation between FBG and enlarged tumor size, increased tumor growth, increased metastatic potential and poor prognosis in various cancers is increasing being recognized [17‐21, 25]. Preston et al. [28] reported that fibrinogen production was elevated in pancreatic adenocarcinoma patients. Shen et al. [20] examined FBG levels in 567 patients with operable non-small cell lung cancer and reported that serum fibrinogen was an independent prognostic factor. Patients with hyperfibrinogenemia in the Shen et al. study had a higher risk of disease progression and mortality when compared with patients that had normal fibrinogen levels [20]. Tanaka et al. [25] reported that preoperative plasma fibrinogen levels higher than 450 mg/dL were an independent risk factor of subsequent tumor recurrence and cancer-specific survival in patients with localized upper tract urothelial carcinomas. Additionally, Tanaka et al. demonstrated that high plasma fibrinogen levels predicted worse pathological features and positive lymphovascular invasion [20]. Lee et al. [15, 29] reported that tumor size, tumor depth, tumor extent, lymph node metastasis and poor patient survival were positively correlated with preoperative plasma fibrinogen levels in advanced GC.

To determine the diagnostic value of serum FBG levels, ROC curve analysis was performed and an area under the curve (AUC) with a 95 % confidence interval (CI) was derived. We set an FBG cut off value of 4.0 g/L. When the FBG cut-off value was ≤ 3.68 g/L, the sensitivity was 78.8 % and the specificity was 40.7 %. A previous study reported that when plasma fibrinogen levels > 402 mg/dL were defined as hyperfibrinogenemia based on ROC curve analysis, fibrinogen concentration had a PPV of 92.73 % [30].

Our current study supports the hypothesis that plasma FBG levels are positively correlated with the advanced T stages, N stages and pathological stages of GC. Furthermore, our results indicate that FBG is an important independent factor that influences the survival of GC patients. These findings are consistent with the findings of previous studies [15, 29] and indicate that elevated fibrinogen levels are associated with advanced GC metastasis and tumor progression [15, 22]. Therefore, serum fibrinogen may be a useful biomarker for the identification of patients with clinically advanced GC. Additionally, preoperative plasma fibrinogen level is a useful predictor of adjacent organ involvement in advanced GC patients [15]. It may also be useful to monitor serum FBG levels during ongoing patient management. This report does not discuss patient management, and a future manuscript will discuss the effects of various therapies on fibrinogen levels in patients with gastric cancer. Although serum FBG is a valuable marker, levels could be affected by underlying disease, such as, for example, in cardiac infarction.

Hyperfibrinogenemia may help provide favorable conditions for cancer cell metastasis via the lymphatic system [22], and preoperative plasma fibrinogen levels are a useful predictor of lymphatic as well as hematogenous metastasis in GC [22, 23]. However, the molecular mechanisms through which fibrinogen promotes tumor metastasis remain unclear. Fibrinogen is a dimeric molecule and has various integrin and non-integrin binding motifs. Because cancer cells usually produce an elevated number of fibrinogen receptors (eg α5β1, αvβ3 integrins and the ICAM-1 molecule), some scholars have proposed that fibrinogen may facilitate tumor and host cell interactions, thus facilitating tumor cell metastasis. Another possible metastasis promoting mechanism is the fibrinogen-facilitated formation of large tumor cell aggregates with platelet αIIbβ3 integrin receptors. By forming these large aggregates, cancer cells are able to avoid detection by the innate immune system and, thus, the metastatic potential of the aggregated cells is increased [23, 31, 32]. A third possible metastasis promoting mechanism is caused by a positive feedback loop between cancer induced inflammation and fibrinogen levels. The increased systemic inflammatory response caused by cancer progression greatly enhances the levels of fibrinogen, and the elevated fibrinogen, in turn, promotes cancer cell metastasis [22].

In addition to FBG levels, we also analyzed the levels of CEA and CA19-9 in GC patients. Both CEA and CA19-9 are well known GC biomarkers [3, 33]. In the present study, we confirmed that patients with higher CEA and CA19-9 levels had a greatly reduced survival time. According to the multivariate analysis conducted in our study, elevated serum CA19-9 levels were an independent predictor of poor survival in GC patients, but CEA levels were not. However, our results indicate that FBG levels may be a better GC biomarker when compared with CEA and CA19-9 levels.

Interestingly, univariate analysis indicated that patient related factors, including age, sex, BMI and comorbidity, had no effect on patient survival. The only exception was a family history of GC. Regarding patient age, the results of our analysis differ from a previous report by Liang et al. [34]. In the Liang et al. study, the authors claimed that patient age greater than 70 years was an independent prognostic factor for GC after gastrectomy, and elderly patients (OS: 22.0 %) had a significantly lower 5-year OS rate when compared with younger (OS: 36.6 %) and middle-aged patients (OS: 38.0 %). Inokuchi et al. [35] reported that comorbidity predicted post-gastrectomy complications in patients with large GC tumors. However, our results indicate that patients both with and without comorbidities have similar median survival times. The differences between the results of our current study and the Inokuchi et al. report is likely due to differences in the severity of comorbidities in each patient population.

We found that patients with a family history of GC have shorter survival times when compared with patients without any family history of GC (41.3 months vs. 44.4 months). This finding is in accordance with a report from Liang et al. [36]. In the Liang et al. report, they compared the clinicopathological characteristics of 91 patients with familial GC (FGC) and 293 patients with sporadic GC (SGC). They reported that the 5-year overall survival rate in the FGC patients was significantly lower than that in the SCG patients (25.6 % vs. 38.9 %, p = 0.001). FGC was correlated with poor GC differentiation and prognosis.

Various studies have suggested that tumor size not only determines the extent of disease, tumor metastasis and invasion, but that it also predicts patient survival [13‐15]. Tumor size has been reported to be an independent prognostic factor, and a modified TNM system based on tumor size accurately predicts patient survival [11]. In the present study, univariate analysis suggested that patients with tumors larger than 5 cm had a shorter survival time when compared with patients that had tumors smaller than 5 cm. Although there were significant differences, tumor size was not found to be an independent predictor of patient survival by our multivariate analysis. Our study agrees with the report from Lu et al. [10]. However, other reports have suggested that tumor size is an independent predictor of patient survival [37]. In addition to tumor size, tumor location is another factor that may influence patient survival. We found that the tumors located in the upper and medium gastric areas were associated with a poor patient prognosis. However, multivariate analysis did not find that tumor location was an independent factor. In contrast with tumor size and location, multivariate analysis indicated that poor differentiation, deep invasion and lymph node metastasis were independent factors.

Lymph node metastasis and advanced TNM stage are considered the most important factors for the prediction of recurrence and survival in GC patients [4‐9]. Lymph node metastases are observed in more than 50 % of GC patients at the time of diagnosis. The 5-year survival rate of patients with lymph node metastasis is reported to be approximately 30 % [9]. The analysis reported here confirms that lymph node metastasis is a critical prognostic factor in GC patients, and that lymph node metastasis correlates strongly with shorter survival time and poor patient prognosis. In addition to lymph node metastasis, we also found that GC invasion of other organs was an independent risk factor for survival.

Surgery is an important factor in the treatment of GC patients, and operation related factors are another type of important risk factor associated with patient mortality and survival. Operational factors that we examined in the present study include the mode of lymph node dissection, operational time, intraoperative blood loss and transfusion treatment. Our analysis indicated that radical lymph node dissection is an independent favorable factor for GC patient survival. Patients that received radical lymph node dissection survived as long as 52 months, while those who did not receive the therapy survived less than one and half a years. A previous report suggested that intraoperative blood loss was an independent prognostic factor for GC patients who had undergone curative resection [12]. Reducing intraoperative blood loss improved the long-term outcome of GC patients treated with curative gastrectomy [12]. In the present study, we did not conduct multivariate analysis on intraoperative blood loss; therefore, we are unable to conclude that intraoperative blood loss is an independent risk factor for survival. However, we do confirm that certain operational factors (operational time more than 150 min, blood loss more than 200 ml and insufficient or delayed blood transfusion) are associated with GC patient survival. Notably, the receipt of a blood transfusion can significantly shorten survival time.

Although this is a comprehensive study related to FBG and other prognostic factors in GC patients, we did not conduct further analysis of risk factors that could affect serum FBG levels.

Preoperative hyperfibrinogenemia is correlated with GC progression, and FBG levels are an independent risk factor of GC patient survival in patients with operable GC. Additionally, serum fibrinogen is a useful biomarker for patients with clinically advanced GC. Furthermore, tumor and operative factors (non-radical lymph node dissection, multi-organ involvement, advanced TNM stages and poor tumor differentiation) and CA199 levels are independent prognostic factors that are also associated with poor GC patient survival after gastrectomy.

ASR, age standardized rates; AUC, area under the curve; CA199, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CI, confidence interval; CI, confidence intervals; FBG, fibrinogen; FGC, familial GC; GC, gastric cancer; HR, hazard ratio; MST, median survival time; OS, overall survival; ROC, receiver operating characteristic; SD, standard deviation; SGC, sporadic GC