Preoperative fibrinogen / albumin ratio (FAR) Can be used to predict the prognosis of urothelial carcinoma patients after radical cystectomy

Purpose ： To explore the feasibility of preoperative fibrinogen / albumin ratio (FAR) as a predictor of the total and elderly patients with urothelial carcinoma after radical cystectomy. Methods ： A cohort of 275 patients who underwent radical cystectomy for bladder tumor at Peking University First Hospital from 2012 to 2016 was analyzed retrospectively. The optimal cut-off value of FAR group was determined according to the survival dependent receiver operating characteristic curve (survival-ROC). Kaplan-Meier curve was used to analysis the overall survival (OS), and Cox proportional


Introduction
Bladder cancer is the 9th common tumor type in the world and urothelial carcinoma is the most common pathological type (1) . For patients who have muscleinvasive bladder cancer (MIBC) or high grade non muscle-invasive bladder cancer, radical cystectomy is the main treatment option (2) .However, the long-term prognosis of most patients with underwent radical cystectomy is poor because the late stage or high malignancy. (3) .Therefore, it is very meaningful to find a factor that can predict the prognosis of patients with urothelial carcinoma underwent radical cystectomy.
Most tumor patients have hypercoagulable state (4) ,some studies have shown that serum high fibrinogen is related to poor prognosis of tumor patients (5,6) ,and fibrinogen has also been found to play a role in many parts of tumor development (7)(8)(9)(10) .Albumin is considered to be an objective indicator of nutritional status (11,12) ,low serum albumin level often indicates poor prognosis of tumor patients (13)(14)(15) .Previously, a retrospective study at Sun Yat sen University found that the preoperative fibrinogen / albumin ratio (FAR) can be used as a predictor of postoperative prognosis in patients with soft tissue sarcoma (16) .After that, many studies were exploring the feasibility of FAR in predicting prognosis of different pathological types of tumors (16)(17)(18)(19) .
However, there is no study to discuss the FAR value in predicting the prognosis of urothelial carcinoma patients after radical cystectomy. Here, we will explore the feasibility of FAR as a preoperative indicator to predict the prognosis of patients with urothelial carcinoma after radical cystectomy.

Patients and follow-up
Retrospective analysis the patients who underwent radical cystectomy for bladder tumor in the Peking University First Hospital from 2012 to 2016. The inclusion criteria included: 1) No neoadjuvant chemotherapy before surgery; 2) Survival more than 30 days after radical cystectomy; 3) Pathological type of bladder cancer is urothelial carcinoma; 4) Complete clinical data are maintained.
Postoperative follow-up was conducted by telephone, and the overall survival (OS)time was calculated from the surgery to October 2018 or the death of the patient. This study was approved by the Research Ethics Committee of Peking University First Hospital, Peking University.

Clinical information collection
Blood samples collected within one week before operation were used for laboratory test. The serum fibrinogen level, albumin level, leukocyte count, neutrophil count, lymphocyte count and platelet count were collected. The clinical information of patients, including gender, age, tumor pathology, BMI were collected by reviewing the medical records. The pathological stage of tumor was based on AJCC 8th Edition. FAR is defined as the ratio of serum fibrinogen(mg/dl) to albumin level(g/L), NLR as the ratio of neutrophil count to lymphocyte count, dNLR as the ratio of neutrophil count / (leukocyte count -neutrophil count), and PLR as the ratio of platelet count to lymphocyte count.

Statistical analysis
Chi-square ( 2 ) test was used for data expressed as percentages between different groups. According to the survival dependent receiver operating characteristic curve (survival-ROC), the maximum Youdan index (YI) was calculated to determine the optimal cut-off value, and the area under the curve (AUCs) was calculated. The survival curve was analyzed by Kaplan-Meier method and compared by log rank test. The survival rate was analyzed by Cox proportional risk model and positive step by step. Cox proportional hazards model was used to do univariate and multivariate analyses of survival. The hazard ratios (HR) and 95% confidence interval (CIs) were reported as relative risks. A two sides P < 0.05 was considered statistical difference. All statistical analysis was performed by R-4.0.0

Baseline information of patients and tumors
The demographic variables and clinicopathological characteristics of 275 cases included in this study are listed in Table 1     We then analyzed patients in different age subgroups. Although FAR had the highest AUCs in both subgroups, the AUC in the old patient subgroup was higher than that in the young patient subgroup (0.633 and 0.558, Figure 4).For old patient subgroup, in univariate analysis, AJCC stage (P < 0.001), FAR (P = 0.004), NLR (P = 0.017), pathological grade (P = 0.010) and low BMI (P = 0.039) were all associated with survival.
In multivariate analysis, only FAR (P = 0.023) and AJCC stage (P < 0.001) associated with survival. Cox regression showed that only AJCC stage (P < 0.001) was associated with survival in young patient subgroup (Table 4 and Table 5).   A meta-analysis which included 12 related studies showed that the survival rate of patients with high FAR was significantly lower than that of patients with low FAR (17) .
Although the fibrinogen / albumin ratio (FAR) has been widely reported to predict tumor prognosis recently (16,18,19) .But as far as we know, this is the first article to report FAR as an independent risk factor to predict the prognosis of patients with urothelial carcinoma after radical cystectomy.
Inflammation is considered to be an important participant in the occurrence, development and metastasis of tumors. Many inflammation related indicators, including the ratio of neutrophil count to lymphocyte count (NLR) (20)(21)(22)(23) 、the ratio of neutrophil count/( leukocyte count -neutrophil count) (dNLR) (20,22,24) and the ratio of platelet count to lymphocyte count (PLR) (19)(20)(21)(22)(23)(24) have been reported to be used to predict the prognosis of human tumors. However, in our study, these indicators can't be used as independent risk factors to predict the prognosis of patients with urothelial carcinoma after radical cystectomy. However, the underlying mechanism of why FAR could be used to predict tumor progression is still not completely clear. Current research shows that in tumor patients, the coagulation system is often activated abnormally, fibrinogen is an important hemostatic factor, tumor patients often show elevated serum fibrinogen level, and hyperfibrinogenemia is related to the poor prognosis of a variety of tumors (4,7,25,26) .
Fibrinogen also plays an important role in angiogenesis, which is conducive to the development of tumors (9,27) .In addition, as an acute phase response protein, fibrinogen can also reflect the state of systemic inflammatory reaction, which is closely related to the development of tumor (26,28) .As an extracellular matrix protein, it can regulate the growth of tumor cells, and promote cell migration, invasion, metastasis and epithelial-mesenchymal transformation by combining with a variety of growth factors (7,8,10,27) . Increased fibrinogen has been shown to be associated with distant metastasis and lymph node metastasis in gastrointestinal tumors (29) .
Albumin is considered as an objective indicator of nutritional status, and low albumin level often indicates malnutrition (11,12) . Some studies have shown that low albumin concentration can promote the inflammatory response of the body to the tumor, promote the release of a series of tumor related cytokines, thus contributing to the development of tumor (30) .In addition, in many clinical studies, low serum albumin level shows a significant correlation with the worse prognosis of different kinds of tumors (13)(14)(15) .
In our study, increased FAR was significantly related to the age of the patients (P = 0.0014), which may be related to the better nutritional status of the younger patients, leading to younger patients being divided into the low FAR group. The significant correlation between increased FAR and gender (P = 0.0278) may be caused by too few female patients (only 16%) in our cohort.
What surprised us was that in the multivariate analysis, pathological grade could not be used as an independent risk factor to predict the prognosis of patients with urothelial carcinoma after radical cystectomy. This is contrary to our traditional acknowledge. Considering that our research object is urothelial carcinoma patients undergoing radical cystectomy, the pathological type of the majority of patients is high-grade urothelial cancer, and the majority of patients with low-grade urothelial cancer only need TUR-Bt, which results in this bias.
In subgroup analysis, the long-term survival of patients in AJCC I+II subgroup, G1 + G2 subgroup, G3 subgroup, lymph nodes negative subgroup and old patient subgroup were all related to FAR, while the 5-years survival of patients in AJCCIII+IV subgroup, lymph nodes positive subgroup and young patient subgroup was not related to FAR. In multivariate analysis, AJCC stages can also be used as an independent risk factor to predict the prognosis of patients. AJCC stages with higher stage indicates poor prognosis, and the prediction effect of AJCC stages is stronger than far. FAR can predict the prognosis of patients with lower AJCC stages, negative lymph nodes and elder age.
We then analyzed patients in different age subgroups. FAR had the highest AUCs in both subgroups, and that in the old patient subgroup was higher than that in the young patient subgroup. In multivariate analysis, only FAR (P = 0.023) and AJCC stage (P < 0.001) associated with survival in old patient subgroup, and only AJCC stage (P < 0.001) was associated with survival in young patient subgroup. This means that FAR may be a better predictor of the prognosis of elderly patients. In clinical practice, we often encounter such a scene, an elderly patient with relatively early muscle invasive bladder cancer, whether to carry out a radical operation or not needs to consider a lot of factors in clinical practice. Here, FAR as an indicator of prognosis of patient may have certain guiding significance for this problem.
Our research has several limitations. First of all, our study is a retrospective study, involving only single center and small sample, which may lead to selection bias. Second, the patient's surgery situation is not fully documented, which may lead to potential bias. Third, the different postoperative treatments were not included in our study.
Therefore, our results need to be validated in a large prospective cohort study.

Conclusion
In summary, FAR value can be used as an independent preoperative risk factor to predict the prognosis of urothelial carcinoma patients after radical cystectomy, especially for patients with elder age, lymph nodes negative, or AJCC I + II stage. Large retrospective or prospective studies are still needed to verify this view.

Ethics approval and informed consent
All procedures performed in this study were in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Research Ethics Committee of Peking University First Hospital, Peking University. As a retrospective study and does not involve secondary injury to patients, the informed consent for the study was waived by the Research Ethics Committee of Peking University First Hospital,