Prognostic value of the fibrinogen/albumin ratio (FAR) in patients with operable soft tissue sarcoma

Soft tissue sarcomas (STSs) are rare and aggressive neoplasms of mesenchymal origin that account for approximately 1–2% of all adults cancers [1, 2]. Despite the improvement in surgical procedures and the development of adjuvant therapy [3], the long-term survival of STS patients with high-grade tumors is still poor. More than 50% of patients with high-risk STS will develop metastases and death [4‐6]. Hence, it is necessary to develop effective biomarkers to identify STS patients at high risk of tumor recurrence and death after surgical treatment.

A hypercoagulable state is correlated with malignancy and it has been showed in almost 50% of the patients with tumor [7]. Among coagulation factors, fibrinogen have been in the limelight due to an essential role in inflammation as well as the development and progression of cancer. Many articles revealed that elevated preoperative plasma fibrinogen levels are significantly correlative with treatment failure or poor outcome in various malignancies [8‐10], including STS [11, 12]. Additionally, accumulating data have demonstrated that preoperative malnutrition is associated with significantly short survival in STS patients [13], with serum albumin serving as a crucial parameter for nutritional status.

Therefore, we propose a novel marker, namely, the preoperative fibrinogen/albumin ratio (FAR) in combination with coagulation and nutritional status to investigate its prognostic impact in patients with operable STS. We also assessed any links between the FAR and clinicalpathological characteristics.

To the best of our knowledge, this was the first study to evaluate the prognostic value of the FAR in STS. Our study demonstrated that preoperative FAR is independently associated with survival in resected STS patients.

Accumulating data has indicated that fibrinogen may provide favorable conditions for tumor development and progression in various malignancies [10]. However, the molecular mechanism underlying this relationship remains unclear. Fibrinogen is a dimeric molecule and serves as a scaffold for binding members of growth factors. This binding could promote tumor cell proliferation and stimulate angiogenesis [16]. Another possible mechanism may be related to the positive feedback loop between platelets and fibrinogen levels. Fibrinogen could help platelets adhere to cancer cells. In turn, these platelets induce more fibrinogen to aggregate around cancer cells, forming micro emboli in targeted organs [17]. In addition, these fibrinogen-platelet micro thrombi could functionally enhance tumor migration by preventing circulating tumor cells from natural killer cells or other cytotoxic cells [18]. A third potential mechanism that may influence prognosis is that fibrinogen may promote the inflammatory response by inducing the overproduction of pro-inflammatory cytokines in malignant cells [19]. As such, it is believed that these inflammatory responses present in the tumor microenvironment may be one of the factors responsible to provide a favorable medium for facilitating tumor proliferation, invasion, and metastases [20].

Albumin, as a chronic phase protein, is an indicator represents the nutritional status of the host, as well as a marker of systemic inflammatory response. Several studies have reported that hypoalbuminemia due to poor performance, weight loss and malnutrition is associated with poor prognosis and postoperative complications in patients with different malignancies [21‐23], including STS [24]. These findings can be explained by the fact that hypoalbuminemia may weaken the human defense mechanisms, blunting the therapeutic response and further accelerating the tumor progression. Further, in patients who suffer from simultaneous nutritional decline, they are more likely to have reduced ability to endure aggressive anti-cancer therapeutics [25].

NLR and PLR are the commonly used blood sample-derived systemic inflammatory response indicators (SIR). Several studies have shown that NLR and PLR were independent prognostic factors in cancer patients [26, 27]. However, there are also some studies showing that NLR and PLR were ineffective in predicting the prognosis [28‐30], indicating the prognostic role of NLR and PLR in cancer still need further investigation. They may should be assessed together with other markers due to the confounding factors regulating by inflammatory conditions.

Considering the above-mentioned evidence, in this study we successfully formulated a new technique by combining both serum fibrinogen and Alb, the FAR, which may have a potent and convincing prognostic ability. Of note, Matsuda et al. [31] recently established a prognostic indicator based on fibrinogen and Alb levels (FA score) and reported that the FA score system could predict the prognosis of patients with esophageal cancer. However, FA may estimate the coagulation and nutrition level erroneously because it evaluates the values of fibrinogen and Alb separately through categorization. Conversely, the FAR is a continuous variable that is calculated using two continuous variables, which reduces the potential bias and stratifies patients to predict survival more accurately.

According to the ROC curve, our data not only showed that the AUC value of FAR was superior to those of the NLR and PLR but also, the optimal FAR cutoff value to predict OS was at 0.0726. These results demonstrated that comparing other inflammation-based prognostic indices, the FAR had comparable prognostic capability and may be more powerful than NLR and PLR.

More importantly, our results also demonstrated that FAR might indicate a more aggressive tumor behavior and associate with the systemic progression of STS since an elevated FAR was significantly related to larger tumor size, aggressive tumor grade, more advanced AJCC stage and worsen prognoses. These findings were in agreement with previous studies demonstrating that FAR was correlated a longer tumor length, deeper tumor invasion, and increased regional lymph node involvement in ESCC patients [32].

Moreover, FAR showed a significant association with both DFS and OS in univariate analysis and was identified as an independent prognostic factor for OS in multivariate analysis. Patients with a high FAR had 1.907 times the risk of death of those with a low FAR. These results suggest that FAR has a substantial impact on patient outcome. In addition, PLR, the other index reflecting coagulation and nutrition status was also an independent prognostic factor. However, we failed to show a clear association between FAR and PFS in multivariate analysis. This may be potentially due to the small sample size, which allows a wide variability in terms of results. Another possible limitation is that unrecorded adjuvant treatments may have affected primary tumor progression.

Surprisingly, AJCC stage was not an independent predictor of OS and DFS in our analysis, which is in contrast with a previous large-scale study [33]. This could be due to the staging defects of human subjectivity and the heterogeneity of STS. The recently released 8th AJCC stage system illustrated an unprecedented change for risk stratification by redefining the T-stage categories [34]. However, the system still needs further investigation. Our data suggest that the FAR could potentially be an effective biomarker and may complement TNM staging predictions to improve risk stratification.

Further subgroup analysis found that a high FAR was associated with decreased OS in patients across all size, depth and AJCC stage subgroups. However, the FAR was not significantly associated with OS for G3 patients. These results suggest that FAR is more predictive of survival in STS patients with low-grade tumors.

It is worth noting that our findings may have important implications for individualized treatment and surveillance of patients with STS. Patients with an elevated FAR may require additional neoadjuvant therapy or more intense adjuvant chemotherapy to reduce the risk of recurrence. Both fibrinogen and Alb are routinely measured in clinical practice; the FAR has the advantage of being inexpensive, repeatable and standardized, thus offering reduced costs and increased convenience for prognostication.

This study has several limitations. First, our study used a retrospective review involving a single-center with a small sample size, which may lead to selection bias. Second, information on operation approach and adjuvant therapy was incomplete, which could lead to potential biases. Moreover, we lacked of verification analysis, which would further demonstrate our conclusions. Therefore, our results need to be verified in a large-scale prospective cohort.

In summary, FAR is associated with tumor progression and can be considered an independent factor for OS of resected STS patients. Moreover, compared to the NLR and PLR, the FAR showed comparable prognostic ability based on our study population. Validation studies or large-scale prospective studies are warranted to verify our findings.