Pretreatment albumin/fibrinogen ratio as a promising predictor for the survival of advanced non small-cell lung cancer patients undergoing first-line platinum-based chemotherapy

Lung cancer (LC) is consistently the leading cause of the cancer-related deaths worldwide [1]. Non small-cell lung cancer (NSCLC), the most common type of LC, compromises for nearly 85% of all LC cases [2]. For early-stage NSCLC, surgery has been widely accepted as the main therapeutic strategy; however, high postoperative recurrence and metastasis rates are commonly observed [3]. Most NSCLC patients are diagnosed at a relatively late stage (stage III or IV), which may preclude surgical resections [4]. Platinum-based chemotherapy, which consists of third-generation chemotherapy and platinum, is widely accepted as a standard treatment for advanced NSCLC [5]. In the past decades, new available therapeutic options for advanced NSCLC have been proposed and developed quickly. Recently, immunotherapy has been increasingly applied as clinical treatments for LC patients [6]. For example, immune checkpoint inhibitors (ICIs), such as anti-programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) have been proven proved to be clinically effective across a broad range of solid tumors, including NSCLC [7]. Targeted therapy, such as anaplastic lymphoma kinase (ALK) inhibitors and tyrosine kinase inhibitors (TKIs), has also attracted much attention due to its improvements in tolerability and efficacy [8]. Other researchers have also suggested that the combination treatment strategies may maximize the treatment efficacy for NSCLC [7].

Due to individual differences in chemotherapy efficacy and the relatively high recurrence rate, an early prediction for chemotherapy response and clinical outcomes is urgently needed [9]. Investigating valid predictive biomarkers can aid in timely, effective intervention and better clinical efficacy. A minimally invasive predictor can serve as a tool for treatment monitoring and provide a new view on future guidance. Furthermore, it is also helpful to explore new and more effective therapeutic targets for advanced NSCLC. Various clinicopathological prognostic factors have been identified by previous studies, however, the prognosis prediction of NSCLC still remains unsatisfactory [10]. In recent decades, many studies have illustrated that inflammation and immunology are two important characteristics that enable malignancies and they are both significantly associated with tumour initiation, distant metastasis and resistance to chemotherapy [11, 12]. Furthermore, significantly different expressions of immune cells and inflammatory proteins such as albumin (Alb) and fibrinogen (Fib) are widely observed in LC patients in comparison with healthy controls [13]. Alb has been widely used as an effective tool for evaluating nutritional and inflammatory status. In addition, recent evidence with various malignancies has also revealed a close relation between coagulation and tumor progression and metastasis [14, 15]. Fib is an essential protein in the coagulation cascade and it has been reported by some studies to be associated with tumor development [16]. However, the correlation between the Alb-to-Fib ratio (AFR) and the prognosis of NSCLC with patients undergoing first-line platinum-based chemotherapy remains unknown until now. Hence, this study aimed to investigate whether the AFR could serve as an effective predictor for the survival of NSCLC patients.

As demonstrated by recent studies, inflammation and nutritional status play key roles in tumor progression [18]. It is also well known that nutritional status and chronic inflammation are two main causes for NSCLC [19]. This current study focused on the potential predictive factors for prognosis in advanced NSCLC patients who underwent first-line platinum-based chemotherapy. Our results showed that the pretreatment AFR was an independent risk factor for both PFS and OS in advanced NSCLC patients. Patients with a lower pretreatment AFR had a worse clinical response to for chemotherapy, PFS and OS than patients with a high pretreatment AFR. In addition to the AFR, the present study also indicated that metastasis stage is a significant prognostic factor for PFS.

Albumin, a sensitive marker in nutritional status assessments, is an acute-phase reactant for systemic inflammation status and its synthesis is suppressed by inflammatory cytokines [20]. A systematic review of the epidemiological literature reveals the significant prognostic role of pretreatment serum albumin in cancer and baseline albumin levels that are recommended for risk stratification [21]. The close association between inflammation and tumors has attracted much attention. Inflammation in the tumor microenvironment plays important roles in the proliferation, survival, angiogenesis and metastasis of malignant cells [18]. Inflammation also accounts for the response alterations of the adaptive immune system to chemotherapeutic agents [18]. It has been demonstrated that malnutrition status is closely related to the progression of malignancy due to its association with high leukocytes levels, high risks of infection, and weak immune systems [21, 22].

Fib, an essential constituent of the coagulation system, plays an important role in platelet aggregation and blood coagulation. Furthermore, Fib is also widely accepted as a reliable biomarker that reflects systemic inflammation and Fib can promote the synthesis of pro-inflammatory cytokines [23]. High Fib expression induced by the excess production of inflammatory cytokines may be associated with tumor aggressiveness in NSCLC patients [24]. Plasma Fib contributes to the coagulation status and promotes the survival and adhesion of tumor cells, which results in LC metastasis [25]. Elevated Fib levels are reported to be tightly associated with high risk of colorectal, lung and breast cancer [26]. Preoperative serum Fib levels are suggested to be a candidate prognostic biomarker in operable NSCLCs [27].

Other studies have indicated the prognostic roles of plasma fibrinogen [28] and albumin [29] for survival in NSCLC patients. Our results showed that the AFR, which takes both albumin and fibrinogen into account, served as a strong predictor for prognosis. The AFR is an indicator of nutritional status, coagulation condition, and systemic inflammation. It has been indicated that the interactions between the inflammatory response and tumor cells promote tumor progression in the host environment [30]. Previous studies have reported that inflammatory cytokines are involved in the proliferation, invasion and metastasis of tumor cells in various cancers [15]. A recent study in advanced esophageal cancer patients reported that changes in AFR can serve as an independent risk factor for prognosis [31]. Moreover, in comparison with single Alb or Fib measurements, the AFR could amplify the sensitivity of nutritional and inflammatory status changes in NSCLC patients. Importantly, pretreatment AFR could clearly predict the clinical response to chemo-radiotherapy, which could partly explain its predictive role for survival. The AFR closely correlates with blood coagulation, nutritional and systemic inflammatory status, which may be possible explanations for the predictive role of AFR for survival in advanced NSCLC patients. In addition, some studies have indicated that chronic inflammation-associated biomarkers (such as elevated neutrophil count, CRP, etc.) can be potential predictors for nivolumab therapy in NSCLC [32]. The status of KRAS mutation has also been suggested as a prognostic biomarker for advanced NSCLC patients undergoing ICIs [33]. Some molecular predictive markers have been applied for NSCLC patients with platinum-based chemotherapy, such as excision repair cross-complementing 1 (ERCC1) [34], ribonucleotide reductase subunit M1 (RRM1) [35], class III β-tubulin (TUBB3) [36] and breast cancer 1 (BRCA1) expression [37]. Another circulating biomarker, the neutrophil-to-lymphocyte ratio (NLR) has been recommended as a potential predictor for outcomes in NSCLC patients treated with nivolumab [38]. Scilla et al. have also indicated that the baseline NLR is a novel prognostic factor in locally advanced NSCLC patients undergoing definitive chemoradiation with or without surgery [39]. However, whether these circulating biomarkers can serve as potential predictive/prognostic markers for NSCLC remains controversial and further validation is required for the clinical application for these markers.

We must admit that this study has some limitations. First, this is a signal-center retrospective study with a small sample size and the results require further validation in larger prospective data sets. Second, the observed sample cohort was quite specific and the lack of control group analyses (e.g. patients who were or were not receiving radiotherapy with platinum-based chemotherapy) was a great limitation for this study. Next, we will perform a study to investigate whether the AFR can serve as a prognostic factor for advanced NSCLC patients undergoing different treatment strategies (e.g. immunotherapy, targeted agents, combination therapy, etc.).