DOI: https://doi.org/10.21203/rs.3.rs-2518663/v1
Previous studies have shown that albumin-to-fibrinogen ratio (AFR) is a novel prognostic biomarker in various diseases. In this study, we investigated the correlation between AFR and clinical outcomes in patients with stage I non-small cell lung cancer (NSCLC).
A total of 212 stage I NSCLC patients who underwent surgical resection were enrolled in this study. Risk factors for recurrence-free survival (RFS) and overall survival (OS) was evaluated by univariate and multivariate Cox proportional regression analyses. The association between OS, RFS and AFR was assessed by the Kaplan–Meier method using log-rank test.
The AFR was significantly associated with tumor stage. Preoperative AFR was an effective predictor for OS in NSCLC patients with a cut-off value of 10.36 and an area under the curve (AUC) of 0.785 (P < 0.001). The univariate and multivariate Cox analyses indicated that AFR was an independent prognostic factor for both OS and RFS (P < 0.05). Kaplan–Meier analysis confirmed that patients with high AFR levels showed significantly higher RFS (P = 0.016) and OS (P = 0.041) than those with low AFR levels.
This study indicated that elevated preoperative AFR might be an independent prognostic factor for stage I NSCLC patients.
1. To investigate the correlation between AFR and clinical outcomes in patients with stage I NSCLC patients.
2. The univariate and multivariate Cox analyses indicated that AFR was an independent prognostic factor for both OS and RFS.
3. This study indicated that elevated preoperative AFR might be an independent prognostic factor for stage I NSCLC patients.
Lung cancer is the leading cause of cancer-related death, accounting for approximately 29% of all cases, approximately 85% of lung cancer cases are non-small cell lung cancer (NSCLC) and have a poor prognosis [1]. Surgery remains the most important treatment method for early NSCLC patients. Conventional platinum-based adjuvant chemotherapy after surgery for patients with stage II-III NSCLC can improve the prognosis [2–5]. However, the current use of postoperative adjuvant therapy for stage IA and stage IB NSCLC is still controversial [6]. About 40–50% of stage I-II NSCLC patients experience local recurrence and/or metastasis following surgical treatment, with a 5-year survival rate of about 60–90% [7, 8]. The international tumor-node-metastasis staging system is an important method to evaluate the extent of lesions of NSCLC, however, differences in prognosis may still exist in patients with similar tumor stage [9, 10]. Therefore, if NSCLC patients at high risk of tumor recurrence or metastasis were screened out in the early stage, more aggressive, systemic, and local treatment could be implemented to prolong patient survival.
Albumin (Alb) and fibrinogen (Fib) are two commonly used circulating inflammatory proteins. Alb has been reported to be a well-established prognostic factor in patients with various diseases, including oral cavity cancer, metastatic pathological femur fractures and amyotrophic lateral sclerosis [11–13]. Moreover, the prognostic role of Fib has also been reported in various studies, such as spontaneous intracerebral haemorrhage and surgically resected NSCLC [14, 15]. The fibrinogen–to-albumin, which considers both inflammatory biomarkers, is a novel prognostic immune biomarker in various diseases [16, 17]. However, the correlation between the AFR and the prognosis of stage I NSCLC patients undergoing surgical resection remains unknown until now. Hence, this study aimed to investigate whether the AFR could serve as an effective predictor for the survival of stage I NSCLC patients.
The study included 283 resected stage I NSCLC patients, 212 of whom had completely medical information and follow-up were included in this retrospective study. All patients underwent complete resection and systematic node dissection of hilar and mediastinal lymph nodes. The included patients met the following criteria: diagnosed with NSCLC by pathology; underwent surgical resection; have complete pre-surgery laboratory data; had no complications of other cancers. The preoperative evaluation included physical examination, biochemistry tests, coagulation tests, complete blood cell counts, flexible bronchoscopy, computed tomography, brain magnetic resonance imaging (MRI), and radionuclide bone scan. All patients were staged according to the 8th edition of the Tumor Node Metastasis Classification of the International Union Against Cancer [18].
The study was approved by the ethics committees of Nanjing Brain Hospital. Due to the retrospective nature of the study, the requirement for informed patient consent was waived. In addition, all patient information was anonymized prior to analysis.
Blood specimens were collected during the week before surgery. Plasma fibrinogen and serum albumin were measured immediately after blood sample collection. Plasma fibrinogen was assayed using Dade Thrombin Reagent (Siemens, Germany) and a CA7000 analyser (Sysmex Corporation). Serum albumin was measured using the bromocresol green dye method and a biochemical analyser (7600 − 210, Hitachi, Japan) in the Nanjing Chest Hospital Clinical Laboratory. The value of the AFR was calculated by dividing the albumin levels by the fibrinogen levels.
After surgery, all patients were followed up every 3 months for the first year, every 6 months for the second year, and then every year until death or the last follow-up. The follow-up included physical examination, blood analysis and chest CT. When recurrence was suspected, further investigation was performed, including chest and abdomen CT, brain MRI, radionuclide bone scan, or PET-CT. The recurrence types were classified as regional and distant metastasis based on imaging or biopsy.
All statistical analyses were performed using SPSS for windows version 22.0 (SPSS Inc., Chicago, IL, USA). The recurrence-free survival (RFS) was defined as the duration of time between the date of surgery and the date of first recurrence or final follow-up. The overall survival (OS) was defined as the length of time from surgery to death or the final follow-up. Receiver operating characteristic (ROC) curve analysis was performed to select the most appropriate cut-off value for AFR. The effect of each significant predictor identified by univariate analysis was assessed using multivariate analysis with the Cox’s proportional hazards model. Survival curves were generated using the Kaplan–Meier method and compared using the Log-rank test. Value P < 0.05 was considered statistically significant.
The study included 283 resected stage I NSCLC patients, 212 of whom had completely medical information and follow-up were analyzed (Fig. 1). The mean age of the patients was 43.5 ± 56.8 years (range 34–82 years). Sixty-four patients (30.19%) were male, 148 (69.81%) were female. Forty-six patients (21.7%) were former or current smokers. The mean size was 24.5 ± 10.3 mm (range 12–40 mm). One hundred and forty-four patients (67.92%) underwent lobectomy and the remaining 68 patients (32.08%) underwent sublobar resection including segmentectomy (n = 48) and wedge resection (n = 20). The most common pathological type of the resected specimens was adenocarcinoma in 178 patients (83.96%) and squamous cell carcinoma in 34 patients (16.04%). There were 128 cases (60.38%) in stage IA, 84 cases (39.62%) in stage IB, 86 cases (40.57%) in well differentiation, 100 cases (47.17%) in moderately differentiated and 26 cases (12.26%) in poor differentiated. The number of patients who were diagnosed with presence of vascular invasion was 42 (19.81%) and lymphatic invasion was 30 (14.15%). The characteristics of resected stage I NSCLC patients are summarized in Table 1.
| Characteristic | Patients, n (%) |
|---|---|
| Number of patients | 212 |
| Age, yrs (mean ± SD) | 43.5 ± 56.8 |
| Sex | |
| Male | 64 (30.19) |
| Female | 148 (69.81) |
| Smoking history, n (%) | |
| Absent | 166 (78.30) |
| Present | 46 (21.70) |
| Resection type, n (%) | |
| Wedge resection | 20 (9.43) |
| Segmentectomy | 48 (22.64) |
| Lobectomy | 144 (67.92) |
| Differentiation | |
| Well | 86 (40.57) |
| Moderate | 100 (47.17) |
| Poor | 26 (12.26) |
| Histological type | |
| Adenocarcinoma | 178 (83.96) |
| Squamous | 34 (16.04) |
| Stage | |
| I A | 128 (60.38) |
| IB | 84 (39.62) |
| Blood vessel invasion | |
| Absent | 170 (80.19) |
| Present | 42 (19.81) |
| Lymph vessel invasion | |
| Absent | 182 (85.85) |
| Present | 30 (14.15) |
| AFR | |
| ≤ 8.36 | 168 (79.25) |
| > 8.36 | 44 (20.75) |
Based on the results of the ROC curve analysis, the optimal cut-off value for the AFR was determined to be 10.36, as assessed by the ROC curve based on the OS, with an area under the curve (AUC) of 0.785, a sensitivity of 63.68% and a specificity of 76.89%, respectively (Fig. 2). According to the cut-off value for the AFR, 168 patients were categorized into the low AFR group (pretreatment AFR ≤ 10.36) and 44 in the high AFR group (pretreatment AFR > 10.36). The clinical characteristics associated with the AFR are shown in Table 2. A comparison of clinical characteristics in high and low AFR groups demonstrated that stage IB (P = 0.007), lymph vessel invasion (P = 0.027) and blood vessel invasion (P = 0.031) were significantly more common in low AFR group. No significant correlation was shown between AFR and age, gender, smoking status, histological type and tumor differentiation.
| Parameters | AFR ≤ 10.36 | AFR > 10.36 | P value |
|---|---|---|---|
| Age (years) | 0.176 | ||
| > 60 | 92 | 20 | |
| ≤ 60 | 76 | 24 | |
| Gender (n, %) | 0.062 | ||
| Male | 46 | 18 | |
| Female | 122 | 26 | |
| Smoking history | 0.102 | ||
| Present | 40 | 6 | |
| Absent | 128 | 38 | |
| Histological type | 0.410 | ||
| Adenocarcinoma | 140 | 38 | |
| Squamous | 28 | 6 | |
| Differentiation | 0.545 | ||
| Well | 68 | 18 | |
| Moderate-poor | 100 | 26 | |
| Stage | 0007 | ||
| IA | 94 | 34 | |
| IB | 74 | 10 | |
| Blood vessel invasion | 0.031 | ||
| Absent | 130 | 40 | |
| Present | 38 | 4 | |
| Lymph vessel invasion | 0.027 | ||
| Absent | 140 | 42 | |
| Present | 28 | 2 |
The overall median follow-up period was 54 months (range: 6–63 months). During the follow-up period, relapse of the disease occurred in 33.02% of 212 patients. The 5-year RFS rate was 66.98%, and the 5-year OS rate was 84.91%. Of the 70 cases with relapse, 61.43% experienced regional recurrence, 47.14% experienced distant metastasis, and 8.57% experienced both. Among the patients with relapse, 12 patients in high AFR group and 21 patients in low AFR group developed distant metastases. The rate of recurrence between patients with high and low AFR (16.67% vs. 57.17%, P = 0.027) was significantly different.
The impact of pretreatment AFR on lung cancer survival was examined with the Cox proportional hazards regression model. In the univariate analysis for RFS and OS, stage (P = 0.024 and 0.015), blood vessel invasion (P = 0.014 and 0.001), and AFR (P = 0.008 and 0.001) were evaluated. Multivariate analyses were performed to evaluate all significant prognostic factors that were found in univariate analyses. The results showed that a high AFR was a significant independent predictor for favorable prognostic measures, including the RFS [hazard ratio (HR): 2.371, 95% confidence interval (CI): 1.120–5.018, P = 0.024] and OS (HR: 2.727, 95% CI: 1.638–4.539, P = 0.001). In addition, the stage, and blood vessel invasion were independent indicators for RFS and OS. The results of univariate and multivariate analyses for both RFS and OS were shown in Table 3.
| Characteristics | Univariate | Multivariate | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| RFS | ||||
| Gender (Male vs. Female) | 1.512(0.631–3.624) | 0.354 | 1.542(0.614–3.875) | 0.357 |
| Age (≤ 60 vs. > 60) | 2.444(0.734–8.143) | 0.0.146 | 1.107(0.674–1.818) | 0.689 |
| Smoking (Yes vs. No) | 0.947(0.485–1.848) | 0.0.873 | 0.734(0.382–1.411) | 0.354 |
| Histological type (Adenocarcinoma vs. Squamous) | 0.895(0.416–1.925) | 0.0.776 | 0.834(0.381–1.784) | 0.624 |
| Stage (IA vs. IB) | 2.677(1.140–6.287) | 0.00.024 | 2.933(1.241–6.934) | 0.014 |
| Differentiation (Well vs. Moderate-poor) | 1.132(0.677–1.894) | 0.00.637 | 1.144(0.684–1.913) | 0.609 |
| Blood vessel invasion (Present vs. Absent) | 1.833(1.131–2.972) | 0.0.014 | 1.866(1.151–3.025) | 0.011 |
| Lymph vessel invasion (Present vs. Absent) | 1.103(0.564–2.158) | 0.00.774 | 1.140(0.582–2.230) | 0.703 |
| AFR (≤ 8.02 vs. > 8.02) | 2.251(1.233–4.110) | 0.00.008 | 2.371(1.120–5.018) | 0.024 |
| OS | ||||
| Gender (Male vs. Female) | 1.136(0.859–1.503) | 0.372 | 0.911(0.642–1.291) | 0.599 |
| Age (≤ 60 vs. > 60) | 1.003(0.635–1.927) | 0.550 | 1.050(0.427–1.745) | 0.970 |
| Smoking (Yes vs. No) | 0.6656(0.258–1.668) | 0.376 | 1.939(0.821–4.628) | 0.136 |
| Histological type (Adenocarcinoma vs. Squamous) | 0.741(0.530–1.035) | 0.079 | 0.724(0.473–1.109) | 0.137 |
| Stage (IA vs. IB) | 1.994(1.145–3.475) | 0.015 | 1.552(1.009–2.389) | 0.046 |
| Differentiation (Well vs. Moderate-poor) | 1.178(0.733–1.892) | 0.00.499 | 1.358(0.930–1.985) | 0113 |
| Blood vessel invasion (Present vs. Absent) | 1.911(1.299–2.811) | 0.001 | 1.923(1.310–2.821) | 0.001 |
| Lymph vessel invasion (Present vs. Absent) | 1.283(0.879–1.872) | 0.196 | 1.317(0.979–1.770) | 0.069 |
| AFR (≤ 8.02 vs. > 8.02) | 2.057(1.204–3.513) | 0.00.006 | 2.727(1.638–4.539) | 0.001 |
| HR, hazard ratio; CI, confidence interval; RFS, recurrence-free survival; OS, overall survival. | ||||
The Kaplan–Meier analysis and Log-rank test were performed to illustrate survival differences among the groups classified by AFR (high vs. low). The 5-year RFS rate in the low AFR group was significantly lower than those in the high AFR group (50.1% vs. 76.3%, P = 0.005) (Fig. 3A). The 5-year OS rate was 95.45% and 82.14%, respectively, and the median survival time was 58.0 and 50.5 months, respectively, for the high AFR group and the low AFR group (P = 0.018) (Fig. 3B).
As demonstrated by recent studies, inflammation and nutritional status play key roles in tumor progression [19]. It is also well known that nutritional status and chronic inflammation are two main causes for NSCLC [20]. This current study focused on the potential predictive factors for prognosis in early NSCLC patients who underwent surgical resection. Our results showed that the preoperative AFR was an independent risk factor for both RFS and OS in early NSCLC patients. Patients with a lower preoperative AFR had a worse RFS and OS than patients with a high preoperative AFR. In addition to the AFR, the present study also indicated that blood vessel invasion is a significant prognostic factor for PFS.
The prognostic role of FAR has been reported for patients with malignancies in recent studies, including esophageal squamous cell carcinoma, breast cancer, colorectal cancer and hepatocellular carcinoma [21–24]. Recently, AFR was reported to be a prognostic factor for clinical outcomes in lung cancer [25–27]. Chen et al. investigated 529 patients with stage I-III resectable NSCLC and identified AFR as an independent prognostic factor in multivariate analysis [17]. By evaluating 270 patients with stage IV NSCLC patients, Ying et al. found that patients with an initial AFR greater 8.02 had a better survival than those with an initial AFR less than or equal to 8.02 [18]. Recently, Li et al. have demonstrated that AFR is a potentially useful marker for predicting the response and prognosis of stage II-III patients NSCLC undergoing chemo-radiotherapy [19]. However, the prognostic value of preoperative AFR patients with stage I NSCLC has not been investigated. Stage I NSCLC account for 15%-20% of newly diagnosed NSCLC, and this subgroup has high survival rate after surgery. A small percentage of patients with stage I NSCLC patients died from recurrence or metastasis within the short period of time. Better prognostic stratification will identify high-risk patients and allow the design of prospective adjuvant therapy. Unlike previous studies, we conducted a retrospective study to investigate the prognostic value of pre-operative AFR in a uniform patient cohort and found a strong association between increased AFR and better survival, including RFS and OS, according to the Cox model, it was also an independent prognostic factor for survival in multivariate analysis. Our results are consistent with previous reports [25–27].
Moreover, Fib and Alb are widely accepted as two acute phase response proteins for the systemic inflammatory status [28]. Fib and Alb are both synthesized by hepatocytes and they vary oppositely under inflammatory stimulation [29]. In short, FAR is a key factor in nutrition condition, coagulation system, and systemic inflammation. Furthermore, these processes were closely associated with the survival, intravasation, and adhesion of tumor cells, leading to increased metastatic potential, which might be a possible explanation for the prognostic role of FAR in NSCLC patients [30].
The cut-off value of AFR in NSCLC is different, varying from 7.80 to 9.67 [25–27]. By using ROC, the cut-off value of AFR was 10.36 in our study, which is comparable with previous studies. The relationship between AFR and clinical parameters was explored. In our study, significant associations between AFR and stage, lymph vessel invasion and blood vessel invasion were identified. Compared with the high AFR group, the rate of recurrence was higher in the low AFR group. To the best of our knowledge, this study may represent the first report of an association between AFR and recurrence rate.
Several limitations of the study should be considered. The main limitation of this study is that, as it is a retrospective study, we can't completely rule out selection bias. Second, although the preoperative Alb and Fib levels were obtained in routine clinical practice and analyzed in our hospital's regular laboratory, we did not perform a specific quality control analysis. Finally, the determination of Alb and Fib levels may be influenced by different factors, although we tried to limit the influence of other factors.
In conclusion, the preoperative higher AFR is a favorable prognostic factor associated with more frequent distant metastasis in stage I NSCLC patients. Therefore, the AFR was a reliable and convenient biomarker for stratifying the risk of death in patients with stage I NSCLC.
Non-small cell lung cancer
Albumin-to-fibrinogen ratio
Overall survival
Recurrence-free survival (RFS).
Acknowledgements
Not applicable.
Authors’ contributions
CHX and LL conceived, designed, and coordinated the study. YCW and QY participated in the data acquisition. WW and QZanalyzed and interpreted the data. CHX and CZC participated in the study design and statistically analyzed the data. CHX, LL and WW helped draft and revise the manuscript for important intellectual content. All authors read and approved the final manuscript.
Funding
The study was supported by the Major Program of Nanjing Medical Science and Technique Development Foundation (ZKX17044).
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The study was approved by the Ethics Committees of Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China. All patients provided written informed consent before enrollment.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1Department of Respiratory Medicine, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China
2Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, Jiangsu 210029, China
3Clinical Center of Nanjing Respiratory Diseases and Imaging, Nanjing, Jiangsu 210029, China