Abstract
Patients with advanced esophageal squamous cell carcinoma (ESCC) is received chemoradiotherapy or chemotherapy for clinical management. However, it is difficult to predict tumor response and prognosis using blood markers before starting treatments. The purpose of this study was to investigate the pre‐treatment plasma fibrinogen and neutrophil–lymphocyte ratio (NLR) in patients with advanced ESCC treated with chemoradiotherapy or chemotherapy, and to assess the clinical utility of a combined score using these blood markers, named as the F‐NLR (fibrinogen and NLR) score, as a predictor of tumor response and prognosis. A total of 98 advanced ESCC patients, treated with chemoradiotherapy or chemotherapy, were classified into three groups: F‐NLR score of 2, having both hyperfibrinogenemia (>400 mg/dL) and high NLR (>3.0), score of 1, one of these hematological abnormalities, and score of 0, having neither hyperfibrinogenemia nor high NLR. Fibrinogen and NLR were significantly higher in the progressive disease (PD) group than the non‐PD group (P = 0.0419, and P = 0.0001, respectively). A significantly higher F‐NLR score was found in the PD group than the non‐PD group (P = 0.0140). Overall survival was significantly lower in patients with an F‐NLR score of 2 than in those with an F‐NLR score of 0 or 1 (P < 0.0001). Multivariate analysis showed that the F‐NLR score was one of the independent prognostic factors (P = 0.0081). Our study demonstrates that the F‐NLR score is promising as a predictive marker for therapeutic effects and prognosis in patients with advanced ESCC.
Keywords: Drug response, esophageal squamous cell carcinoma, fibrinogen, neutrophils, prognosis
Esophageal cancer is one of the most aggressive carcinomas in many gastrointestinal tract cancers. Chemoradiotherapy has been recognized as an effective treatment for patients with esophageal cancer since the 1980s.1, 2, 3 Ishida et al.4 reported that concurrent chemoradiotherapy using 5‐fluorouracil and cisplatin along with radiation therapy was suitable for the clinical treatment of patients with unresectable advanced esophageal squamous cell carcinoma (ESCC) in Japan. However, since the recurrence rate of ESCC is high, the prognosis remains unsatisfactory.5 It is important to predict tumor response to chemoradiotherapy or chemotherapy and prognosis using several indicators before starting these treatments. To date, many investigators have demonstrated several potential blood markers for predicting disease recurrence after surgery, tumor response to chemoradiotherapy or chemotherapy, and prognosis in several malignancies including ESCC.6, 7, 8, 9, 10, 11, 12, 13 The Glasgow Prognostic Score (GPS) consists of C‐reactive protein (CRP) and serum albumin. Many investigators have reported the clinical impact of GPS as a predictive marker of prognosis in patients with various malignancies.14 Recently, the GPS was modified (mGPS) regarding cut‐off values of CRP and albumin. The mGPS score has been introduced as a new predictive marker of disease outcomes.15, 16 However, there are few useful predictive markers with the exception of GPS. We focused on the plasma fibrinogen and Neutrophil‐lymphocyte ratio (NLR) and reported the clinical usefulness of these combined markers in patients with surgery alone for ESCC.17 We have never assessed plasma fibrinogen and NLR in patients with advanced ESCC treated with chemoradiotherapy or chemotherapy.
Fibrinogen is a pro‐inflammatory protein produced in the liver via stimulation of interleukin (IL)‐6 and IL‐1β.18, 19 Fibrinogen is transformed to fibrin by activated thrombin in the coagulation cascade, which plays an important role in the malignant process of tumor progression and metastasis.20, 21 Recent studies demonstrate that plasma fibrinogen levels are associated with tumor development in several types of malignancies.6, 22, 23, 24 Similarly, NLR has been focused on as a prognostic factor in patients with many malignancies.9, 25, 26, 27 Neutrophils promote tumor development and progression by providing an adequate tumor microenvironment via the production of cytokines and chemokines.28 However, there have been no studies regarding a combined analysis based on plasma fibrinogen and NLR in patients with advanced ESCC treated with chemoradiotherapy or chemotherapy.
In this study, we investigated plasma fibrinogen, NLR, CRP, and albumin levels between responders and non‐responders to chemoradiotherapy or chemotherapy in patients with advanced ESCC. Furthermore, we assessed the clinical utility of a combined score using cut‐off values of fibrinogen and NLR (F‐NLR score) as a predictor of tumor response and prognosis.
Materials and Methods
Patients
One hundred and nine patients with ESCC treated with chemoradiotherapy or chemotherapy at Kagoshima University Hospital between 2011 and 2014 were retrospectively analyzed. The exclusion criteria of this study were as follows: patients without detailed post‐therapeutic information (n = 10) and patients with unknown fibrinogen concentrations (n = 1). Finally, 98 patients (86 men and 12 women; age range, 46–86 years; average, 64.9 years) with ESCC were enrolled in this study (Fig. 1). All patients were evaluated by blood examinations, esophagogastroduodenoscopy, fluoroscopy, endoscopic ultrasonography, and computed tomography (CT) before starting treatment. To date, we have demonstrated the clinical usefulness of endoscopic ultrasonography for predicting lymph node metastasis in patients with ESCC.29, 30 According to these published reports, lymph nodes were classified into three grades (grade 1, grade 2, and grade 3). Lymph nodes with grade 2 or grade 3 were determined as a metastatic status in the present study. Patients were classified and staged based on the 7th International Union Against Cancer (UICC) criteria of tumor‐node‐metastasis (TNM) classification for esophageal carcinoma.31 Clinicopathological features are shown in Table 1. In the present study, we defined advanced ESCC as a tumor status of clinical stage III or IV. The number of patients in clinical stage III and IV was 48 and 50, respectively. Among 50 patients with stage IV disease, distant lymph node metastases were identified in 36 patients. Eight and 28 patients had metastatic lesions in para‐aortic lymph nodes and supraclavicular lymph nodes, respectively. Liver metastasis was found in seven patients, bone in five patients, and lung in two patients. In this study, resectable ESCC was defined as clinical stage III and T1–3 tumors (n = 31). Two therapeutic strategies were planned in resectable group. From 2011 to 2012, patients with ≥4 metastatic lymph nodes were treated with neoadjuvant chemoradiotherapy. From 2013, neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy were selected based on randomized control trial. On the other hand, unresectable ESCC was defined as clinical stage IV or T4 tumors (n = 67). In the unresectable group, patients with distant metastasis or para‐aortic lymph node metastasis were treated with chemotherapy. Patients having cT4 tumors without distant metastasis or para‐aortic lymph node metastasis were treated with chemoradiotherapy.
Figure 1.
In total, 109 patients with advanced esophageal squamous cell carcinoma (ESCC) treated with chemoradiotherapy or chemotherapy were enrolled in this study. Eleven patients were excluded from this study: 10 without detailed post‐therapeutic information, and one with an unknown fibrinogen concentration. Finally, 79 patients with chemoradiotherapy and 19 patients with chemotherapy were assessed in the analysis.
Table 1.
Clinicopathological characteristics of 98 patients with advanced esophageal squamous cell carcinoma (n = 98)
| Characteristic | n |
|---|---|
| Sex (male/female) | 86/12 |
| Age (range) | 64.9 (46–86) |
| Tumor location | |
| Upper/Middle/Lower | 22/59/17 |
| Depth of tumor invasion | |
| T1/T2/T3/T4 | 4/2/56/36 |
| Lymph node metastasis | |
| N1/N2/N3 | 22/34/42 |
| cStage | |
| III/IV | 48/50 |
| Treatment | |
| Chemoradiotherapy (+Surgery) | 79 (20) |
| Chemotherapy (+Surgery) | 19 (4) |
| Tumor response | |
| Non‐PD (CR‐PR‐SD) | 60 (7/34/19) |
| PD | 38 |
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
The study received approval from the Ethics Committee of Kagoshima University and all patients provided written informed consent for the use and publication of their information.
Treatment and assessment of therapeutic effect
Seventy‐nine of 98 patients received chemoradiotherapy. In chemoradiotherapy, the chemotherapy consisted of two different regimens as follows: a low‐dose FP regimen using 5‐fluorouracil (350 mg/body over 24 h) and cisplatin (7 mg/body over 2 h) or a DCF regimen using docetaxel (60 mg/m2 over 2 h), cisplatin (60 mg/m2 over 2 h), and 5‐fluorouracil (350 mg/m2 over 24 h). Fifty‐nine and 20 patients received a low‐dose FP regimen and a DCF regimen, respectively. A total dose of concurrent fractionated radiation for neoadjuvant and definitive chemoradiotherapy in the same period was 40 Gy and 60 Gy, respectively.1 Twenty‐eight and 51 patients received neoadjuvant chemoradiotherapy and definitive chemoradiotherapy, respectively. Nineteen patients received chemotherapy alone. Chemotherapy was intravenously performed by a DCF regimen using docetaxel (60 mg/m2 over 1.5 h), cisplatin (70 mg/m2 over 3 h), and 5‐fluorouracil (700 mg/m2 over 24 h) or a modified DCF regimen using docetaxel (60 mg/m2 over 2 h), cisplatin (6 mg/m2 over 2 h), and 5‐fluorouracil (350 mg/m2 over 24 h).
Clinical responses were evaluated by CT, 1 month after chemoradiotherapy and two cycles of chemotherapy. Tumor response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).32 Accordingly, tumor response was classified into four groups as follows; complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD).
Clinical follow‐up
All patients were followed‐up by routine blood tests including tumor marker studies (carcinoembryonic antigen, SCC antigen, and p53), CT every 3 months, and endoscopy 6–12 months after discharge. The median follow‐up period in all patients was 15.4 months (range, 1.5–53.5 months). The median follow‐up period in surviving patients was 29.1 months (range, 16.3–53.5 months).
Blood assessment for determination of fibrinogen, NLR, CRP, and albumin
Blood samples were obtained within the 2 weeks before the start of treatment. Plasma fibrinogen concentrations were assayed by the Clauss method using a STA‐R coagulation analyzer (Roche Diagnostics K.K., Tokyo, Japan). Neutrophils and lymphocytes were counted using the XE‐2100 automated hematology analyzer (Sysmex Co., Kobe, Japan). Then, the NLR was indicated as the neutrophil count divided by the lymphocyte count. CRP and albumin levels were determined by a JCA‐BM automatic analyzer (JEL Ltd., Tokyo, Japan).
Grading system for F‐NLR score and GPS
The cut‐off value of plasma fibrinogen concentrations was set at 400 mg/dL based on previous published reports.17, 33, 34 On the other hand, we set the cut‐off value for the NLR at 3.0 based on previous published reports.26, 27, 35 The F‐NLR score was classified into three groups based on each cut‐off value of plasma fibrinogen and NLR as follows; F‐NLR score of 2: both hyperfibrinogenemia (>400 mg/dL) and high NLR (>3.0), F‐NLR score of 1: one of these hematological abnormalities, and F‐NLR score of 0: neither hyperfibrinogenemia nor high NLR. GPS was classified into three groups, as previously described; GPS of 2: both an elevated CRP (>1.0 mg/dL) and hypoalbuminemia (<3.5 g/dL), GPS of 1: one of these hematological abnormalities, and GPS of 0: neither an elevated CRP nor hypoalbuminemia.14
Statistical analysis
The Wilcoxon rank sum test was used to evaluate differences in the relationship among fibrinogen, NLR, CRP, or albumin and tumor response. Overall survival curves were calculated using the Kaplan–Meier method and prognostic differences were determined by the log‐rank test. Prognostic factors were assessed using univariate and multivariate analyses (Cox proportional hazard regression model). All statistical analyses were done using SAS statistical software (SAS Institute Inc., Cary, NC, USA). A P‐value of < 0.05 was considered statistically significant.
Results
Tumor response to chemoradiotherapy or chemotherapy and additional surgery
Seven, 34, 19, and 38 patients had CR, PR, SD, and PD as a tumor response, respectively. Consequently, 60 and 38 patients were grouped as non‐PD and PD, respectively. The disease control rate was 61.2% (60/98). Additional esophagectomy with lymphadenectomy was performed in 21 patients with non‐PD and three patients with PD. The R0 resection rate was 91.7% (22/24).
Correlation between tumor response and fibrinogen, NLR, CRP, or albumin
Plasma fibrinogen concentrations range from 236 to 789 mg/dL in 98 patients with ESCC. The mean fibrinogen concentration (±SD) was 448.2 ± 122.2 mg/dL in all patients. The mean fibrinogen concentrations (±SD) for patients in the PD and non‐PD groups were 481.0 ± 126.5 and 427.5 ± 115.7 mg/dL, respectively (Fig. 2a). Fibrinogen was significantly higher in the PD group than the non‐PD group (P = 0.0419). The mean NLR (±SD) was 3.3 ± 2.8 in all patients (range, 0.57–22.2). The mean NLR (±SD) in patients in the PD and non‐PD groups was 4.4 ± 3.8 and 2.5 ± 1.5, respectively (Fig. 2b). NLR was significantly higher in the PD group than the non‐PD group (P = 0.0001).
Figure 2.
Relationship between tumor response and value of (a) fibrinogen, (b) neutrophil–lymphocyte ratio (NLR), (c) C‐reactive protein (CRP), or (d) albumin. Horizontal bars indicate mean value of each blood marker.
The mean CRP (±SD) values in patients with PD and non‐PD were 2.0 ± 3.1 and 1.0 ± 2.7 mg/dL, respectively (Fig. 2c). CRP was significantly higher in PD group than non‐PD group (P = 0.0254). The mean albumin (±SD) values in patients with PD and non‐PD were 3.6 ± 0.5 and 3.9 ± 0.4 mg/dL, respectively (Fig. 2d). Accordingly, albumin was significantly lower in PD group than non‐PD group (P = 0.0305).
Prognostic analysis based on fibrinogen or NLR levels
Based on the cut‐off value of plasma fibrinogen concentration, 63 and 35 patients were classified into two groups at high (>400 mg/dL) and low (≤400 mg/dL) fibrinogen levels, respectively. Furthermore, 38 and 60 patients had high (>3.0) and low (≤3.0) NLR levels, respectively, according to the determined cut‐off value for the NLR. Patients with high fibrinogen and NLR levels had a significantly worse prognosis than those with low fibrinogen and NLR levels (P = 0.0242 and P = 0.0019, respectively; Fig. 3).
Figure 3.
Kaplan–Meier survival curves according to (a) plasma fibrinogen level and (b) neutrophil–lymphocyte ratio (NLR).
Correlation between tumor response and F‐NLR score and GPS
According to the grading system of the F‐NLR score, 25 (25.5%), 45 (45.9%), and 28 (28.6%) patients had an F‐NLR score of 0, 1, and 2 respectively. An F‐NLR score of 0, 1, and 2 was identified in six (15.8%), 15 (39.5%), and 17 (44.7%) of the 38 patients with PD, respectively (Table 2). In the 60 patients with non‐PD, 19 (31.7%), 30 (50.0%), and 11 (18.3%) had an F‐NLR score of 0, 1, 2 respectively (Table 2). A high F‐NLR score had a significantly closer relationship in patients with PD, than those with non‐PD (P = 0.0140).
Table 2.
Relationship between clinicopathological characteristics and F‐NLR score or GPS (n = 98)
| Factors | F‐NLR score (%) | GPS (%) | ||||||
|---|---|---|---|---|---|---|---|---|
| 0 (n = 25) | 1 (n = 45) | 2 (n = 28) | P‐value | 0 (n = 54) | 1 (n = 30) | 2 (n = 14) | P‐value | |
| Sex | ||||||||
| Male | 22 (88.0) | 39 (86.7) | 25 (89.3) | 0.9455 | 48 (88.9) | 26 (86.7) | 12 (85.6) | 0.9268 |
| Female | 3 (12.0) | 6 (13.3) | 3 (10.7) | 6 (11.1) | 4 (13.3) | 2 (14.4) | ||
| Age (year) | ||||||||
| <70 | 17 (68.0) | 32 (71.1) | 19 (67.9) | 0.9434 | 42 (77.8) | 17 (56.7) | 9 (64.3) | 0.1196 |
| ≥70 | 8 (32.0) | 13 (28.9) | 9 (32.1) | 12 (22.2) | 13 (43.3) | 5 (35.7) | ||
| Tumor location | ||||||||
| Upper | 3 (12.0) | 11 (24.4) | 8 (28.6) | 0.4042 | 12 (22.2) | 5 (16.7) | 5 (35.7) | 0.3775 |
| Middle | 19 (76.0) | 26 (57.8) | 14 (50.0) | 35 (64.8) | 17 (56.7) | 7 (50.0) | ||
| Lower | 3 (12.0) | 8 (17.8) | 6 (21.4) | 7 (13.0) | 8 (26.7) | 2 (14.3) | ||
| Depth of tumor invasion | ||||||||
| T1–T3 | 21 (84.0) | 21 (46.7) | 20 (71.4) | 0.0046 | 38 (70.4) | 19 (63.3) | 5 (35.7) | 0.0565 |
| T4 | 4 (16.0) | 24 (53.3) | 8 (28.6) | 16 (29.6) | 11 (36.7) | 9 (64.3) | ||
| Lymph node metastasis | ||||||||
| N1–N2 | 16 (64.0) | 27 (60.0) | 16 (57.1) | 0.8778 | 33 (61.1) | 20 (66.7) | 6 (42.9) | 0.3225 |
| N3 | 9 (36.0) | 18 (40.0) | 12 (42.9) | 21 (38.9) | 10 (33.3) | 8 (57.1) | ||
| Stage | ||||||||
| III | 14 (56.0) | 24 (53.3) | 10 (35.7) | 0.2419 | 28 (51.9) | 15 (50.0) | 5 (35.7) | 0.5510 |
| IV | 11 (44.0) | 21 (46.7) | 18 (64.3) | 26 (48.1) | 15 (50.0) | 9 (64.3) | ||
| Treatment | ||||||||
| Chemoradiotherapy | 21 (84.0) | 37 (82.2) | 21 (75.0) | 0.6628 | 47 (87.0) | 22 (73.3) | 9 (64.3) | 0.1010 |
| Chemotherapy | 4 (16.0) | 8 (17.8) | 7 (25.0) | 7 (13.0) | 8 (26.7) | 5 (35.7) | ||
| Tumor response | ||||||||
| Non‐PD(CR‐PR‐SD) | 19 (76.0) | 30 (66.7) | 11 (39.3) | 0.0140 | 38 (70.4) | 18 (60.0) | 4 (28.6) | 0.0165 |
| PD | 6 (24.0) | 15 (33.3) | 17 (60.7) | 16 (29.6) | 12 (40.0) | 10 (71.4) | ||
F‐NLR Score, fibrinogen and neutrophil‐lymphocyte ratio score; GPS, Glasgow prognostic score; PD, progressive disease.
Next, the GPS classification showed 54 (55%), 30 (31%), and 14 (14%) patients with a GPS of 0, 1, and 2, respectively. A GPS of 0, 1, and 2 was identified in 16 (42.1%), 12 (31.6%), and 10 (26.3%) of the 38 patients with PD, respectively (Table 2). In the 60 patients with non‐PD, 38 (63.3%), 18 (30.0%), and four (6.7%) had a GPS of 0, 1, and 2, respectively (Table 2). Patients with PD had a significantly higher GPS than those with non‐PD (P = 0.0165).
Prognostic analysis based on F‐NLR score or GPS
The median survival of patients with F‐NLR scores of 0–1 and 2 was 16.9 and 8.7 months, respectively (Fig. 4a). Prognosis was significantly worse in patients with an F‐NLR score of 2, than those with an F‐NLR score of 0–1 (P < 0.0001). Similarly, the median survival of patients at a GPS of 0–1 and 2 was 13.9 and 4.4 months, respectively (Fig. 4b). Survival rate was significantly lower in patients with a GPS of 2 than those with a GPS of 0–1 (P < 0.0001).
Figure 4.
Kaplan–Meier survival curves according to (a) fibrinogen and neutrophil–lymphocyte ratio (F‐NLR) score and (b) Glasgow Prognostic Score (GPS).
Univariate analysis demonstrated clinical stage, treatment, F‐NLR score, and GPS as independent prognostic factors (P = 0.0157, P = 0.0177, P = 0.0001, and P = 0.0002, respectively) (Table 3). F‐NLR score, and GPS were selected as independent prognostic factors in the multivariate analysis (P = 0.0081 and P = 0.0086, respectively) (Table 3).
Table 3.
Univariate and multivariate survival analyses
| Independent factor | Univariate analysis | Multivariate analysis | ||||
|---|---|---|---|---|---|---|
| Hazard ratio | 95% CI | P‐value | Hazard ratio | 95% CI | P‐value | |
| Gender | ||||||
| Male/Female | 1.03 | 0.52–2.33 | 0.9419 | |||
| Age | ||||||
| ≥70/<70 | 1.03 | 0.61–1.70 | 0.9039 | |||
| cStage | ||||||
| 3/4 | 1.78 | 1.12–2.89 | 0.0157 | 1.29 | 0.78–2.16 | 0.3180 |
| Tumor marker | ||||||
| CEA | 0.75 | 0.36–1.40 | 0.3872 | |||
| SCC | 1.09 | 0.66–1.83 | 0.7494 | |||
| Treatment | ||||||
| Chemoradiotherapy/Chemotherapy | 2.01 | 1.14–3.38 | 0.0177 | 1.71 | 0.94–2.97 | 0.0785 |
| F‐NLR score | ||||||
| 0–1/2 | 2.74 | 1.66–4.43 | 0.0001 | 2.10 | 1.22–3.54 | 0.0081 |
| GPS | ||||||
| 0–1/2 | 3.78 | 1.96–6.80 | 0.0002 | 2.60 | 1.29–4.92 | 0.0086 |
CEA, carcinoembryonic antigen; CI, confidence interval; F‐NLR score, fibrinogen and neutrophil‐lymphocyte ratio score; GPS, Glasgow prognostic score; SCC, squamous cell carcinoma antigen.
Discussion
In this study, we assessed the clinical significance of pre‐treatment fibrinogen and NLR levels in patients with advanced ESCC treated with chemoradiotherapy or chemotherapy. Both fibrinogen and NLR have been known to be associated with tumor progression and metastatic developments in patients with various malignancies including ESCC.6, 10, 22, 23, 24, 25, 36 Interestingly, several investigators have demonstrated hyperfibrinogenemia and elevated NLR as a predictor of poor therapeutic response in blood analysis before starting treatment.8, 9, 26, 33 In the present study, the blood levels of fibrinogen and NLR were significantly higher in patients in the PD group than those in the non‐PD group. These findings indicate that fibrinogen and NLR are one of the promising markers for predicting tumor response to the initial chemoradiotherapy or chemotherapy in patients with advanced ESCC. Furthermore, hyperfibrinogenemia (>400 mg/dL) and high NLR (>3.0) significantly correlated with a worse prognosis in this study (P = 0.0242 and P = 0.0019, respectively). According to previous published reports, fibrinogen and NLR are potential predictive markers for prognosis in untreated patients in several resectable cancers, including ESCC.6, 22, 24, 25, 36, 37, 38 However, we simultaneously investigated fibrinogen and NLR to assess the relationship between the values of these blood markers and prognosis in patients with advanced ESCC treated with chemoradiotherapy or chemotherapy. To the best of our knowledge, this is the first report to demonstrate the clinical impact of fibrinogen and NLR in patients with ESCC treated with chemoradiotherapy or chemotherapy due to advanced tumor stage.
The most attractive issue of the present study is that we assess the clinical significance of the F‐NLR score, which consisted of the plasma fibrinogen level and NLR, in patients with advanced ESCC treated with chemoradiotherapy or chemotherapy. We had already demonstrated that F‐NLR score is a useful blood predictor for tumor progression and prognosis in ESCC patients without preoperative treatment.17 In this study, surprisingly, 17 patients (44.7%) had an F‐NLR score of 2 among the 38 patients in the PD group and 11 patients (18.3%) had an F‐NLR score of 2 among the 60 patients in the non‐PD group (Table 2). These findings indicate a close relationship between F‐NLR score and therapeutic effect. Furthermore, this study showed that the median survival times of patients with F‐NLR scores of 0–1 and 2 were 16.9 and 8.7 months, respectively. The survival rate was significantly lower in patients with an F‐NLR score of 2 than in those with an F‐NLR score of 0–1 (P < 0.0001). These results suggest that patients with an F‐NLR score of 2 exhibit aggressive tumor behavior due to the resistance to chemoradiotherapy or chemotherapy. Here, we assessed the relationship between F‐NLR score and tumor response in therapeutic modalities. In chemoradiotherapy group (n = 79), F‐NLR score was significantly correlated with tumor response (P = 0.0062, data not shown). However, tumor response in chemotherapy group was not significantly associated with F‐NLR score (P = 0.9169, data not shown). These inconsistent results may depend on the small patient sample in chemotherapy group (n = 19). It is clinically difficult to discriminate responder from non‐responder before starting chemoradiotherapy or chemotherapy. Additionally, few candidate blood markers for predicting tumor response and prognosis are presently available in patients with advanced ESCC. It is important to solve these key issues in clinical management. Consequently, the F‐NLR score may be focused on as a promising indicator for considering the therapeutic strategy in patients with unresectable advanced ESCC. Since the F‐NLR score, from fibrinogen and the NLR, is determined by conventional blood examinations, a blood approach using the F‐NLR score is a simple and cost‐effective method.
We investigated not only fibrinogen and NLR but also CRP and albumin in the present study. CRP and albumin, underlying the GPS, have been recognized as a prognostic marker in patients with many malignancies.14 Kimura et al.,13 in a study of 142 esophageal cancer patients with stage III and IV receiving chemoradiotherapy, reported that GPS may be a good predictor of chemoradiotherapeutic responsiveness and a prognostic indicator for progression‐free and disease‐specific survival in patients with advanced ESCC. In this study, a high GPS was also significantly associated with a worse tumor response and prognosis. Unfortunately, mGPS was not significantly associated with tumor response (P = 0.3514, data not shown). Therefore, we adopted GPS rather than mGPS as a predictor of tumor response in the present study. Here, we compared the F‐NLR score with the GPS to assess the clinical significance of these scores. Univariate and multivariate analysis of survival showed that F‐NLR score, and GPS were independent prognostic factors in this study. This finding indicates that F‐NLR score, as well as GPS, has a clinical utility for predicting prognosis in patients with advanced ESCC treated with chemoradiotherapy or chemotherapy.
There are some limitations in this study. First, this retrospective study was planned by a single institution. Next, 98 patients with ESCC were enrolled in the present study and the sample size may be insufficient to strengthen our results. Accordingly, further, multicenter validation studies are required to confirm our hypothesis. However, the clinical impact of the F‐NLR score has shown that it may have a prominent role as a preliminary data.
In conclusion, we demonstrated that F‐NLR score, as well as GPS, has clinical potential as a predictive marker for tumor response to chemoradiotherapy or chemotherapy and prognosis in patients with advanced ESCC. The F‐NLR score may serve as an economical biomarker for determining the therapeutic plan in patients with advanced ESCC.
Disclosure Statement
All manuscripts have no conflicts of interest, and no financial disclosures. All manuscripts have no acknowledgement for the authors.
Cancer Sci 108 (2017) 193–199
Funding Information
None.
References
- 1. Natsugoe S, Okumura H, Matsumoto M et al Randomized controlled study on preoperative chemoradiotherapy followed by surgery versus surgery alone for esophageal squamous cell cancer in a single institution. Dis Esophagus 2006; 19: 468–72. [DOI] [PubMed] [Google Scholar]
- 2. John MJ, Flam MS, Mowry PA et al Radiotherapy alone and chemoradiation for nonmetastatic esophageal carcinoma. A critical review of chemoradiation. Cancer 1989; 63: 2397–403. [DOI] [PubMed] [Google Scholar]
- 3. Naunheim KS, Petruska P, Roy TS et al Preoperative chemotherapy and radiotherapy for esophageal carcinoma. J Thorac Cardiovasc Surg 1992; 103: 887–93; discussion 893–5. [PubMed] [Google Scholar]
- 4. Ishida K, Ando N, Yamamoto S et al Phase II study of cisplatin and 5‐fluorouracil with concurrent radiotherapy in advanced squamous cell carcinoma of the esophagus: a Japan Esophageal Oncology Group (JEOG)/Japan Clinical Oncology Group trial (JCOG9516). Jpn J Clin Oncol 2004; 34: 615–9. [DOI] [PubMed] [Google Scholar]
- 5. Ando N, Kato H, Igaki H et al A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5‐fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol 2012; 19: 68–74. [DOI] [PubMed] [Google Scholar]
- 6. Takeuchi H, Ikeuchi S, Kitagawa Y et al Pretreatment plasma fibrinogen level correlates with tumor progression and metastasis in patients with squamous cell carcinoma of the esophagus. J Gastroenterol Hepatol 2007; 22: 2222–7. [DOI] [PubMed] [Google Scholar]
- 7. Tomimaru Y, Yano M, Takachi K et al Correlation between pretherapeutic d‐dimer levels and response to neoadjuvant chemotherapy in patients with advanced esophageal cancer. Dis Esophagus 2008; 21: 281–7. [DOI] [PubMed] [Google Scholar]
- 8. Sato H, Tsubosa Y, Kawano T. Correlation between the pretherapeutic neutrophil to lymphocyte ratio and the pathologic response to neoadjuvant chemotherapy in patients with advanced esophageal cancer. World J Surg 2012; 36: 617–22. [DOI] [PubMed] [Google Scholar]
- 9. Noble F, Hopkins J, Curtis N et al The role of systemic inflammatory and nutritional blood‐borne markers in predicting response to neoadjuvant chemotherapy and survival in oesophagogastric cancer. Med Oncol 2013; 30: 596. [DOI] [PubMed] [Google Scholar]
- 10. Matsuda S, Takeuchi H, Fukuda K et al Clinical significance of plasma fibrinogen level as a predictive marker for postoperative recurrence of esophageal squamous cell carcinoma in patients receiving neoadjuvant treatment. Dis Esophagus 2014; 27: 654–61. [DOI] [PubMed] [Google Scholar]
- 11. Feng JF, Huang Y, Chen QX. Preoperative platelet lymphocyte ratio (PLR) is superior to neutrophil lymphocyte ratio (NLR) as a predictive factor in patients with esophageal squamous cell carcinoma. World J Surg Oncol 2014; 12: 58. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Matsuda S, Takeuchi H, Kawakubo H et al Cumulative prognostic scores based on plasma fibrinogen and serum albumin levels in esophageal cancer patients treated with transthoracic esophagectomy: comparison with the Glasgow prognostic score. Ann Surg Oncol 2015; 22: 302–10. [DOI] [PubMed] [Google Scholar]
- 13. Kimura J, Kunisaki C, Makino H et al Evaluation of the Glasgow Prognostic Score in patients receiving chemoradiotherapy for stage III and IV esophageal cancer. Dis Esophagus 2015; 2016; 29: 1071–80. [DOI] [PubMed] [Google Scholar]
- 14. McMillan DC. The systemic inflammation‐based Glasgow Prognostic Score: a decade of experience in patients with cancer. Cancer Treat Rev 2013; 39: 534–40. [DOI] [PubMed] [Google Scholar]
- 15. Hirashima K, Watanabe M, Shigaki H et al Prognostic significance of the modified Glasgow prognostic score in elderly patients with gastric cancer. J Gastroenterol 2014; 49: 1040–6. [DOI] [PubMed] [Google Scholar]
- 16. Nakagawa K, Tanaka K, Nojiri K et al The modified Glasgow prognostic score as a predictor of survival after hepatectomy for colorectal liver metastases. Ann Surg Oncol 2014; 21: 1711–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Arigami T, Okumura H, Matsumoto M et al Analysis of the fibrinogen and neutrophil‐lymphocyte ratio in esophageal squamous cell carcinoma: a promising blood marker of tumor progression and prognosis. Medicine (Baltimore) 2015; 94: e1702. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Yamaguchi T, Yamamoto Y, Yokota S et al Involvement of interleukin‐6 in the elevation of plasma fibrinogen levels in lung cancer patients. Jpn J Clin Oncol 1998; 28: 740–4. [DOI] [PubMed] [Google Scholar]
- 19. Tennent GA, Brennan SO, Stangou AJ et al Human plasma fibrinogen is synthesized in the liver. Blood 2007; 109: 1971–4. [DOI] [PubMed] [Google Scholar]
- 20. Zacharski LR, Meehan KR, Algarra SM et al Clinical trials with anticoagulant and antiplatelet therapies. Cancer Metastasis Rev 1992; 11: 421–31. [DOI] [PubMed] [Google Scholar]
- 21. Mantovani A, Allavena P, Sica A et al Cancer‐related inflammation. Nature 2008; 454: 436–44. [DOI] [PubMed] [Google Scholar]
- 22. Ghezzi F, Cromi A, Siesto G et al Prognostic significance of preoperative plasma fibrinogen in endometrial cancer. Gynecol Oncol 2010; 119: 309–13. [DOI] [PubMed] [Google Scholar]
- 23. Zhao J, Zhao M, Jin B et al Tumor response and survival in patients with advanced non‐small‐cell lung cancer: the predictive value of chemotherapy‐induced changes in fibrinogen. BMC Cancer 2012; 12: 330. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Sun ZQ, Han XN, Wang HJ et al Prognostic significance of preoperative fibrinogen in patients with colon cancer. World J Gastroenterol 2014; 20: 8583–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. McNamara MG, Templeton AJ, Maganti M et al Neutrophil/lymphocyte ratio as a prognostic factor in biliary tract cancer. Eur J Cancer 2014; 50: 1581–9. [DOI] [PubMed] [Google Scholar]
- 26. Cho IR, Park JC, Park CH et al Pre‐treatment neutrophil to lymphocyte ratio as a prognostic marker to predict chemotherapeutic response and survival outcomes in metastatic advanced gastric cancer. Gastric Cancer 2014; 17: 703–10. [DOI] [PubMed] [Google Scholar]
- 27. Peng B, Wang YH, Liu YM et al Prognostic significance of the neutrophil to lymphocyte ratio in patients with non‐small cell lung cancer: a systemic review and meta‐analysis. Int J Clin Exp Med 2015; 8: 3098–106. [PMC free article] [PubMed] [Google Scholar]
- 28. Gregory AD, Houghton AM. Tumor‐associated neutrophils: new targets for cancer therapy. Cancer Res 2011; 71: 2411–6. [DOI] [PubMed] [Google Scholar]
- 29. Natsugoe S, Yoshinaka H, Shimada M et al Number of lymph node metastases determined by presurgical ultrasound and endoscopic ultrasound is related to prognosis in patients with esophageal carcinoma. Ann Surg 2001; 234: 613–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Sakamoto F, Natsugoe S, Yoshinaka H et al Endosonographic detection of mediastinal lymph node metastasis in superficial carcinoma of the esophagus: assessment by type classification and histogram. J Gastroenterol 2004; 39: 7–13. [DOI] [PubMed] [Google Scholar]
- 31. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010; 17: 1471–4. [DOI] [PubMed] [Google Scholar]
- 32. Eisenhauer EA, Therasse P, Bogaerts J et al New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–47. [DOI] [PubMed] [Google Scholar]
- 33. Lu K, Zhu Y, Sheng L et al Serum fibrinogen level predicts the therapeutic response and prognosis in patients with locally advanced rectal cancer. Hepatogastroenterology 2011; 58: 1507–10. [DOI] [PubMed] [Google Scholar]
- 34. Qiu J, Yu Y, Fu Y et al Preoperative plasma fibrinogen, platelet count and prognosis in epithelial ovarian cancer. J Obstet Gynaecol Res 2012; 38: 651–7. [DOI] [PubMed] [Google Scholar]
- 35. Feng JF, Huang Y, Chen QX. The combination of platelet count and neutrophil lymphocyte ratio is a predictive factor in patients with esophageal squamous cell carcinoma. Transl Oncol 2014; 7: 632–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Shimada H, Takiguchi N, Kainuma O et al High preoperative neutrophil‐lymphocyte ratio predicts poor survival in patients with gastric cancer. Gastric Cancer 2010; 13: 170–6. [DOI] [PubMed] [Google Scholar]
- 37. Yuan D, Zhu K, Li K et al The preoperative neutrophil‐lymphocyte ratio predicts recurrence and survival among patients undergoing R0 resections of adenocarcinomas of the esophagogastric junction. J Surg Oncol 2014; 110: 333–40. [DOI] [PubMed] [Google Scholar]
- 38. Lee SE, Lee JH, Ryu KW et al Preoperative plasma fibrinogen level is a useful predictor of adjacent organ involvement in patients with advanced gastric cancer. J Gastric Cancer 2012; 12: 81–7. [DOI] [PMC free article] [PubMed] [Google Scholar]