Abstract
Background/Aim: Esophageal squamous cell carcinoma (ESCC) is a deadly malignant disease. This study examined whether the platelet-to-lymphocyte ratio (PLR) can be used as a biomarker to evaluate prognosis in patients with advanced ESCC following neoadjuvant chemotherapy (NAC) and undergoing minimally invasive esophagectomy (MIE). Patients and Methods: We examined 174 patients between January 2010 and December 2015 at the Kobe University. Of these, 121 were treated with NAC. The PLR cutoff was determined through receiver-operating characteristic curve analysis. Univariate and multivariate analyses were conducted to identify prognostic factors for overall survival (OS). Results: The PLR cutoff for OS in 121 patients was 169.6. Patients with PLR ≥169.6 had worse 5-year OS rates (31.1%) than those with a PLR <169.6 (61.1%, p=0.001). Multivariate analysis revealed that a PLR of ≥169.6 was an independent factor for poor prognosis. Conclusion: PLR is an independent prognostic factor for patients with ESCC after NAC and MIE.
Esophageal squamous cell carcinoma (ESCC) is the sixth leading cancer-related cause of death worldwide (1). Despite improvements in surgical techniques (2-4), treatment strategies, and postoperative care, the morbidity and mortality associated with ESCC remain serious, with 5-year overall survival (OS) rates ranging within 15-25% (5, 6). Neoadjuvant chemotherapy (NAC) is one of the standard treatment strategies used worldwide. In Japan, 5-fluorouracil and cisplatin (FP) are typically used preoperatively in patients with advanced ESCC (7). However, esophagectomy is an invasive surgery and thought to be a cause of high morbidity and mortality (8, 9). Minimally invasive esophagectomy (MIE), which employs both laparoscopic and thoracoscopic approaches, has become popular for downregulating invasiveness and the overall risk of postoperative respiratory complications, such as atelectasis (10-13). Furthermore, perioperative inflammatory responses play a key role in carcinogenesis (14). For instance, the neutrophil-to-lymphocyte ratio (NLR), which is a clear and immediate inflammatory marker, has been used as a prognostic biomarker in ESCC (15). In addition, the serum platelet-to-lymphocyte ratio (PLR) has been used to predict tumor behavior in several solid tumors (16-20). However, there have been no reports on PLR in ESCC patients treated with MIE after NAC. Despite platelets acting as primary agents in hemostasis (21), the interaction between tumor microenvironments and platelets controls the modulation of angiogenesis (22). Therefore, this study examined whether the preoperative PLR is a useful prognostic factor for ESCC patients treated with MIE after NAC.
Patients and Methods
McKeown MIE, which is our standardized surgical procedure, was performed between January 2010 and December 2015 in 220 patients with ESCC placed in the prone position. Among them, 22 patients with metastatic spread, five patients who underwent macroscopic incomplete resection, one patient who underwent salvage operation, and 18 patients with missing reports were excluded. In total, 174 patients with ESCC, of which 121 were treated with NAC, were enrolled. NAC comprised two 21-day courses of FP (800 mg/m2 of 5-fluorouracil and 80 mg/m2 of cisplatin). Esophagectomy alone was performed in the remaining 53 patients with a cT1N0M0 status. PLR was calculated from the hematological data obtained during the initial and preoperative medical examinations.
The patients were then divided into two groups according to the PLR cutoff for OS, which was calculated using receiver operating characteristic (ROC) analysis (23, 24). We assessed the relationship between the PLR values and clinicopathological factors. We then investigated the independent prognostic factors for OS using the Cox proportional hazard model. We also classified the patients according to sex, age, tumor location, tumor invasion depth, lymph node metastasis, postoperative anastomotic leakage, postoperative pneumonia, operative time, and operative blood loss. The tumor invasion depth and lymph node metastasis were evaluated using the eighth edition of the Union for International Cancer Control classification of malignant tumors (25). Perioperative complications were evaluated according to the Clavien–Dindo classification (26). Our research was approved by the institutional review board of the Kobe University.
Statistical analyses. The PLR cutoffs for OS, age, operative time, and amount of blood loss during surgery were determined using ROC curve analysis. To evaluate the relationship between PLR values and clinicopathological factors, we used the χ2 test. Survival curves by PLR were examined using the Kaplan–Meier and log-rank tests. To identify independent prognostic factors for OS, univariate and multivariate analyses were performed using the Cox proportional hazard model. Statistical significance was set at p<0.1 in the univariate analysis and p<0.05 in the subsequent multivariate analysis. We used JMP® (version 14.2; SAS Institute Inc., Cary, NC, USA) for all analyses.
We used ROC curves to plot the sensitivity and false-positive rates for the cutoffs, and the area under the ROC curve (AUC) indicated the accuracy of the test (23).
Results
According to the ROC curve, the PLR cutoff for OS was 169.6 (p=0.0183; Figure 1). The patients were divided into two groups based on their PLRs (PLR ≥169.6, n=58; and PLR <169.6, n=116). Table I presents the characteristics of both groups. The cutoff values for age, operative time, and intraoperative blood loss, which were determined according to the ROC curve for OS, were 63 years, 740 minutes, and 415 ml, respectively. There were no significant differences in clinicopathological factors according to PLR values (Table I). Figure 2 presents the OS curves for both groups. The OS was shorter in those with a PLR ≥169.6 (p=0.0089). The 5-year OS rates among those with a PLR <169.6 and those with a PLR ≥169.6 were 66.1% and 46.6%, respectively. As presented in Table II, multivariate analysis showed that a PLR of ≥169.6 [hazard ratio (HR)=1.812; 95% confidence interval (CI)=1.063-3.089; p=0.028], tumor invasion depth (p<0.0001), lymph node metastasis (p<0.0001), pneumonia (HR=1.791; 95%CI=1.086-2.953; p=0.022), and operative time (HR=1.819; 95% CI=1.095-3.021; p=0.020) were independent prognostic factors of low OS.
To assess the correlation between the cutoff value of PLR and overall survival in 174 patients, we performed an ROC curve analysis. p=0.0183, AUC=0.60872. PLR, Platelet-to-lymphocyte ratio; ROC, receiver operating characteristic; AUC, area under the curve.
Characteristics of 174 patients who were grouped based on the PLR cutoff value.
Kaplan–Meier curve analysis was performed to evaluate overall survival differences in 174 patients. Patients were divided into two groups according to the PLR cutoff value of 169.6. Those with a PLR ≥169.6 exhibited worse overall survival than those with a PLR <169.6 (p=0.0089). PLR, Platelet-to-lymphocyte ratio.
Univariate and multivariate analyses of prognostic factors for overall survival in 174 patients.
We also analyzed the data of 121 patients who underwent NAC followed by MIE. As presented in Figure 3, the PLR cutoff was also 169.6 (p=0.0016), and the AUC was 0.6439. The patients were also divided by PLR cutoff values (PLR ≥169.6, n=40; and PLR <169.6, n=81). Table III illustrates the characteristics of both groups. The cutoff values for age, operative time, and perioperative blood loss, that were determined according to the ROC curve for OS, were 63 years, 711 minutes, and 415 ml, respectively. We found a significant difference in intraoperative blood loss based on PLR (p=0.0233). Figure 4 presents the OS curves for the two groups. The OS was shorter in those with a PLR ≥169.6 (p=0.0010). The 5-year OS rates among those with a PLR <169.6 and those with a PLR ≥169.6 were 61.1% and 31.1%, respectively. As presented in Table IV, multivariate analysis showed that a PLR of ≥169.6 (HR=2.350; 95% CI=1.293-4.243; p=0.005), tumor invasion depth (p=0.0161), lymph node metastasis (p<0.0001), and intraoperative blood loss (HR=1.775; 95% CI=1.008-3.126; p=0.046) were independent factors of poor prognosis.
To assess the correlation between the cutoff value of PLR and overall survival in 121 patients, we performed ROC curve analysis. p=0.0016, AUC=0.64393. PLR, Platelet-to-lymphocyte ratio; ROC, receiver operating characteristic; AUC, area under the curve.
Characteristics of 121 patients who received neoadjuvant chemotherapy grouped by PLR.
Kaplan–Meier curve analysis was performed to evaluate overall survival differences among 121 patients who received NAC. Patients were divided into two groups according to the PLR cutoff value of 169.6. Those with a PLR ≥169.6 (31%) exhibited worse overall survival than those with a PLR <169.6 (61%, p=0.0010). NAC, neoadjuvant chemotherapy; PLR, platelet-to-lymphocyte ratio.
Univariate and multivariate analyses of prognostic factors for overall survival in 121 patients following neoadjuvant chemotherapy.
Discussion
To the best of our knowledge, this is the first study to examine preoperative PLR as a prognostic factor in patients undergoing MIE and NAC who were using FP. Our findings are specific because all patients underwent MIE. Compared to findings of previous studies that describe post-thoracostomy esophagectomy, those of our study are novel. Inflammations in living bodies, such as breast tumors, play an important role in tumor proliferation and promotion of angiogenesis and metastasis (27). In addition, inflammation may be associated with the microenvironment where malignant cell growth is promoted (28, 29). Platelets produce various cytokines, such as vascular endothelial growth factors, which regulate angiogenesis (30, 31). Platelets, which are activated by inflammatory cells, can also promote neoplasm growth in endothelial cells (32). For example, in gastric cancer, research shows that platelets promote a malignant reaction to gastric cancer cells through direct contact between the epithelium and the mesenchyme (33). Therefore, the role of platelets in tumor growth, inflammation, and regeneration has become widely recognized.
Conversely, since 1863 it has been suggested that lymphoreticular cell infiltration may contribute to carcinogenesis at chronic inflammatory sites (34). Specific tumor-infiltrating lymphocyte subsets (TILs) influence tumor growth and regression (28). The impact of TILs has generally been investigated on several digestive organ tumors (35). However, few studies have examined the relationship between TILs and prognosis of esophageal cancers (36, 37).
Our study demonstrated that a higher PLR before NAC was related to poor immune function and poor prognosis. According to the CheckMate 577 trial, adjuvant therapy using nivolumab prolonged the disease-free survival in patients with resected gastroesophageal junctions or esophageal cancers who were treated with neoadjuvant chemoradiotherapy (38). The significance of NAC for advanced ESCC has been recognized; however, there are few effective regimens (7). Therefore, it is important to identify novel biomarkers that may respond to chemotherapy or immune checkpoint inhibitors (ICIs). Long-term results have demonstrated the efficacy of ICIs in patients with ESCC. PD-L1 tumor expression and TILs could also be useful for determining whether to introduce ICI therapy (39). Our results suggest that PLR may help predict the efficacy of NAC and ICIs. However, it is difficult to prognosticate using a single biomarker. Further studies are required to identify biomarkers in larger populations.
This study has several limitations. First, there was potential selection bias because the patients were retrospectively analyzed. Second, the study had a small sample size and was conducted at a single center. Therefore, a larger trial size, based on a bigger dataset, is needed to confirm our findings. Moreover, prospective studies should also be considered to improve these limitations.
Acknowledgements
We thank the members of the Department of Gastrointestinal surgery, Kobe University for their valuable insight and technical guidance.
Footnotes
Authors’ Contributions
Takashi Kato, Taro Oshikiri, Hironobu Goto, and Yoshihiro Kakeji designed the study. Hitoshi Harada, Naoki Urakawa, and Shingo Kanaji interpreted the study data. Ryuichiro Sawada, Hiroshi Hasegawa, Kimihiro Yamashita, and Takeru Matsuda analyzed the data. All authors revised the report, commented on the manuscript, and approved the final report.
Conflicts of Interest
The Authors declare no conflicts of interest.
- Received January 12, 2022.
- Revision received March 16, 2022.
- Accepted March 23, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
