Abstract
Background/Aim: The perioperative nutritional status has recently been reported to influence the prognosis of various types of cancer. We investigated the relationship between the Geriatric Nutritional Risk Index (GNRI) and overall survival (OS) and recurrence-free survival (RFS) in patients with esophageal cancer who received radical and adjuvant therapy. Patients and Methods: Patients who underwent radical resection for esophageal cancer at our hospital (n=187) were included. Background characteristics, surgical factors, and OS were examined retrospectively. The GNRI was calculated using preoperative values, with GNRI <98 classified as low-GNRI. Results: Seventy-five and 112 patients were classified into the GNRI-low and -high groups, respectively. The 3- and 5-year OS rates were 75.7% and 66.7%, respectively, in the GNRI-high group and 43.2% and 36.7% in the GNRI-low group; the difference was statistically significant (p<0.001). In the univariate and multivariate analyses, low-GNRI was selected as a risk factor for OS. The hazard ratio for low-GNRI was 2.184 (95% confidence interval=1.361-3.508, p=0.001). The 5-year RFS rate in the high- and low-GNRI groups was 54.6% and 25.0%, respectively (p=0.001). In the univariate and multivariate analyses, low-GNRI was a risk factor for RFS. The hazard ratio for low-GNRI was 1.704 (95%CI=1.121-2.590, p=0.013). Regarding the type of recurrence, lymph node recurrence was significantly more common in the low-GNRI group (p=0.008). Conclusion: Low-GNRI was an independent risk factor for OS and RFS after radical resection of esophageal cancer. The preoperative GNRI may be a useful prognostic factor after esophageal cancer surgery.
Esophageal cancer is the seventh most common type of cancer and sixth leading cause of cancer-related mortality worldwide (1). Curative resection and perioperative adjuvant treatment are the standard treatments for resectable esophageal cancers (2, 3). Although the survival rate after surgery and adjuvant treatment is gradually increasing, almost half of all patients develop recurrent disease even after curative treatment (4). Once recurrence occurs, the prognosis is poor; therefore, it is necessary to identify prognostic factors and add appropriate treatment for high-risk patients.
Recently, perioperative nutritional status has been shown to affect short-term oncological outcomes, such as the incidence of postoperative surgical complications, physical activity after surgery, and the introduction of adjuvant treatment (5). Furthermore, the perioperative nutritional status has been shown to strongly affect long-term oncological outcomes (6). Various nutritional assessment tools, such as the Glasgow Prognostic Score, Prognostic Nutritional Index, and Controlling Nutritional Status, have been evaluated for the clinical impact of oncological treatment and have demonstrated a significant relationship between nutritional assessment tools and oncological outcomes. Among these nutritional assessment tools, the Geriatric Nutritional Risk Index (GNRI) is a promising nutritional assessment tool for the treatment of gastrointestinal cancer. The GNRI, which as published in 2005 by Bouillanne et al., is a nutritional risk index for elderly individuals that is calculated using serum albumin level and actual body weight/ideal body weight (7). However, few studies have evaluated the clinical impact of GNRI in the treatment of esophageal cancer.
In the present study, we evaluated the clinical impact of the GNRI in patients with esophageal cancer who received radical and perioperative adjuvant therapy. We also examined the association between the GNRI and the clinicopathological features of esophageal cancer.
Patients and Methods
Patients and setting. This retrospective study sought to identify the risk factors affecting the overall survival (OS) and recurrence-free survival (RFS) of individuals who had undergone surgical treatment for esophageal cancer. Consecutive patients who received complete resection for primary esophageal cancer at Yokohama City University between 2005 and 2020 were selected based on their medical records. The following inclusion criteria were applied: 1) common pathological type of esophageal cancer, 2) curative resection of esophageal cancer was successfully performed, and 3) the patient had no synchronous or metachronous malignancies. A histopathological examination of the resected specimens was performed, with staging according to the eighth edition of the UICC TNM. The present study received approval from the Research Ethics Committee of Yokohama City University. All patients gave their informed consent for the use of their clinical data without identifying personal information.
GNRI. The GNRI, a nutritional risk index for the elderly, was introduced by Bouillanne et al. in 2005. It is calculated using the following formula:
[1.489 × serum albumin (g/l)] + [41.7 × (current body weight/ideal weight)]. The ideal weights were determined separately for males and females using the Lorentz equation, as follows:
Ideal weight for males: height (cm) − 100 − [(height (cm) − 150)/4] Ideal weight for females: height (cm) − 100 − [(height (cm) − 150)/2.5]. Patients with a GNRI of ≤98 were considered to be at risk for poor nutrition based on previous studies.
Surgical procedure. As a standard procedure, subtotal esophagectomy performed through right thoracotomy or video-assisted surgery, followed by reconstruction using a gastric tube, is the preferred approach. Two-field lymph node dissection is recommended for tumors situated in the middle to lower thoracic esophagus, while three-field dissection is employed for tumors located in the upper thoracic region.
Follow-up. Every patient participated in postoperative follow-up assessments every three months. When possible, data on survival, disease progression, and time of death were recorded for a minimum of five years.
Evaluations and statistical analysis. We defined overall survival (OS) as the duration between surgical treatment and death and defined RFS as the duration between surgery and recurrence or death (whichever came first). For patients who did not experience an event, data were censored at the date of the last observation. The Kaplan–Meier method was employed to plot the OS and RFS curves, which were compared using the log-rank test. The unpaired chi-square test or Student’s t-test was used for comparisons of two groups. Data were expressed as the median (range). p-Values of <0.05 were considered to indicate statistical significance. All statistical analyses were conducted using SPSS (ver.27.0 J Win; IBM, Armonk, NY, USA).
Results
Patients. A total of 187 patients were included in this study. The patients’ ages ranged from 37 to 90 years (median: 69 years). Ninety-nine patients were over 70 years of age, 88 patients were under 70 years of age, 159 patients were men, and 28 patients were women. Seventy-five patients were classified into the low-GNRI group (GNRI <98) and 112 were classified into the high-GNRI group (GNRI >98). There were 110 T2-T3 cases (58.8%) and 88 patients with positive lymph nodes (47.1%). Postoperative complications occurred in 55 (29.4%) patients. When comparing the patient background factors between the low- and high-GNRI groups, there were significant differences in T factor and vascular invasion. The number of patients with aggressive disease was higher in the low-GNRI group.
Survival and prognostic factor analyses. The 3- and 5-year OS rates were 75.7% and 66.7%, respectively, in the high-GNRI group and 43.2% and 36.7% in the low-GNRI group, which amounted to a significant difference (Table I, Figure 1) (p<0.001). Table II shows the univariate and multivariate Cox proportional hazards analyses of the clinicopathological factors for OS. In the univariate analysis, tumor depth on pathology, positive lymph node metastasis, positive lymphatic invasion, positive venous invasion, and GNRI were identified as factors affecting OS. In the multivariate analysis, tumor depth, lymphatic invasion, and GNRI were selected as risk factors for OS. The hazard ratio for low-GNRI was 2.184 [95% confidence interval (CI)=1.361-3.508, p=0.001].
Comparison of survival rates stratified by patient characteristics.
Overall survival of patients with esophageal cancer in the Geriatric Nutritional Risk Index (GNRI)-high (≥98) and GNRI-low (<98) groups.
Uni and Multivariate Cox proportional hazards analysis of clinicopathological factors for overall survival.
The 5-year RFS rates were 54.6% and 25.0% in the high and low GNRI groups, respectively, which amounted to a significant difference (Figure 2) (p=0.001). Table III shows the univariate and multivariate Cox proportional hazards analyses of clinicopathological factors associated with RFS. In the univariate analysis, tumor depth on pathology, positive lymph node metastasis, positive lymphatic invasion, positive venous invasion, and GNRI were also risk factors for RFS. In the multivariate analysis, tumor depth, lymphatic invasion, and GNRI were also selected as risk factors for RFS. The hazard ratio for a low GNRI was 1.704 (95% CI=1.121-2.590, p=0.013).
Recurrence-free survival of patients with esophageal cancer in the Geriatric Nutritional Risk Index (GNRI)-high (≥98) and GNRI-low (<98) groups.
Uni and Multivariate Cox proportional hazards analysis of clinicopathological factors for recurrence-free survival.
When the patterns of recurrence were compared between the high- and low-GNRI groups, lymph nodes (23.2% vs. 41.3%, p=0.008) and local recurrence (10.7% vs. 22.7%, p=0.027) were significantly more common in the low-GNRI group (Table IV).
Patterns of recurrence according to pretreatment fibrinogen levels.
Perioperative clinical course of the GNRI-high group and GNRI-low group. When postoperative surgical complications were compared between the GNRI-low and GNRI-high groups, there were marginal differences in postoperative surgical complications. The incidence of anastomotic leakage in the low- and high GNRI groups was 38.7% and 29.4%, respectively, while that of pneumonia was 29.3% and 22.3%.
Discussion
The purpose of the present study was to determine the clinical impact of the GNRI in patients with esophageal cancer after radical resection. Among patients with esophageal cancer who underwent radical surgery, patients in the low-GNRI group had significantly worse 3- and 5-year OS in comparison to patients in the high-GNRI group. Similarly, the 5-year RFS was worse in the low-GNRI group. In the multivariate analysis, GNRI was also an independent risk factor for OS and RFS. Therefore, our study suggests that the GNRI may be a prognostic factor after the radical resection of esophageal cancer.
In the present study, the GNRI was an independent prognostic factor. Previous studies have reported similar results. Yamana et al. evaluated the clinical impact of the GNRI in 216 patients with esophageal cancer who received curative treatment (8). They were classified into four groups: severe risk (GNRI <82), moderate risk (GNRI 82-92), low risk (GNRI 92-98), and no risk (GNRI >98). They reported that a decreased GNRI was significantly correlated with unfavorable OS (p<0.001), and that a severe or moderate risk classification (GNRI <92) was an independent prognostic factor (hazard ratio=0.50; p=0.002). In addition, Kubo et al. reported the clinical impact of the GNRI in 240 patients with esophageal cancer who underwent curative treatment (9). They were divided into GNRI-low and GNRI-high groups using a cut-off value of 92. In their study, a low GNRI value was an independent prognostic factor for OS (hazard ratio=1.687; p=0.035). In a stage-specific analysis, the primary tumor was larger and preoperative dysphagia was more common in the Stage III low-GNRI group. Both OS and CSS were significantly worse in the low-GNRI group in patients with Stage III disease, but not in patients with other disease stages. Therefore, the GNRI is a useful prognostic factor after esophageal cancer surgery.
Why does the GNRI affect the survival of patients with esophageal cancer? The most likely explanation is that the GNRI status affects postoperative surgical complications. Yamana et al. studied the impact of the GNRI on complications in 122 patients with esophageal cancer who received esophagectomy (10). Patients with GNRI ≥90 and GNRI <90 were classified into the high-GNRI group and low-GNRI groups, respectively. Mortality and morbidity were compared between the two groups, especially with respect to respiratory complications and anastomotic leakage. No significant differences in background or operative factors were found between the two groups. The incidence of respiratory complications was significantly higher in the low-GNRI group (p=0.002), and the multivariate analysis showed that GNRI was the only independent risk factor for respiratory complications (hazard ratio=3.41, 95%CI=1.19-9.76, p=0.022). Kubo et al. analyzed 240 patients with esophageal cancer. Their univariate analysis of postoperative complications showed that the incidence of pulmonary complications was significantly higher in the GNRI-low group than in the GNRI-high group (p=0.024) (9). However, in the multivariate analysis, GNRI was not an independent risk factor for pulmonary complications (odds ratio=1.746; p=0.126). Fang et al. studied 373 patients with esophageal cancer who underwent radical esophagectomy after NAC (11). They reported that the low-GNRI group had a higher incidence of postoperative complications compared to the high-GNRI group (odds ratio=2.023; 95%CI=1.208-3.389, p=0.007). Wang et al. also reviewed and analyzed a prospective institutional database of 192 esophageal cancer patients who underwent esophagectomy. GNRI <92 was considered to indicate nutritional risk. A GNRI of <92 was a risk factor for infection, complications, and delayed discharge (p<0.01) (12).
Regarding the form of recurrence, in our study, lymph node and local recurrences were more common in the low GNRI group. However, there was no difference in hematogenous metastasis, and the reason for this is unclear. Further studies are needed to address this issue.
The present study was associated with some limitations, including its retrospective design and single institution setting. Second, the GNRI is a nonspecific marker of nutrition, and other systemic diseases may affect the GNRI. Therefore, larger multicenter prospective observational studies are needed to establish the role of the GNRI in predicting the outcomes of patients with esophageal cancer.
In conclusion, the GNRI affected both OS and RFS in patients with esophageal cancer. The GNRI also affects postoperative surgical complications and may therefore be a promising prognostic and predictive factor for patients with esophageal cancer that can be used by physicians to select optimal treatment strategies.
Acknowledgements
This study was supported in part by the nonprofit organization of the Yokoyama Surgical Research Group (YSRG).
Footnotes
Authors’ Contributions
AK and TA contributed substantially to this concept and design. TA, YM, KH, KK, and MN made substantial contributions to the data acquisition, analysis, and interpretation. TA, AT, HC, JM, MT, TO, AS, NY, and YR were involved in drafting the manuscript and critically revising it for important intellectual content. TA and IH approved the final version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in association with the present study.
- Received November 15, 2023.
- Revision received December 3, 2023.
- Accepted December 4, 2023.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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