Prognostic impact of preoperative immunenutritional indices in patients undergoing curative resection for non-small cell lung cancer: a retrospective analysis

Introduction

Background

Lung cancer remains one of the leading causes of cancer-related mortality worldwide, and surgical resection is the standard treatment with curative intent. However, even among patients who undergo complete resection, a substantial proportion experience postoperative recurrence, which remains a major determinant of poor prognosis (1). Therefore, accurate identification of high-risk patients prior to surgery is crucial for optimizing therapeutic strategies and postoperative follow-up planning.

Recent studies have demonstrated that inflammation and immune responses within the tumor microenvironment contribute to tumor initiation, progression, and metastasis (1,2), and hematologic indices reflecting these processes have attracted attention as prognostic biomarkers (3-6). Among them, the neutrophil-to-lymphocyte ratio (NLR) has been widely investigated as an indicator of systemic inflammation and immune balance that can be readily calculated from peripheral blood (7). Neutrophils can promote angiogenesis and metastasis through the production of tumor-promoting cytokines and growth factors (8), whereas lymphocytes play a central role in antitumor immunity (9). Consequently, an elevated NLR reflects a “pro-inflammatory and immunosuppressed state”, which has been reported to correlate with tumor progression and an increased risk of recurrence (9).

Rationale and knowledge gap

Although NLR has been identified as an independent prognostic factor in various malignancies, including lung (10), gastric (11), and colorectal cancers (12), most of these studies have focused on patients with unresectable advanced or metastatic disease (13,14). Thus, the prognostic value of NLR for predicting recurrence in completely resected cases has not been fully established (9,15,16).

Moreover, only a limited number of studies have evaluated the relative significance of NLR by comparing it with other immunonutritional indices—such as the prognostic nutritional index (PNI) and the controlling nutritional status (CONUT) score (17-19).

Objective

In this study, we investigated the prognostic utility of preoperative peripheral blood NLR for predicting recurrence in patients with completely resected non-small cell lung cancer (NSCLC). Additionally, we compared NLR with other immunonutritional markers [PNI, geriatric nutritional risk index (GNRI), and CONUT score] to clarify its clinical relevance in risk stratification for recurrence, particularly among patients with pathological stage I disease. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0464/rc).

Methods

Study design

This study was approved by the Ethics Committee of Kochi Medical School (No. ERB-112413), and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The requirement for informed consent was waived due to the retrospective nature of this single-center study.

Patients

The patient selection process is illustrated in Figure 1. Between January 2012 and December 2022, a total of 923 patients with NSCLC underwent complete surgical resection at the Department of Thoracic Surgery, Kochi Medical School. Patients were excluded if they had pathological stage 0 or IIIB, had undergone non-radical resection, had received neoadjuvant treatment, or had incomplete clinicopathological data. Additionally, patients with evidence of active infection, clinically overt inflammatory disease, or were receiving systemic corticosteroid therapy were excluded, given the potential impact of these conditions on systemic inflammatory markers such as NLR.

Figure 1 Flow chart of patient selection. NSCLC, non-small cell lung cancer.

After applying these criteria, 789 patients were included in the final analysis (Cohort 1). Patients with pathological stage I disease were further classified as Cohort 2.

Data collection and follow-up

Patient data, including age, gender, body mass index (BMI), smoking history, surgical procedure, histological subtype, pathological stage, presence of lymphatic, vascular, or pleural invasion, NLR, PNI, GNRI, and CONUT score were retrospectively extracted from pathology reports, electronic medical records, and clinical charts. Although some clinicopathological variables were assessed postoperatively, the primary objective of this study was to evaluate the prognostic impact of preoperative immunenutritional indices, particularly NLR. Blood samples obtained from 2 weeks before surgery to the day before surgery were used for preoperative laboratory analyses. Postoperative follow-up consisted of physical examinations, blood tests, and chest radiographs every three months for the first three years, and every six months thereafter. Chest and abdominal computed tomography (CT) scans were performed at least annually. Clinicopathological characteristics and recurrence-free survival (RFS) were retrospectively analyzed.

Statistical analysis

To identify predictors of postoperative recurrence, receiver operating characteristic (ROC) curve analysis was performed for continuous variables such as age, BMI, NLR, PNI, GNRI and CONUT score. Optimal cutoff values were determined using the maximum Youden index. Univariate and multivariate Cox proportional hazards regression analyses were used to identify potential preoperative predictors of recurrence. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. A two-sided P value of <0.05 was considered statistically significant.Variables included in the univariate analysis were gender, age, BMI, smoking history, surgical procedure, histological subtype, pathological stage, the presence of lymphatic, vascular, or pleural invasion and immunenutritional factors such as NLR, PNI, GNRI and CONUT score. Due to the retrospective nature of the study, these variables were assessed postoperatively. Continuous variables are presented as medians and ranges and were compared using the Student’s t-test. Categorical variables were compared using the chi-square test. Statistical analyses were performed using JMP Pro (SAS Institute, Cary, NC, USA). Although the primary aim of this study was to evaluate preoperative predictors of recurrence, several postoperative pathological variables (e.g., lymphatic, vascular, and pleural invasion) were included in the analysis to adjust for tumor aggressiveness. These factors were not intended for preoperative risk stratification but were incorporated to assess the independent prognostic value of preoperative immunonutritional indices. Multicollinearity with pathological stage was assessed separately in each cohort; therefore, the variables included in the final multivariable model differed between Cohort 1 and Cohort 2 according to the results of the multicollinearity assessment.

Results

Patient characteristics

A total of 789 patients were included in the analysis (Cohort 1). Their clinicopathological characteristics are summarized in Table 1. The median age was 73 years (range, 19–92 years); 389 patients (49.3%) had a history of smoking, and 476 (60.3%) were male. A sublobar resection was performed in 277 patients (35.1%). The majority of patients (71.7%) were diagnosed with adenocarcinoma. Postoperative recurrence was observed in 178 cases (22.6%).

In Cohort 2, pathological stage IA and IB accounted for 79.2% and 20.8% of patients, respectively, and 75.5% were diagnosed with adenocarcinoma. Postoperative adjuvant chemotherapy was administered in 53 patients (8.9%). Postoperative recurrence was observed in 91 cases (15.3%) (Table 2).

ROC analysis of clinical factors for RFS prediction

To evaluate the predictive performance of various clinical parameters—namely age, BMI, NLR, PNI, GNRI and CONUT score—in RFS, ROC curve analyses were performed.

The optimal cut-off values for each factor were determined within each cohort. In Cohort 1, the cut-off values were as follows: age, 65 years; BMI, 19.7; NLR, 2.12; PNI, 47.5; GNRI, 104.7; CONUT score, 2. In Cohort 2, the respective cut-offs were 71 years, 21.2, 2.28, 52.5, 112.3, 4. In Cohort 2, ROC curves were generated to compare the utility of NLR and other immunonutritional markers for predicting recurrence, as shown in Figure 2. Among the evaluated indices, NLR was identified as the most sensitive prognostic marker.

Figure 2 Receiver operating characteristic curves to compare the immunonutritional markers for predicting recurrence. Among the evaluated indices, NLR was identified as the most sensitive prognostic marker (AUC: 0.642). AUC, area under the curve; CONUT, controlling nutritional status; GNRI, geriatric nutritional risk index; NLR, neutrophil-to-lymphocyte ratio; PNI, prognostic nutritional index.

Survival analysis according to NLR and PNI level

The optimal cut-off values of NLR for RFS, as determined by ROC curve analysis, were 2.12 in Cohort 1 and 2.28 in Cohort 2. In Cohort 1, 314 patients (39.8%) were classified into the low-NLR group, and 475 patients (60.2%) into the high-NLR group. Kaplan-Meier survival analysis revealed that patients in the high-NLR group had significantly poorer RFS compared to those in the low-NLR group (5-year RFS: 67.8% vs. 80.3%, P<0.001; Figure 3A).

Figure 3 Kaplan-Meier curves for RFS between high and low NLR groups. (A) Overall (Cohort 1: n=789); (B) pathological stage I (Cohort 2: n=596). NLR, neutrophil-to-lymphocyte ratio; RFS, recurrence-free survival.

Similarly, in Cohort 2, 48.2% of patients were categorized into the high-NLR group and demonstrated significantly worse RFS (5-year RFS: 75.6% vs. 87.8%, P<0.001; Figure 3B).

Regarding the PNI, the cut-off values were 47.5 in Cohort 1 and 52.5 in Cohort 2. Patients in the low-PNI group showed significantly worse RFS compared to those in the high-PNI group (Cohort 1: P<0.001, Figure 4A; Cohort 2: P=0.01, Figure 4B).

Figure 4 Kaplan-Meier curves for RFS between high and low PNI groups. (A) Overall (Cohort 1: n=789); (B) pathological stage I (Cohort 2: n=596). PNI, prognostic nutritional index; RFS, recurrence-free survival.

We performed subgroup analyses of NLR and PNI according to surgical procedure—limited resection and lobectomy or more extensive resection (Figures 5,6).

Figure 5 Kaplan-Meier curves for RFS between high and low NLR groups stratified by surgical procedure in patients with pathological stage I disease. (A) Sublobar resection; (B) lobectomy. NLR, neutrophil-to-lymphocyte ratio; RFS, recurrence-free survival.

Figure 6 Kaplan-Meier curves for RFS between high and low PNI groups stratified by surgical procedure in patients with pathological stage I disease. (A) Sublobar resection; (B) lobectomy. PNI, prognostic nutritional index; RFS, recurrence-free survival.

In patients who underwent lobectomy, both markers showed significant differences in RFS between high and low groups. In contrast, no statistically significant differences were observed in patients who underwent limited resection.

Prognostic impact of the immunonutritional score and other clinicopathological factors

Table 3 presents the results of the analysis in Cohort 1. In the univariate Cox regression analysis, sex, age, BMI, histological subtype, pathological stage, lymphatic invasion, vascular invasion, pleural invasion, as well as NLR, PNI and CONUT score were identified as significant prognostic factors. In the multivariate analysis, excluding lymphatic, vascular, and pleural invasions due to multicollinearity with pathological stage, sex (P=0.03), age (P=0.01), BMI (P=0.02), and pathological stage (P<0.001) remained independent adverse prognostic factors for RFS. NLR did not reach statistical significance (P=0.07), although a trend toward worse RFS was observed.

In Cohort 2, multivariate analysis revealed that age (P=0.04), pathological stage (P=0.006), lymphatic invasion (P=0.046), and elevated NLR were independent adverse prognostic factors (HR: 1.67, 95% CI: 1.05–2.64; P=0.03) (Table 4).

Discussion

In the present study, we demonstrated that the preoperative NLR is a useful predictor of recurrence in patients with NSCLC who underwent complete resection. Patients in the high NLR group had significantly shorter RFS, and NLR was identified as an independent predictor of recurrence even in pathological stage I cases. Although NLR was associated with prognosis in the overall cohort, it did not retain its independence in multivariable analysis. These findings suggest that NLR may reflect both the biological aggressiveness of the tumor and the host’s immune-inflammatory status.

The prognostic significance of NLR in NSCLC has been previously reported (4,9,15,20), with proposed cutoff values ranging from 1.5 to 3.5 in stage I disease (9,20). The cutoff value identified in this study (2.28) is consistent with these reports. Although stage I NSCLC is generally associated with a favorable prognosis, a subset of patients experience recurrence, highlighting the need for more precise risk stratification. Many previous studies have focused on advanced or unresectable cases (13,14), and evidence in completely resected cases remains limited (9,15,16). Our study helps address this gap. Postoperative adjuvant chemotherapy was administered in only a small proportion of patients (8.9%), and its impact on recurrence was limited, without affecting the multivariable analysis. In addition, factors such as lymphatic and vascular invasion included in the multivariable model are postoperative pathological findings and are not available preoperatively. Therefore, caution is required when interpreting NLR as a preoperative biomarker, and further studies focusing solely on preoperative factors are warranted.

In this study, we compared several immunonutritional indices; however, in the analysis limited to stage I cases, only NLR remained an independent predictor of recurrence. This may be explained by differences in the biological background reflected by each index. NLR directly reflects the balance between systemic inflammation and antitumor immunity: neutrophils promote tumor progression through angiogenesis and suppression of cytotoxic lymphocyte activity, whereas lymphocytes play a central role in immune surveillance (3,9,21). In contrast, indices such as PNI, GNRI, and CONUT are strongly influenced by nutritional status, particularly serum albumin levels, and may not adequately reflect tumor-specific immune responses, especially in early-stage disease.

Furthermore, the majority of patients in our cohort had pathological stage I disease and were generally well-nourished. Such homogeneity may have reduced the discriminatory ability of nutrition-based indices. In contrast, NLR may capture subtle differences in inflammation and immune response even in early-stage disease. Nutritional indices are also susceptible to the effects of aging, comorbidities, and chronic inflammation, whereas NLR, derived from leukocyte differentials, may better reflect tumor-specific prognostic information. Additionally, methodological differences such as cutoff values and study design may contribute to discrepancies among studies. The cutoff values derived from ROC analysis within our cohort may also have influenced the relative performance of each index.

Biologically, an elevated NLR may contribute to tumor progression through multiple mechanisms. Tumor-associated neutrophils promote angiogenesis via vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs), and facilitate metastasis through the formation of neutrophil extracellular traps (NETs) (22,23). Conversely, lymphopenia reflects impaired cellular immunity and is associated with reduced ability to eliminate residual tumor cells after surgery. Thus, a high NLR represents a tumor-promoting systemic condition characterized by enhanced inflammation and immunosuppression, which may explain its association with postoperative recurrence.

Although an association between high NLR and poor prognosis in lung cancer has been reported (1,24). Most studies have focused on advanced or unresectable disease, and investigations evaluating recurrence in completely resected cases remain limited. Our study addresses this knowledge gap, and given the increasing use of sublobar resection for early-stage NSCLC, NLR may be a particularly useful biomarker for postoperative risk stratification.

Clinical implications

Clinically, incorporating preoperative NLR into perioperative risk stratification offers several potential advantages. First, it may help identify high-risk patients even among those with stage I disease, who are generally considered low risk, thereby enabling closer postoperative surveillance. Second, NLR may complement conventional clinicopathological factors and contribute to identifying a “biologically high-risk” subgroup. Third, although not directly examined in this study, elevated preoperative NLR may serve as a potential indicator for risk-adapted treatment strategies in the future, such as patient selection for clinical trials or adjuvant therapy (25,26). However, these clinical applications require validation in prospective studies. Overall, NLR is a simple and readily available biomarker that may contribute to individualized postoperative management.

Limitations

This study has several limitations. First, it is a retrospective single-center study and may be subject to selection bias. Second, NLR may be influenced by transient inflammatory conditions such as infection, physiological stress, and comorbidities. Although patients with infection or steroid use were excluded, subclinical inflammatory conditions could not be completely eliminated. Third, NLR was assessed at a single preoperative time point, which may limit reproducibility. In addition, the cutoff value was derived from the same cohort, raising the possibility of overfitting and necessitating external validation. Finally, the inclusion of postoperative pathological factors in the multivariable analysis represents a methodological limitation, restricting the direct applicability of the findings to preoperative risk stratification.

Conclusions

In this study, NLR was identified as a potentially useful predictor of recurrence in patients with pathological stage I NSCLC who underwent complete resection, although its prognostic value was not independent in the overall cohort. NLR is a practical and non-invasive risk assessment marker that can be easily calculated from routine blood tests. Further research is warranted to elucidate the relationship between perioperative changes in NLR and patient outcomes and to explore clinical applications such as follow-up strategies based on longitudinal NLR monitoring.

Acknowledgments

This study was presented as an abstract at the 43rd Annual Meeting of the Japanese Association for Chest Surgery, held on May 14–15, 2026, in Ibaraki, Japan.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0464/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0464/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0464/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0464/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Ethics Committee of Kochi Medical School (No. ERB-112413), and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The requirement for informed consent was waived due to the retrospective nature of this single-center study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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