Predictive factors for late recurrence beyond 5 years after curative resection of stage I non-small cell lung cancer: a risk scoring approach

Introduction

Background

Lung cancer remains a leading cause of cancer-related mortality worldwide, with a generally poor prognosis. In this study, early-stage non-small cell lung cancer (NSCLC) is defined as pathological stage I NSCLC based on the 8th edition of the Union for International Cancer Control (UICC) classification. Even in such early-stage cases, including pathological stage IA, the 5-year overall survival (OS) rate ranges from 80% to 93% (1-5).

Postoperative recurrence poses a major challenge, with approximately 80% of recurrences occurring within the first two years after surgical resection (3,6). Consequently, most follow-up protocols emphasize surveillance during this early period. While several studies have identified prognostic factors associated with recurrence within five years of surgery (7), limited data are available regarding recurrence patterns and long-term outcomes beyond this timeframe.

Notably, Nakao et al. (8) conducted a prospective observational study involving 26 patients who underwent intentional limited resection (ILR) and reported that 15% experienced likely local recurrence at the resection margin more than five years postoperatively. These findings suggested that the conventional five-year follow-up period may be insufficient to detect all clinically significant recurrences. Furthermore, data from a nationwide retrospective registry established by the Japanese Association for Thoracic Surgery showed a 5-year recurrence-free survival (RFS) rate of 93.3% following ILR (9). While the majority of recurrences occurred within the first three years, a second peak in recurrence incidence was observed approximately 8 to 9 years after surgery.

Rationale and knowledge gap

These observations raise an important clinical question: whether it is appropriate to discontinue surveillance five years after surgery for early-stage NSCLC. Identifying patients at risk for late recurrence remains an unmet need and is essential for optimizing long-term follow-up strategies.

Objective

Therefore, the aim of this study is to investigate the clinical characteristics and risk factors of patients with pathological stage I NSCLC who experienced recurrence more than five years after surgery, and to propose evidence-based recommendations for long-term postoperative surveillance. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1257/rc).

Methods

Patient population

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. It was approved by the institutional ethics committee of Kochi Medical School (No. ERB-10449). In this retrospective study, the requirement for individual informed consent was waived.

A detailed flowchart outlining the patient selection process is presented in Figure 1. Between January 2012 and December 2022, 923 patients underwent curative-intent surgical resection for NSCLC at our institution. Patients were excluded if they met any of the following criteria: history of prior thoracic or lung cancer surgery; diagnosis of another malignancy within the preceding five years; receipt of neoadjuvant therapy for lung cancer, or insufficient clinical data. After applying these criteria, 829 patients remained eligible. Subsequently, patients were excluded if they had pathological stage 0, II, III, or IV disease (n=289) or a postoperative follow-up period of less than five years (n=354). As a result, the final analysis included 186 patients with pathological stage I NSCLC and a minimum follow-up duration of five years after surgical resection.

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

Preoperative staging

All patients underwent preoperative chest contrast-enhanced computed tomography (CT) and positron emission tomography (PET)/CT imaging, except in a few cases deemed clinically unnecessary. In cases with suspicious mediastinal lymphadenopathy on imaging, further evaluation was performed using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) or mediastinoscopy.

Surgical procedure

Surgical procedures included lobectomy, segmentectomy, and wedge resection, based on tumor size, location, and patient condition. Systematic mediastinal lymph node dissection was performed in the majority of cases, while lymph node sampling was adopted in selected low-risk patients.

Patient outcomes and follow-up

Postoperative follow-up consisted of chest CT, physical examinations, and blood tests every 3–6 months for the first 3 years and every 6–12 months thereafter. Additional imaging, including ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI), was performed when clinically indicated. The median follow-up duration was 74 months (mean: 81.9; range, 61–153 months). The primary outcome was RFS, defined as the interval from initial surgical resection to the first documented recurrence, diagnosed primarily through imaging and physical examination, with histopathological confirmation when feasible. Second primary tumors were identified based on pathological and radiological findings, using modified Martini and Melamed criteria (10). Additionally, patients diagnosed with second primary lung cancers based on modified Martini and Melamed criteria were excluded from this study.

CT evaluation of primary tumor

Contrast-enhanced CT was performed using a 64-slice multidetector scanner (LightSpeed VCT, GE Medical Systems, Milwaukee, WI, USA). The largest axial dimension of the solid component, excluding any non-solid parts, was measured on lung window settings and defined as the solid part size. The maximum tumor diameter was also measured in the axial plane. Ground-glass opacity (GGO) was defined as a hazy area of increased lung attenuation that did not obscure the underlying bronchial or vascular structures. Preoperative CT images were analyzed to assess the overall tumor diameter, total lesion area, consolidation-to-tumor (C/T) ratio, and the mean CT attenuation value (mCT value).

Statistical analysis

To evaluate predictors of postoperative recurrence, receiver operating characteristic (ROC) curve analysis was performed for continuous variables, including age, body mass index (BMI), standardized uptake value (SUV), carcinoembryonic antigen (CEA) level, C/T ratio, mCT value, and tumor size. Optimal cutoff values were determined based on the maximum Youden index.

Univariate and multivariate Cox proportional hazards regression analyses were conducted to identify potential clinicopathological predictors of recurrence. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated, and P values <0.05 were considered statistically significant (two-sided). Variables assessed in the univariate analysis included age, sex, BMI, smoking status, PET-derived SUV, CEA level, C/T ratio, mCT value, whole and invasive tumor size, surgical procedure, histological type, pathological stage, and presence of lymphatic, vascular, or pleural invasion. These variables were selected postoperatively due to the retrospective nature of the study. Variables with P<0.05 in univariate analysis were included in the multivariate model. Continuous variables are presented as mean ± standard deviation (SD), and comparisons between groups were made using the Student’s t-test. Categorical variables were compared using the chi-square test. All statistical analyses were performed using SAS software (SAS Institute Inc., Cary, NC, USA).

Results

Clinicopathological characteristics of the patients according to the presence of late recurrence

Among 540 patients with pathological stage I disease, 23 patients (4.3%) experienced late recurrence beyond 5 years. Among the 186 patients who were recurrence-free at 5 years and followed for more than 5 years, 23 (12.4%) subsequently experienced late recurrence beyond 5 years, while 163 (87.6%) remained recurrence-free during the extended follow-up period. The overall 5-year OS rate was 92.4%.

The clinicopathological backgrounds of patients with and without recurrence are summarized in Table 1. Patients with recurrence were significantly older, had higher CEA levels, larger tumor diameter, and more frequent lymphatic invasion. Although not statistically significant, there was a tendency toward lower BMI, higher mCT values, and more frequent pleural invasion in the recurrence group.

Initial site of failure of late recurrence

Table 2 summarizes the patterns and sites of late recurrence in 23 cases. Twelve cases involved locoregional recurrence, while 11 cases presented with distant metastasis. Among the locoregional recurrences, 5 cases involved mediastinal lymph nodes, 2 cases each involved the surgical margin, hilar lymph nodes, and pleural dissemination, and 1 case involved supraclavicular lymph nodes. Four cases exhibited recurrence in multiple organs, whereas 7 cases had recurrence confined to a single organ. In the two cases with ipsilateral pulmonary lesions, the diagnosis of recurrence was made based on radiographic continuity, morphological similarity, and timing of the new lesion, which were consistent with modified Martini and Melamed criteria for recurrent disease rather than second primary lung cancer. Among the patients who underwent segmentectomy (n=54), local recurrence occurring more than five years postoperatively was observed in 3 cases, resulting in a local recurrence rate of 5.6% in the segmentectomy group. In contrast, in the lobectomy group (n=115), 8 cases (7.0%) developed local recurrence. However, this difference was not statistically significant (P=0.42). The number of recurrent cases for each year is presented in Table S1.

Univariate and multivariate analysis for recurrence

Results of univariate and multivariate analyses are presented in Table 3. In the univariate analysis, age, CEA level, pathological invasive size, and presence of lymphatic invasion were identified as significant predictors of recurrence beyond 5 years after surgery. In the multivariate analysis, three factors were found to be independently associated with late recurrence: age ≥69 years, CEA level ≥2.8 ng/mL, and presence of lymphatic invasion.

A risk scoring system

Based on the number of these three significant factors present in each patient (age ≥69 years, CEA ≥2.8 ng/mL, and lymphatic invasion), a recurrence score ranging from 0 to 3 was assigned. The association between this recurrence score and recurrence beyond 5 years was analyzed. Figure 2 shows the relationship between late recurrence (beyond 5 years) and the recurrence score. The incidence of late recurrence was 0% in patients with a score of 0, 2.7% in those with a score of 1, 26.9% in those with a score of 2, and 77.8% in those with a score of 3.

Figure 2 Relation between recurrence score and late recurrence rate after 5 years.

Discussion

In the presented study, we investigated patients with pathological stage I NSCLC who remained recurrence-free for five years after surgery, comparing those who experienced late recurrences beyond five years with those who did not. We aimed to identify predictive factors for late recurrence. Furthermore, we proposed a scoring system based on these factors, which may help identify patients who would benefit from extended follow-up beyond the five-year postoperative period.

There are no formally established diagnostic criteria for distinguishing between recurrent lung cancer and metachronous primary lung cancer, and this differentiation remains a subject of ongoing debate (11). When multiple pulmonary nodules appear synchronously, they are often diagnosed as intrapulmonary metastases. However, in cases with a solitary nodule, it is challenging to determine whether the lesion represents an intrapulmonary metastasis or a second primary lung cancer. In this study, the differential diagnosis was made based on the criteria proposed by Martini and Melamed (10).

There are few reports that have investigated the risk of recurrence more than 10 years after treatment in solid tumors other than breast cancer. In prostate cancer, several studies have reported that a small percentage of patients experience recurrence more than five years after complete resection (12), and thus, postoperative prostate-specific antigen (PSA) monitoring beyond five years is recommended (13). Regarding lung cancer, Maeda et al. (14) reported that 4.8% of patients with pathological stage IA NSCLC developed recurrence more than five years after lobectomy. These findings suggest the need for postoperative follow-up beyond five years, even in patients with early-stage lung cancer. Therefore, criteria for identifying patients who require longer follow-up periods need to be established.

Several studies have investigated prognostic factors associated with late recurrence occurring more than five years after surgery. Kanzaki et al. (15) reported that pleural invasion is a risk factor for late recurrence, while Maeda et al. (14) identified vascular invasion as a significant predictor. Furthermore, it has been reported that a considerable proportion of patients who experienced recurrence beyond five years after surgery for early-stage lung cancer harbored driver mutations, suggesting the importance of long-term surveillance in such cases (16). Maeda et al. (14) also stated that the presence of vascular invasion in patients with stage IA NSCLC precludes definitive conclusions regarding cure, even in the absence of recurrence for five years postoperatively. In contrast, patients without vascular invasion may be considered cured if no recurrence is observed five years after resection.

In the present analysis, age ≥69 years, serum CEA level ≥2.8 ng/mL, and lymphatic invasion were identified as independent predictive factors for late recurrence. These factors may serve as important indicators reflecting both the “biological aggressiveness of the tumor” and the “systemic condition of the patient”. With respect to age, it is well established that age-related declines in immune function and tissue repair capacity contribute to the risk of latent tumor regrowth. Previous studies by Maeda et al. (14) and Kanzaki et al. (15) have also reported cases of late recurrence in elderly patients. Regarding CEA, it has long been recognized as a prognostic and recurrence marker in NSCLC, even in early-stage disease, as it is thought to reflect tumor activity. Notably, in this study, a cut-off value of 2.8 ng/mL—lower than the conventional threshold of 5.0 ng/mL—was determined using ROC curve analysis, suggesting its utility in detecting subtle tumor activity. However, it should be emphasized that this cut-off value does not represent a diagnostic or generally accepted upper limit of normal, but rather serves as a relative index for stratifying recurrence risk.

In recent years, several studies have reported on the prognostic value of the pre- to postoperative CEA ratio in patients with lung adenocarcinoma who have undergone lobectomy (17). However, in the present study, early postoperative CEA values were missing for many patients, making it difficult to conduct an analysis based on the ratio. Future large-scale prospective studies will be needed to investigate not only the absolute CEA values but also their postoperative dynamics and ratios. Lymphatic invasion is known to provide a microenvironment conducive to micrometastasis, and previous reports have also suggested its importance in late recurrence (14,15). In particular, recurrence occurring more than five years postoperatively is likely due to the reactivation of dormant tumor cells, with residual microscopic disease spreading via lymphatic pathways. Thus, the findings of this study are consistent with existing literature, while offering a novel contribution by demonstrating that the combination of these three factors can be used to develop a scoring system for clinical risk stratification of late recurrence.

Regarding postoperative surveillance, several guidelines on lung cancer recommend regular CT scans every six months for the first two years after treatment, followed by annual imaging thereafter (18-20). The rationale for surveillance following initial treatment of NSCLC is to detect recurrence at an early stage, thereby improving OS and quality of life. However, there have been no randomized trials comparing different postoperative surveillance strategies, including appropriate surveillance intervals (21). This study is expected to provide important insights that will contribute to building evidence in this area.

This study has several limitations. First, it was conducted at a single institution, which may have introduced selection bias. Second, the study employed a retrospective design, and factors such as cohort composition and follow-up intervals were not standardized. Third, the study included patients treated over a 10-year period during which therapeutic strategies for lung cancer underwent significant changes. Moreover, post-recurrence treatments administered beyond five years after surgery varied considerably. Fourth, the diagnosis of recurrence was not always confirmed histologically, as biopsies were not performed in all cases. In recent years, the involvement of driver gene mutations in recurrent cases or during long-term postoperative follow-up has attracted increasing attention; however, comprehensive genomic analyses of preoperative specimens or recurrent lesions were not systematically performed in this study, and information on genetic mutations could not be comprehensively collected as part of the study data. Another limitation is the relatively small number of patients with late recurrence, which may limit the statistical power and generalizability of the findings. Further multi-institutional studies are warranted to validate our results.

Conclusions

In conclusion, patients with pathological stage I lung cancer who experience recurrence more than five years after surgery tend to exhibit certain high-risk characteristics, including age ≥69 years, preoperative CEA level ≥2.8 ng/mL, and presence of lymphatic invasion. These factors may be used to create a risk scoring system to identify patients who require extended follow-up beyond five years. Future prospective studies are warranted to establish optimal treatment strategies for this patient population.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1257/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1257/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1257/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-2025-1257/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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional ethics committee of Kochi Medical School (No. ERB-10449) and individual consent for this retrospective analysis was waived.

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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