Neoadjuvant chemoimmunotherapy versus chemoradiotherapy for non-small cell lung cancer: a comparative analysis of clinical outcomes and pathologic response

Introduction

Locally advanced non-small cell lung cancer (NSCLC) is a highly heterogeneous disease that requires complex and individualized treatment strategies (1,2). Surgical resection remains a viable option for select patients, particularly when combined with multimodal therapies. The rationale for neoadjuvant treatment in resectable NSCLC includes eradicating micrometastatic disease, delivering systemic therapy while patients are in a better physiological condition, and assessing tumor response to systemic therapy prior to definitive surgery (3-5).

The role of neoadjuvant immunotherapy has evolved rapidly in recent years. Previously, the benefits of neoadjuvant treatment were uncertain, as studies failed to demonstrate consistent survival advantages over surgery alone (6,7). However, the advent of immunotherapy has substantially transformed neoadjuvant treatment strategies. Several recent clinical trials (8-10) have demonstrated that neoadjuvant chemoimmunotherapy (neoCIT) significantly improves long-term survival and leads to higher pathological complete response (pCR) rates than chemotherapy alone. Based on these findings, perioperative immunotherapy has been incorporated into standard treatment guidelines for resectable NSCLC (1,2). The NADIM II trial further supported this approach by demonstrating favorable survival outcomes in patients with stage IIIA and IIIB NSCLC, expanding the potential role of neoadjuvant immunotherapy to more advanced cases (11).

Neoadjuvant concurrent chemoradiotherapy (neoCCRT) has long been explored as a treatment option for NSCLC owing to its ability to combine the systemic effects of chemotherapy with the local control benefits of radiotherapy. Additionally, radiotherapy may induce an abscopal effect, potentially enhancing systemic tumor response (12-14). Despite these theoretical advantages, its use in resectable NSCLC remains controversial because of concerns regarding increased perioperative morbidity and uncertain survival benefits (15-18). Some studies (19,20) have suggested that neoCCRT may improve pCR rates and disease-free survival compared to chemotherapy alone in stage III N2 NSCLC.

Despite these advancements, a direct comparison of neoCCRT and neoCIT has not yet been conducted. Although neoCIT has demonstrated a survival benefit over chemotherapy, its efficacy compared to CCRT, particularly in terms of local tumor control, pCR rates, and long-term survival, remains unclear. Therefore, in this study, we aimed to compare the efficacy and safety of neoCCRT and neoCIT in patients with locally advanced NSCLC. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-953/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was reviewed and approved by the Institutional Review Board of Seoul National University Hospital as a minimal-risk retrospective study (H-2311-154-1487), and the requirement for written informed consent was waived.

Patients

We conducted a retrospective cohort study of patients with locally advanced NSCLC who received either neoCCRT or neoCIT followed by surgical resection between January 2010 and April 2024. Patients for whom pathological images of the tumor tissue could not be obtained and those who received concurrent chemotherapy for other cancers at the time of diagnosis were excluded. All patients were restaged using the eighth edition of the Tumor, Node, Metastasis (TNM) lung cancer classification (21).

Staging work up

All patients underwent a thorough assessment by a multidisciplinary tumor board including pulmonologists, radiologists, nuclear medicine specialists, medical oncologists, radiation oncologists, and thoracic surgeons. The initial staging workup included high-resolution chest computed tomography (CT), positron emission tomography-CT (PET-CT), brain magnetic resonance imaging (MRI), and pulmonary function testing. Mediastinal and hilar lymph node involvement was evaluated using endobronchial ultrasonography when clinically indicated. After completing neoadjuvant therapy, all patients were reassessed using chest CT and PET/CT to evaluate the treatment response. Only patients without radiographic evidence of disease progression were considered suitable candidates for curative-intent thoracic surgery.

Neoadjuvant treatment

Patients in the neoCCRT group underwent neoadjuvant chemotherapy with a regimen consisting of docetaxel and cisplatin. The number of chemotherapy cycles was determined at the discretion of the treating physician based on clinical and radiologic responses. Concurrent neoadjuvant chemoradiotherapy was administered to the primary tumor, with additional field coverage depending on the extent of lymph node involvement. Radiation doses ranged from 44 to 60 Gy and were delivered in 22–30 fractions.

In the neoCIT group, chemotherapy regimens were tailored to tumor histology and included combinations such as gemcitabine plus cisplatin, pemetrexed plus cisplatin, or paclitaxel plus carboplatin. Regarding immune checkpoint inhibitors, two patients received durvalumab, while the remaining patients were treated with nivolumab. Detailed information on the specific neoadjuvant chemoimmunotherapy regimens, including the type of immune checkpoint inhibitor and the accompanying chemotherapy backbone, is provided in Table S1. The number of neoCIT cycles was determined at the clinician’s discretion based on individual clinical and radiological responses.

Pathologic response assessment

Macroscopic and microscopic assessments of the resected specimens followed the International Association for the Study of Lung Cancer (IASLC) guidelines (22). For tumors measuring ≤3 cm in maximum diameter, complete tumor sampling was performed. In cases where the tumor exceeded 3 cm, a minimum of one tissue block per centimeter of the tumor bed was collected. All retrieved lymph nodes were comprehensively sampled. Patients with no histological evidence of treatment-induced changes and no residual tumors in the lymph nodes were classified as having pretreatment N-negative disease, whereas those displaying treatment-related alterations and/or residual tumor cells in the lymph nodes were designated as pretreatment N-positive.

The percentage of residual viable tumor was determined by calculating the proportion of the remaining tumor relative to the tumor bed area. This quantification was based on the tumor bed dimensions (width × length) in each histological section, consistent with established criteria (22). A pathological response evaluation was performed to identify major pathological response (MPR) and pCR. MPR was defined as ≤10% viable tumor across all identifiable tumor beds, while pCR was characterized by the complete absence of viable tumor cells in the primary tumor and all sampled lymph nodes upon histopathological examination.

All slides were independently reviewed by two pathologists (J.K. and K.C.L.), a board-certified pathologist and a pathology resident. TNM classification was performed according to the 8th edition of the American Joint Committee on Cancer TNM staging system (21).

Histopathologic evaluation of treatment-related features

We estimated the percentage of well-known treatment-related features, including necrosis and stromal fibrosis, according to the IASLC guidelines (22). These parameters were semi-quantitatively scored based on their proportions within the total tumor bed: score 0, <1%; score 1, 1–10%; score 2, 11–30%; and score 3, >30%. Immune cell infiltration, primarily lymphocyte infiltration, was scored according to its extent within the tumor as follows: 0, absent to minimal; 1, mild; 2, moderate; and 3, marked.

Follow-up

Postoperative complications during the follow-up period were assessed using the Clavien-Dindo classification system. Major complications were defined as those of grade III or higher, which require surgical, endoscopic, or radiological intervention, life-supporting therapy, or result in permanent disability or death.

Postoperative surveillance was conducted at 3- to 6-month intervals depending on the disease stage. In the absence of symptoms, routine follow-up included chest CT. If patients developed symptoms or abnormalities on imaging, additional evaluations, such as PET-CT, brain MRI, or bone scans, were performed to assess potential recurrence. Recurrence was classified based on the location of disease progression. Locoregional recurrence was defined as any new lesion at the resection site, regional lymph nodes, ipsilateral lungs, or pleura. Distant recurrence included metastases to the contralateral lung, pleura, or extrathoracic sites beyond the criteria for locoregional recurrence. Overall survival (OS) was defined as the time from surgery to death from any cause. Recurrence-free survival (RFS) was defined as the time from surgery to first detection of recurrence or death.

Statistical analysis

Continuous variables were analyzed using the Student’s t-test or Wilcoxon rank-sum test, depending on their distribution, while categorical variables were compared using the Chi-squared test or Fisher’s exact test, as appropriate. OS and RFS were estimated using the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. Inter-observer agreement between the pathologists was evaluated using Cohen’s kappa coefficient.

Baseline characteristics between the groups were compared using both P values and standardized mean differences (SMDs). To reduce selection bias and address baseline imbalance, 1:1 propensity score matching (PSM) without replacement was performed using logistic regression including the following covariates: age, sex, body mass index (BMI), smoking status preoperative forced expiratory volume in one second (FEV₁), preoperative diffusing capacity of the lungs for carbon monoxide (DLCO), clinical stage, clinical T stage, clinical N stage, histologic subtype, Eastern Cooperative Oncology Group (ECOG) score, and comorbidities. After matching SMDs were reassessed to evaluate covariate balance. Due to residual imbalance in clinical stage, clinical N stage, and histology after matching, Firth’s penalized logistic regression was subsequently conducted to identify independent factors associated with treatment group assignment.

To adjust for potential residual confounding, we conducted multivariable logistic regression analysis using treatment group (neoCCRT vs. neoCIT) as the dependent variable, and clinical stage (as a continuous variable), clinical N-stage (binary), and histology (squamous vs. non-squamous) as independent variables.

For key clinical outcomes, including MPR, recurrence, and survival, we additionally performed multivariable analyses with group as the primary independent variable, adjusting for the aforementioned confounders to evaluate the independent effect of treatment strategy.

All statistical analyses were conducted using IBM SPSS (IBM Corp., Armonk, NY, USA) and R (version 4.4.1; R Foundation for Statistical Computing, Vienna, Austria), with a P value <0.05 considered statistically significant.

Results

Patient characteristics

Baseline patient characteristics are presented in Table 1. Among the 71 included patients, 38 (53.5%) received neoCCRT and 33 (46.5%) received neoCIT. There were no significant differences between the two groups in terms of age, sex, smoking status, or preoperative lung function. A significant difference was observed in histologic subtypes: non-squamous carcinoma was more prevalent in the neoCCRT group (60.5%), whereas squamous carcinoma was predominant in the neoCIT group (75.8%) (P=0.002). The distribution of clinical stages also differed between the groups (P=0.041). While stage IIIA was the most common in both groups, the neoCCRT group primarily consisted of stage IIIA (60.5%) and stage IIIB (26.3%), whereas the neoCIT group mainly included stage IIB (24.2%) and stage IIIA (66.7%) patients. When clinical T and N stages were analyzed separately, there was no statistically significant difference in the clinical T stage between the groups. T4 was the most frequent T stage in the neoCCRT group (50.0%), while T2 was the most common in the neoCIT group (42.4%) (P=0.33). In contrast, the proportion of lymph node-positive cases was significantly higher in the neoCIT group (87.9%) than in the neoCCRT group (60.5%) (P=0.009).

After PSM, 66 patients (33 in each group) were matched. Despite matching, SMDs indicated persistent imbalance in clinical stage (SMD =0.592), clinical N stage (SMD =0.581), and histology (SMD =0.923). Firth’s logistic regression identified higher clinical stage [odds ratio (OR) =4.42, 95% confidence interval (CI): 1.68–13.84, P=0.002] as significantly associated with receiving neoCCRT. In contrast, node-positive disease (OR =0.07, 95% CI: 0.01–0.34, P<0.001) and squamous cell carcinoma histology (OR =0.13, 95% CI: 0.03–0.44, P<0.001) were independently associated with the neoCIT group.

Postoperative outcomes

Postoperative outcomes are summarized in Table 2. There was no significant difference in the extent of surgery between the two groups. Lobectomy was the most frequently performed procedure in both the neoCCRT (89.5%) and neoCIT groups (90.9%) groups. Pneumonectomy was more commonly performed in the neoCCRT group neo-CCRT (10.5%) compared to the neo-CIT (3.0%). In the neoCIT group, segmentectomy was performed in two patients due to poor preoperative pulmonary function.

All patients underwent mediastinal lymph node dissection, and complete resection was achieved in 98.6% of cases. One patient (1.4%) in the neoCIT group did not achieve complete resection due to chest wall invasion and underwent resection of the left 2nd to 5th ribs, but positive surgical margins were noted in the left 4th to 5th rib paravertebral areas.

The median length of hospital stay was 6 days in both groups (P=0.45). Postoperative complications did not differ significantly between the two groups (neoCCRT, 21.1%; neoCIT, 27.3%; P=0.54). Furthermore, the incidence of major complications (classified as Clavien-Dindo grade 3 or higher) was not significantly different between the groups (neoCCRT: 5.3% vs. neoCIT: 0.0%, P=0.50).

Pathological assessment

While the distribution of pathological stages varied, the downstaging rates from clinical to pathological stage were similar between the two groups (downstaging: 57.9% vs. 57.6%, no change: 36.8% vs. 36.4%, upstaging: 5.3% vs. 6.1%, P>0.99) (Table 3). Changes in clinical and pathological stages are visualized in Figure 1. Most patients in both groups experienced either stage reduction or no change in stage.

Figure 1 The Sankey diagram illustrates the changes from clinical stage to pathologic stage after (A) neoCCRT and (B) neoCIT in locally advanced NSCLC patients. Each color represents a different clinical or pathologic stage and the width of the flows represents the number of patients transitioning between stages. c, clinical; neoCCRT, neoadjuvant concurrent chemoradiotherapy; neoCIT, neoadjuvant chemoimmunotherapy; NSCLC, non-small cell lung cancer; p, pathological.

Two pathologists independently assessed the MPR and pCR according to the IASLC guidelines. There was a strong correlation between the pathologists’ evaluations of pathologic response rates (P<0.01) (Figure S1A). The agreement between the two pathologists in determining the MPR and pCR status was assessed using contingency tables (Figure S1B,S1C). The results demonstrated excellent inter-observer agreement for both MPR and pCR classifications, with a Cohen’s kappa value of 1.00 in each case. Pathological responses in the primary tumor revealed statistically significant differences in MPR rates (neoCCRT: 55.3% vs. neoCIT: 30.3%, P=0.03). However, there were no significant differences in the pCR rates between the groups (neoCCRT: 15.8% vs. neoCIT: 15.2%, P=0.94) (Figure 2).

Figure 2 Comparison of pathologic response rates between neoCCRT and neoCIT groups. (A) MPR rates were significantly higher in the neoCCRT group compared to the neoCIT group. (B) pCR rates were comparable between the two groups. MPR, major pathologic response; neoCCRT, neoadjuvant concurrent chemoradiotherapy; neoCIT, neoadjuvant chemoimmunotherapy; pCR, pathologic complete response.

In multivariable logistic regression, the treatment group (neoCIT vs. neoCCRT) was significantly associated with a higher likelihood of achieving major pathologic response (OR =5.78, P=0.03), while node positive status was inversely associated (OR =0.15, P=0.02). However, no significant associations were observed for pCR.

When comparing pathological changes between the neoCCRT and neoCIT groups, the neoCCRT group exhibited significantly greater fibrosis than the neoCIT group. By contrast, the neoCIT group demonstrated a significantly higher degree of immune cell infiltration than the neoCCRT group (Figure S2). Further analysis within each treatment group revealed that among neoCCRT-treated patients, there was no significant difference in fibrosis or immune cell infiltration between responders (MPR+) and non-responders (MPR–). However, in the neoCIT group, fibrosis was significantly more pronounced in responders, whereas immune cell infiltration was less prominent in responders compared to non-responders (Figure S3).

Long-term outcomes

We compared OS and RFS between patients treated with neoCCRT and those treated with neoCIT. The median follow-up duration was 37.5 months [interquartile range (IQR), 11.8–60.0 months] for the neoCCRT group and 10.0 months (IQR, 7.0–12.0 months) for the neoCIT group.

To account for this disparity and minimize time-related bias in survival comparison, we conducted a 1-year landmark analysis. Based on this analysis the 1-year cancer-related mortality rate did not significantly differ between the two group (neoCCRT: 7.9% vs. neoCIT: 0%, P=0.24). Similarly, the 1-year recurrence rate was comparable between the groups (neoCCRT: 10.5% vs. neoCIT: 15.2%, P=0.73). In Firth’s logistic regression, sarcomatoid histology was independently associated with 1-year mortality (OR =42.74, 95% CI: 1.23–8,995.6, P=0.04), whereas no variables showed significant associations with 1-year recurrence.

Additionally, when examining recurrence patterns within 2 years post-surgery, locoregional recurrence rates were 13.2% in the neoCCRT group and 9.1% in the neoCIT group, with no statistically significant difference (P=0.72). Although distant recurrence rates were relatively higher in the neoCCRT group (26.3% vs. 9.1%), the difference was not statistically significant (P=0.06) (Table 3).

There were no statistically significant differences in OS (P=0.17) or RFS (P=0.30) between the two groups (Figure S4). In Cox regression analysis, the treatment group was not significantly associated with OS [hazard ratio (HR) =6.25×10⁹, 95% CI: 0.00–infinite, P>0.99] or RFS (HR =0.60, 95% CI: 0.14–2.62, P=0.50), after adjusting for clinical stage, clinical N-stage, and histology.

Given the significantly higher MPR rate in the neoCCRT group, we conducted a subgroup analysis of patients who achieved MPR. However, even within this subgroup, no significant differences in OS (P=0.49) or RFS (P=0.77) were observed between the treatment groups (Figure S5). We also examined survival outcomes among patients who achieved a pCR. Consistent with the MPR subgroup findings, no statistically significant differences in OS (P>0.99) or RFS (P>0.99) were noted between the neoCCRT and neoCIT groups in pCR-positive patients (Figure S6).

Subgroup analysis in patients with clinical stage IIIA NSCLC

To ensure a more homogeneous comparison and minimize stage-related confounding, a subgroup analysis was conducted including only patients with clinical stage IIIA NSCLC (neoCCRT: n=23; neoCIT: n=22). Clinical stage IIIA represents a subset with relatively favorable resectability and a consistent rationale for both neoadjuvant chemoradiotherapy and chemoimmunotherapy. In contrast, stage IIIB disease—characterized by T4 or N3 involvement—has markedly different surgical eligibility and prognosis, which may bias treatment comparisons if included. By focusing on stage IIIA patients, this analysis allowed for a more balanced and clinically meaningful evaluation of treatment outcomes (Table S2).

Consistent with the overall cohort, the neoCIT group showed a higher prevalence of node-positive disease (90.9% vs. 47.8%, P=0.002) and squamous cell carcinoma histology (72.7% vs. 34.8%, P=0.01). Patients in the neoCIT group were also significantly older (median age: 67.0 vs. 60.0 years, P=0.004).

In contrast to the entire cohort where the neoCCRT group showed a significantly high MPR rate, there was no statistically significant difference in MPR between the group in this subset (27.3% vs. 47.8%, P=0.16). Importantly, recurrence was significantly less frequent in the neoCIT group (13.6% vs. 47.8%, P=0.01), particularly in terms of distant metastasis (4.5% vs. 39.1%, P=0.01).

Discussion

This study aimed to compare the efficacy and safety of neoCIT and neoCCRT in patients with locally advanced NSCLC. Although neoCCRT was associated with a significantly higher MPR rate, there were no significant differences between the two groups in terms of pCR, recurrence rates, or survival outcomes. Additionally, postoperative complication rates and hospital stay durations were similar between the two treatment strategies, suggesting comparable perioperative safety.

The observed increase in MPR rates in the neoCCRT group aligns with previous studies, underscoring the local control benefits of radiotherapy. Radiotherapy is known to induce tumor debulking and may also trigger an abscopal effect, potentially enhancing systemic immune responses beyond the primary tumor site (12-14). However, given that OS outcomes were not significantly different between the groups, our results suggest that achieving MPR does not necessarily translate long-term survival benefits. This finding is consistent with prior studies indicating that, although MPR is an important prognostic marker, its direct impact on survival remains variable.

Although the overall clinical stages appeared comparable between the two groups, the underlying components of staging differed. In the noeCCRT group, there was a higher prevalence of advanced T-stage tumors, largely due to invasion into adjacent structures such as the mediastinum, chest wall, or great vessels. As a result, more extensive surgical procedures such as pneumonectomy were frequently required, and open thoracotomy was often planned in anticipation of technical challenges, including the need for angioplasty or complex resections. In contrast, the neoCIT group had a greater proportion of patients with node-positive disease. These differences in tumor characteristics and resectability may have influences both the choice of neoadjuvant strategy and the subsequent surgical approach.

Despite having similar overall clinical stages, the neoCCRT group included more T4 tumors, whereas the neoCIT group had a higher proportion of node-positive cases. These imbalances may have influenced the treatment response. Importantly, neoCIT demonstrated comparable long-term outcomes even in the presence of a higher nodal burden, suggesting a potential systemic benefit of immunotherapy for micrometastatic disease control. Histological subtype differences were also notable, with non-squamous carcinoma being more common in the neoCCRT group, and squamous cell carcinoma being predominant in the neoCIT group. Given the known variations in treatment sensitivity according to histology, such differences may have contributed to the observed differences in the pathological response. Prior studies have suggested better local control with radiotherapy for adenocarcinoma and enhanced immunogenicity of squamous tumors (23,24). These biological variations may influence the selection of optimal neoadjuvant modalities.

These findings highlight the importance of individualized treatment selection when determining the optimal neoadjuvant treatment approach for patients with locally advanced NSCLC. Our results suggest that neoCCRT may be preferred in cases requiring improved local control, particularly in patients with bulky tumors, adjacent structural invasion, or non-squamous histology, whereas neoCIT may be more beneficial for patients at a higher risk of distant metastasis due to nodal involvement.

The major histopathological alterations following neoadjuvant therapy include stromal fibrosis, necrosis, and immune cell infiltration. In neoCCRT, fibrosis is commonly observed as a direct consequence of radiation effects and necrosis frequently occurs (25). In contrast, neoCIT is associated with increased tumor antigen exposure due to chemotherapy along with restored immune cell function, leading to enhanced immune cell recruitment and infiltration. CIT facilitates immune cell activation by augmenting tumor antigen exposure through chemotherapy while simultaneously restoring immune cell function, ultimately resulting in greater immune cell recruitment and infiltration (26). Consistent with these findings, our study demonstrates a significantly higher degree of immune cell infiltration and lower levels of fibrosis in the neoCIT group than in the neoCCRT group. This suggests that the tumor microenvironment undergoes distinct changes depending on the treatment modality.

However, when analyzing the correlation between treatment response and histopathological parameters for each treatment modality, neoCCRT did not show significant differences based on the response status. In contrast, in the neoCIT group, the responders exhibited significantly increased fibrosis and decreased immune cell infiltration. These results suggest that in responders in the neoCIT group, rapid immune activation induced by treatment may have led to the elimination of tumor cells, followed by their replacement with fibrosis. Other studies have also reported that a higher degree of fibrosis in surgical specimens following neoadjuvant therapy is associated with an improved prognosis (25), which is consistent with our findings.

Despite the valuable insights gained in this study, certain limitations must be acknowledged. First, due to its retrospective design, there is a potential for selection bias. Although we performed PSM to adjust for differences in baseline characteristics, residual imbalances remained. To account for this, we additionally performed multivariable regression analyses for clinically meaningful variables that showed imbalance and could potentially influence the study outcomes. Second, the relatively small sample size may limit the statistical power. Third, the follow-up duration in the neoCIT group was significantly shorter than that of the neoCCRT group. Although we addressed this issue by conducting a landmark analysis, the possibility of underestimating late recurrence events in the neoCIT group remains. Fourth, the absence of biomarker data, including PD-L1 expression and tumor mutational burden, limits the ability to predict responses and guide personalized treatment. Fifth, although this study was conducted at a single high-volume tertiary referral center, differences in institutional expertise, drug accessibility, and treatment strategies across regions may limit the generalizability of our findings. Future validation in prospective, multi-center cohort would be necessary to confirm our observations. Lastly, the timing of treatment initiation differed between groups, with the neoCIT cohort being treated more recently. Therefore, advances in perioperative care, radiologic evaluation, and management of adverse events over time may have confounded survival and recurrence outcomes.

Future directions include prospective randomized trials directly comparing neoCCRT and neoCIT with longer follow-up periods and integrated biomarker analyses. Additionally, hybrid approaches that incorporate radiotherapy and immunotherapy, either sequentially or concurrently, may further improve outcomes, particularly in high-risk subgroups. The PACIFIC trial (27) has already demonstrated the survival benefits of adjuvant immunotherapy following chemoradiation; extending this concept to the neoadjuvant setting warrants further investigation.

Conclusions

neoCCRT and neoCIT are effective and safe strategies for treating locally advanced NSCLC. Although neo-CCRT resulted in higher MPR rates, it did not confer a survival advantage. These findings support an individualized approach for neoadjuvant treatment selection based on the tumor location, nodal status, and histological subtype. Further prospective trials are essential to optimize therapeutic strategies and improve patient outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-953/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-953/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-953/prf

Funding: This work was supported by Research Program 2022 funded by the Seoul National University College of Medicine Research Foundation (No. 800-20220528). The funder had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-953/coif). K.J.N. is the cofounder and shareholder of Portrai, Inc., which is unrelated to the submitted work. The other 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 protocol was reviewed and approved by the Institutional Review Board of Seoul National University Hospital as a minimal-risk retrospective study (H-2311-154-1487), and the requirement for written informed consent 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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