Combining recombinant human endostatin with third-generation EGFR-TKIs in advanced EGFR-sensitive mutant non-small cell lung cancer

Introduction

Lung cancer is the most common cancer and the leading cause of cancer-related death worldwide with an estimated 2.2 million new cases and 1.8 million deaths occurred in 2020 (1). Non-small cell lung cancer (NSCLC) accounts for approximately 80–85% of all lung cancer cases (2). Despite significant advancements in diagnosis and treatment, a substantial number of patients are diagnosed at an advanced stage, resulting in a 5-year survival rate of only about 16% (3).

The emergence of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in recent decades has revolutionized the therapeutic landscape for advanced epidermal growth factor receptor (EGFR)-mutant NSCLC patients (4). These agents have demonstrated significant survival benefits compared to conventional chemotherapy (5,6). Osimertinib, a third-generation EGFR-TKI, has notably achieved a median progression-free survival (mPFS) of 18.9 months, establishing it as the frontline standard treatment for EGFR-mutant advanced NSCLC (7). Other third-generation EGFR-TKIs have also shown remarkable therapeutic effects. However, resistance to EGFR-TKIs inevitably develops, limiting their sustained efficacy (8-10). Factors contributing to a poor response include co-existing genetic alterations, which are associated with an inferior prognosis compared to single mutations (11), worse survival outcomes for patients with complex EGFR mutations (12-14), and dysregulated tumor angiogenesis promoting drug resistance (15).

Tumor angiogenesis, characterized by aberrant neovascularization, plays a pivotal role in tumor growth and metastasis (16). Clinical studies have shown the promise of combination anti-angiogenic therapy as a viable treatment strategy. Phase-II trials have reported prolonged mPFS for combinations of erlotinib with bevacizumab compared to erlotinib alone (17), and phase-III trials have reported superior mPFS in the bevacizumab plus erlotinib combination therapy group compared to the erlotinib monotherapy group (18). EGFR-TKIs combined with bevacizumab have achieved significant success in the treatment of EGFR-mutant advanced NSCLC; however, unfortunately, phase-II trials have shown that the combination of osimertinib and bevacizumab does not significantly improve the progression-free survival (PFS) of patients compared to osimertinib (19); however, the specific reasons as to why this occurs are still unknown. Currently, research on the combination of third-generation EGFR-TKIs with anti-angiogenic drugs is relatively limited, and the success rates of clinical trials have varied (19-21). Therefore, research needs to be conducted to explore alternative anti-angiogenic therapies in combination with EGFR-TKIs.

Endostar, a recombinant human endostatin, is an endogenous pan-targeted angiogenesis inhibitor (22) that has distinct advantages over larger molecular single-target anti-angiogenic agents like bevacizumab (23), including enhanced safety, compliance, and broad-spectrum efficacy (24). Preclinical evidence suggests that endostatin combined with erlotinib enhances anti-tumor activity in EGFR-mutant NSCLC (25), and our previous studies have shown benefits for advanced NSCLC patients (26,27). However, limited data exist on the use of third-generation EGFR-TKIs in combination with recombinant human endostatin therapy. Therefore, this retrospective study aimed to explore and analyze the efficacy and safety of combining third-generation EGFR-TKIs with recombinant human endostatin compared to monotherapy with third-generation EGFR-TKIs in previously untreated advanced EGFR-mutant NSCLC patients. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1223/rc).

Methods

Patients

This retrospective study collected the data of 118 treatment-naive patients with advanced NSCLC, who had been confirmed to harbor EGFR mutations by next-generation sequencing (NGS) (28), at the First Affiliated Hospital of Nanchang University between April 1, 2020 and June 30, 2023. NGS testing was conducted by Keytest Medical Laboratory. Patients were allocated to the monotherapy group (n=71), which was treated solely with third-generation EGFR-TKIs, and the combination group (n=47), which was treated with a combination of third-generation EGFR-TKIs and recombinant human endostatin (Endostar), based on treatment decisions made by physicians and patients after comprehensive discussion of therapeutic options, potential toxicities, and financial factors. This was a nonrandomized, real world retrospective study reflecting clinical practice.

To be eligible for inclusion in the study, the patients had to meet the following inclusion criteria: (I) be aged between 18 and 75 years; (II) have histologically or cytologically confirmed stage IIIB–IV NSCLC; (III) the EGFR-sensitive mutations allowed in this study included common sensitizing mutations such as exon 19 deletions and L858R point mutations in exon 21 (as confirmed by NGS); (IV) have an Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 0–2; (V) have a treatment-naive status; (VI) have measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) (29); and (VII) have undergone first-line treatment with either third-generation EGFR-TKIs alone or in combination with Endostar. Patients were excluded from the study if they met any of the following exclusion criteria: (I) were aged below 18 or above 75 years; (II) had concurrent malignancies; (III) had incomplete medical records or were unable to comply with follow-up; (IV) had their treatment interrupted or modified for reasons other than drug intolerance before disease progression; (V) had previously received non-first-line third-generation EGFR-TKIs or Endostar; and/or (VI) had a treatment duration of fewer than two cycles.

A review of the mutational features of each gene was performed. The clinical data and medical course data of each patient were retrospectively collected from the inpatient medical records. The pathological classification of tumors was based on the World Health Organization (2015 edition) pulmonary tumor tissue type (30). Clinical stage at the time of EGFR-TKI treatment was classified according to the American Joint Commission on Cancer (AJCC), 8^th Edition Lung Cancer Stage Classification (31).

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Nanchang University (approval/reference number IIT2024342), and the requirement of informed consent for this retrospective analysis was waived.

Treatment regimens

Patients in the monotherapy group (T group) received third-generation EGFR-TKIs alone, specifically osimertinib 80 mg once daily (qd), aumolertinib 110 mg (qd), or furmonertinib 80 mg (qd). Patients in the combination group (E + T group) were treated with a combination of Endostar (210 mg, which was continuously infused over 96 hours via micro-pump) and third-generation EGFR-TKIs, specifically osimertinib 80 mg (qd), aumolertinib 110 mg (qd), or furmonertinib 80 mg (qd). Following two cycles of combination therapy, the patients in the combination group could proceed to receive maintenance monotherapy. Dose adjustments were made as necessary based on observed adverse events (AEs), and treatment was continued until disease progression or death.

Response evaluation

All the included patients underwent treatment evaluation. Therapeutic efficacy was measured every 6–8 weeks from the beginning of the EGFR-TKI treatment in accordance with the RECIST, version 1.1 using computed tomography scans. Two independent radiologists blinded to treatment allocation evaluated the scans, with any discrepancies resolved by a senior oncologist. Tumor responses included a complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). The tumor response rate was expressed as the objective response rate (ORR) and disease control rate (DCR). The ORR was defined as the percentage of patients who achieved a CR or PR. The DCR was defined as the percentage of patients who achieved a CR, PR or SD. PFS was defined as the interval from the initiation of the third-generation EGFR-TKI treatment to the occurrence of disease progression, death from any cause, or the last follow-up visit. Overall survival (OS) was calculated from the date of the initiation of the EGFR-TKI treatment to the date of cancer-related death, or the last day of follow-up. AEs were evaluated according to the Common Terminology Criteria for Adverse Events 5.0 (CTCAE 5.0) (32). One patient in the T group and one in the E + T group discontinued treatment due to adverse events and were censored at the last follow-up for survival analyses. The follow-up time of each patient was calculated from the beginning of treatment to the time of the relevant end point or the date of the most recent patient follow-up evaluation. The data collection cut-off time was March 31, 2024, and the patients had a median follow-up time of 30.9 months (range, 11.8–48.7 months).

Statistical analysis

The baseline characteristics of the patients were analyzed using the Chi-squared test or Fisher’s exact test. The Kaplan-Meier method was employed to estimate the mPFS and median OS, and survival differences between groups were assessed using the log-rank test. Univariate and multivariate Cox regression models were used to identify independent prognostic factors influencing PFS. Survival curves for PFS and OS were plotted using GraphPad Prism 9.0 (GraphPad Software Inc., San Diego, CA, USA). All the statistical analysis tests were performed using SPSS 26.0 software (IBM Corp., Armonk, NY, USA) and R software version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria). Missing ECOG-PS scores (n=1) were imputed using the median value. Patients who dropped out or died were censored at the last follow-up. A P value <0.05 was considered statistically significant.

Results

Baseline characteristics of patients

A total of 840 patients were diagnosed with advanced NSCLC with EGFR mutations at the First Affiliated Hospital of Nanchang University from April 1, 2020 to June 30, 2023. Of these patients, 146 patients met the study inclusion criteria, and 118 NSCLC patients treated with only the third EGFR-TKIs (T) or the combination of Endostar and EGFR-TKIs (E + T) were ultimately enrolled in the study (Figure 1).

Figure 1 Flowchart of the patient inclusion process. EGFR, epidermal growth factor receptor; EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; NSCLC, non-small cell lung cancer.

The baseline characteristics of the included patients are set out in Table 1. In total, 118 patients diagnosed with advanced NSCLC, who had been confirmed to harbor EGFR mutations via NGS, at the First Affiliated Hospital of Nanchang University, were included in the study between April 1, 2020 and June 30, 2023. The included patients were allocated to the following two groups: the T group (N=71) and the E + T group (N=47). Among the 118 patients, 61 were male (51.7%) and 57 were female (48.3%). The ages of the patients ranged from 25 to 75 years (mean age: 57.89 years). Of the patients, 83 (70.3%) had co-mutated genes, while 35 (29.7%) had single mutations. EGFR compound mutations were observed in 22 cases (18.6%). The E21 L858R mutation was the most common mutation in both groups. The other baseline characteristics were balanced between the two groups (P>0.05).

Distribution of the TP53 mutation and EGFR compound mutations

Among the 83 patients with EGFR co-mutations, 74 (89.16%) had EGFR/TP53 co-mutations, and 10 (12.05%) had EGFR/PIK3CA co-mutations. Most patients (80.72%) had mutations in one gene, but 16.87% had mutations in two genes, and 2.41% had mutations in three co-mutated genes. The TP53 mutations were predominantly located in exon 5–8 (82.05%), with the following distributions: exon 5 (n=17, 22%), exon 6 (n=6, 8%), exon 7 (n=22, 28%) and exon 8 (n=19, 25%). Mutations in other exons accounted for the remaining 17% and included exon 9 (n=4, 5%), exon 10 (n=4, 5%), exon 4 (n=4, 5%), exon 3 (n=1, 1%), and exon 11 (n=1, 1%). Additionally, two cases of triple co-mutations were identified as follows: TP53 exon 7 p.R248L + TP53 exon 6 p.D207Xfs + PIK3CA exon 21 p.M1043I; and TP53 exon 8 p.E287Q + TP53 exon 8 p.R280T + ESR1 exon 1 (Figure 2A). There were 22 cases of EGFR compound mutations, primarily involving rare EGFR mutations or amplifications, and the E21 L858R mutation was the most common mutation (n=15, 68%) (Figure 2B).

Figure 2 Distribution of the TP53 mutation (A) and EGFR compound mutations (B) in EGFR-mutant NSCLC patients. EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer.

Prognostic risk-factor analysis for PFS

All the relative variables were collected and analyzed to determine the potential factors that could influence PFS, and the results are set out in Table 2. The univariate analysis revealed that the ECOG-PS score (P<0.001), brain metastasis (P<0.001), number of organs with metastasis (P<0.001), EGFR co-mutations (P<0.001), clinical stage (P=0.009), EGFR complex mutations (P=0.01), and treatment modality (P=0.002) were significantly associated with PFS. The multivariate Cox regression analysis of the factors in the univariate analysis with P values <0.05 indicated that the ECOG-PS score [hazard ratio (HR): 5.403, 95% confidence interval (CI): 2.401–12.157, P<0.001], brain metastasis (HR: 4.400, 95% CI: 2.544–7.611, P<0.001), EGFR co-mutations (HR: 1.776, 95% CI: 1.054–2.994, P=0.03), and treatment modality (HR: 2.059, 95% CI: 1.268–3.343, P=0.004) were independent prognostic factors for disease progression in patients with EGFR-mutant NSCLC.

Clinical efficacy

The therapeutic efficacy results are summarized in Table 3. No patient achieved a CR in either group. Of the patients, 2.8% had PD in the T group and 2.1% had PD in the E + T group, but the difference between the groups was not statistically significant (P>0.99). A significantly higher proportion of patients achieved SD in the E + T group than the T group.

Compared to the T group, the E + T group had a significantly higher proportion of patients who achieved a PR (91.5% vs. 77.5%, P=0.047) and a significantly higher ORR (91.5% vs. 77.5%, P=0.047), but the DCR did not differ significantly between the two groups (97.2% vs. 97.9%, P>0.99). The mPFS was 17.6 months (95% CI: 15.79–19.41) in the T group, and 20.2 months (95% CI: 18.83–21.57) in the E + T group, and the difference between the two groups was statistically significant (P=0.002) (Figure 3A). A borderline statistically significant improvement in the median OS was observed (33.8 months in the T group, 95% CI: 30.71–36.89; 41.5 months in the E + T group, 95% CI: 38.31–44.69) (P=0.04) (Figure 3B).

Figure 3 Kaplan-Meier curves for PFS (A) and OS (B) in patients with advanced EGFR-mutant NSCLC in different treatment groups. T group, EFGR-TKIs group; E + T group, Endostar + EGFR-TKIs group. CI, confidence interval; EGFR, epidermal growth factor receptor; EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; HR, hazard ratio; mOS, median overall survival; mPFS, median progression-free survival; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival.

Subgroup analyses

We also performed a subgroup analysis based on the clinical characteristics of the patients. The results suggested that PFS was superior in the E + T group than the T group in most subgroups, except in terms of the population with hepatic metastasis (Figure 4). Additionally, we carried out an intra-group comparison of the number of organs with metastasis and EGFR/TP53 co-mutation in both groups (Figure 5). As expected, ≥2 organs with metastasis (HR: 0.482, P=0.01) and the EGFR/TP53 co-mutation (HR, 0.535, P=0.02) were associated with a poor prognosis in the T group but not in the E + T group, which shows the clinical utility of E + T treatment in high-risk populations.

Figure 4 Subgroup analysis of the PFS of patients with advanced EGFR-mutant NSCLC in the T and E + T groups. T group, EGFR-TKIs group; E + T group, Endostar + EGFR-TKIs group. CI, confidence interval; HR, hazard ratio; ECOG-PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; NSCLC, non-small cell lung cancer; PFS, progression-free survival.

Figure 5 Kaplan-Meier curves for PFS in patients with or without at least a single metastasis or the TP53 co-mutation. (A,B) Kaplan-Meier curves for PFS in patients with <2 organs with metastasis and ≥2 organs with metastasis in the E + T and T groups. (C,D) Kaplan-Meier curves for PFS comparing patients without the TP53 co-mutation and with the TP53 co-mutation in the E + T and T groups. T group, EGFR-TKIs group; E + T group, Endostar + EGFR-TKIs group. CI, confidence interval; EGFR-TKI, epidermal growth factor receptor tyrosine kinase inhibitor; HR, hazard ratio; mPFS, median progression-free survival; PFS, progression-free survival.

Safety and AEs

The incidence of AEs of any grade was higher in the E + T group than the T group (53.2% vs. 45.1%, P=0.39). The main AEs in the T group were abnormal electrocardiogram results (25.4%) and decreased appetite (19.7%), while those in the E + T group were decreased appetite (25.5%), and cardiac toxicity, including abnormal myocardial enzyme spectrum and electrocardiogram results (21.3%); the incidence of gingival bleeding (12.8% vs. 0.0%, P=0.008), epistaxis (8.5% vs. 0.0%, P=0.048), an abnormal cardiac enzyme profile (21.3% vs. 7.0%, P=0.02), and hemoptysis/hemorrhage (14.9% vs. 2.8%, P=0.04) was higher in the E + T group than the T group, and the differences between the two groups were statistically significant. The key AEs of grade ≥3 in the E + T group were mainly hemorrhagic events (hemoptysis/hemorrhage: 6.4%; gingival bleeding: 4.3%; epistaxis: 2.1%; decreased fibrinogen: 2.1%), while no corresponding grade ≥3 AEs occurred in the T group. No treatment-related deaths were observed in either group. For further information, see Table 4.

Discussion

The emergence of targeted therapy has significantly prolonged the survival of advanced EGFR-mutated NSCLC patients (5). However, the benefit of EGFR-TKIs alone is limited (8). Combining EGFR-TKI with anti-vascular therapy has produced beneficial outcomes (17,18). Endostar, an endogenous broad-spectrum angiogenesis inhibitor, has better safety and a broader spectrum than other anti-angiogenesis drugs like bevacizumab (24). Thus, this study aimed to explore and analyze the efficacy and safety of third-generation EGFR-TKIs combined with Endostar in the treatment of previously untreated advanced EGFR-mutant NSCLC patients compared to third-generation EGFR-TKI monotherapy. Little is known about the use of EGFR-TKIs plus anti-vascular therapy. To our knowledge, this study conducted the first real-world retrospective analysis of the efficacy and safety of third-generation EGFR-TKIs combined with Endostar as a first-line treatment in patients with advanced NSCLC harboring EGFR mutations. Our results indicate that this combination significantly improved the ORR (91.5% vs. 77.5%, P=0.047) and had promising short-term efficacy. Additionally, it significantly improved the PFS (20.2 vs. 17.6 months, P=0.002) and OS (41.5 vs. 33.8 months, P=0.04) of patients, with statistically significant differences observed between the two groups. Our research findings indicate that advanced NSCLC patients with EGFR mutations can benefit from E + T therapy. Thus, this represents a new treatment option for patients in whom EGFR-TKI monotherapy has poor efficacy.

A study suggests that the anti-angiogenic effects of inhibitors on tumor vasculature are not irreversible, with approximately 20% of remaining tumor vasculature regenerating after treatment interruption, leading to revascularization (33). We also analyzed whether the duration of Endostar use in the combination group affected patient prognosis. The patients who received fewer than six cycles had a mPFS of 19.4 months (95% CI: 18.605–20.195), while those who received six or more cycles had a mPFS of 21.0 months (95% CI: 20.388–21.612) (P=0.01). These findings suggest that the duration of anti-angiogenesis therapy may need to be extended.

Given the high incidence of TP53 co-mutations in patients with EGFR mutations (54.6–64.6%) (34), which are often associated with a worse prognosis under EGFR-TKI monotherapy (35-39), we also analyzed whether E + T therapy could reverse the poor prognosis of patients with the EGFR/TP53 co-mutation. Interestingly, we found that the EGFR/TP53 co-mutation had a significant effect on PFS in the T group (15.7 vs. 19.4 months; P=0.02), but not in the E + T group (19.9 vs. 20.2 months; P=0.12). This suggests that anti-angiogenic therapy may have no effect on the poor prognosis of patients with the EGFR/TP53 co-mutation.

Previous clinical studies have shown that patients with a higher number of metastatic organs have a worse prognosis (19,20). In our subgroup analysis, although the patients with <2 metastatic organs in the E + T group had a longer survival period than those with ≥2 metastatic organs (20.7 vs. 19.4 months), no statistically significant difference was found (P=0.04); Conversely, the patients with <2 metastatic organs in the T group had a longer survival period than those with ≥2 metastatic organs (18.8 vs. 15.2 months), and the difference was statistically significant (P=0.01). Therefore, the combination of Endostar with third-generation EGFR-TKIs as a first-line treatment may result in greater survival benefits for patients with the EGFR/TP53 co-mutation and ≥2 metastatic organs. Subgroup analyses for high-risk populations (e.g., ≥2 metastatic organs, TP53 comutations) were exploratory and require validation in larger cohorts due to limited statistical power.

We also analyzed the factors affecting PFS, and found that the use of third-generation EGFR-TKIs combined with Endostar was an independent protective factor of PFS in patients with EGFR-mutant NSCLC (HR: 2.059, 95% CI: 1.268–3.343, P=0.004). Brain metastasis, EGFR co-mutations, and high ECOG-PS scores were independent risk factors for shorter PFS (HR: 4.400, 95% CI: 2.544–7.611, P<0.001; HR: 1.776, 95% CI: 1.054–2.994, P=0.03; HR: 5.403, 95% CI: 2.401–12.157, P<0.001, respectively). However, our findings need to be validated in large prospective randomized clinical trials.

In terms of drug safety, large randomized controlled trials such as JO25567 (17), NEJ026 (18), WJOG9717L (19), and 8715L (20) have shown that combining EGFR-TKIs with anti-angiogenesis therapy is generally safe, and does not significantly increase the frequency or severity of AEs compared to EGFR-TKI monotherapy. In this study, there were 4 cases (8.5%) of grade 3 and above AEs in the E + T group, and 6 cases (8.4%) in the T group, but there was no statistically significant difference between the two groups (P>0.99). The incidence of AEs of any grade was higher in the E + T group than the T group (53.2% vs. 45.1%, P=0.39). The incidence of gingival bleeding (12.8% vs. 0.0%, P=0.008), epistaxis (8.5% vs. 0.0%, P=0.048), an abnormal cardiac enzyme profile (21.3% vs. 7.0%, P=0.02), and hemoptysis/hemorrhage (14.9% vs. 2.8%, P=0.04) was higher in the E + T group than the T group, and the differences between the two groups were statistically significant. This is consistent with a previous report that the common AEs of Endostar mainly include bleeding and cardiac toxicity (40). Thus, in clinical settings, patients should be asked whether they have hypertension or a history of heart disease before receiving Endostar treatment, and should undergo examinations such as electrocardiogram and myocardial enzyme spectrum examinations. Patients with cardiovascular and hemorrhagic diseases should carefully consider the advantages and disadvantages of E + T therapy. However, most patients show good drug tolerance and can undergo treatment without issue after symptomatic treatment or dose adjustment.

Our study had some limitations. First, it was a single-center study with a relatively small sample size, findings may not generalize to other populations or healthcare settings. As a retrospective study, our findings are subject to potential selection bias. Thus, larger, multi-center prospective studies need to be conducted to confirm our findings. Second, the current OS data is insufficient, and differences in subsequent therapies could significantly affect OS. Thus, longer follow-up is needed to determine the survival benefits of combination therapy.

Conclusions

Recombinant human endostatin combined with third-generation EGFR-TKIs is an effective and tolerable first-line treatment option for advanced NSCLC patients harboring EGFR mutations, particularly for those patients with ≥2 metastatic organs and EGFR/TP53 co-mutations.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1223/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1223/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1223/prf

Funding: This study was funded by the National Natural Science Foundation for Regional Fund (No. 82360507), the Hospital Clinical Research Cultivation Project (No. YFYLCYJPY202302), and the Innovation Special Fund Project for Graduate Students of Jiangxi Province (No. YC2023-S175).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1223/coif). A.C.T. receives grants (to institution) from Takeda and AstraZeneca; honoraria from Roche, AstraZeneca, Guardant, Merck, Amgen, Takeda; participated in Advisory Board from Amgen, Bayer, Pfizer. 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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Nanchang University (approval/reference number IIT2024342), and the requirement of informed 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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(English Language Editor: L. Huleatt)