Efficacy and safety of integrating consolidative thoracic radiotherapy with immunochemotherapy in extensive-stage small cell lung cancer: a real-world retrospective analysis

Introduction

Small cell lung cancer (SCLC) is an extremely aggressive type of lung cancer, accounting for approximately 15% of all new lung cancer cases (1). Early metastasis is a hallmark biological behavior of SCLC, with more than two-thirds of patients presenting with contralateral thoracic or distant metastasis at initial diagnosis (2), known as extensive-stage SCLC (ES-SCLC). It is also associated with a poor prognosis; randomized clinical trials (RCTs) have shown that patients with ES-SCLC receiving standard management have a median overall survival (OS) of approximately one year, with only a small subgroup surviving beyond 3 years (3,4).

Platinum-based systemic chemotherapy is the backbone of SCLC treatment, inducing an objective response in over 70% of patients, which allows its widespread application across all stages and treatment settings (5). Additionally, radiotherapy also plays a pivotal role in the management of SCLC (6). For limited-stage SCLC (LS-SCLC), in which tumor cells are confined within a unilateral thoracic region, the combination of systemic chemotherapy with thoracic radiotherapy is the current standard treatment (5). This chemoradiotherapy approach for LS-SCLC is potentially curable, with 5-year OS rates reported as up to 34% (7). In the case of ES-SCLC, the worldwide recommended standard treatment regimen is platinum-based systemic chemotherapy (with or without immunotherapy), but prospective and retrospective studies have indicated that the integration of consolidative thoracic radiotherapy (cTRT) in responded patients to chemotherapy can improve local control and OS (8-10). Consolidative radiotherapy of the primary thoracic tumor following initial treatment to improve patient prognosis has emerged as a routine practice in real-world settings.

The IMpower133 study significantly impacted the treatment of ES-SCLC (11). Based on this study, the Food and Drug Administration (FDA) approved the addition of atezolizumab, a monoclonal antibody targeting programmed cell death ligand-1 (PD-L1), to the platinum-based chemotherapy regimen of etoposide combined with either cisplatin or carboplatin for the first-line treatment of ES-SCLC in 2019. This milestone marked a significant advancement in the field of SCLC. Subsequent RCTs have confirmed the efficacy and safety of combining immunotherapy with chemotherapy as a first-line treatment for ES-SCLC, ushering in a new era for SCLC therapy (12-15). While immunotherapy has improved progression-free survival (PFS) and OS for ES-SCLC patients, it has not addressed the specific challenges of early drug resistance and the inherent aggressiveness of SCLC, which remains the most malignant type of lung cancer. Similarly, cTRT after induction of immunochemotherapy for ES-SCLC patients is also a routine option in real-world scenarios, aiming to further improve patient prognosis.

Combining radiotherapy and immunotherapy enhances tumor cell immunogenicity and modulates the tumor microenvironment, improving local control and potentially preventing or reversing resistance to immunotherapy (16). However, the data supporting immunochemotherapy in combination with cTRT in ES-SCLC remain limited, highlighting the need for further investigation. We conducted a single-center retrospective analysis to demonstrate the efficacy and safety of first-line immunochemotherapy combined with cTRT in a real-world setting for ES-SCLC patients. Our findings will provide the necessary evidence to guide future treatment strategies. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1592/rc).

Methods

Patients and treatments

This retrospective study analyzed medical records of patients diagnosed with ES-SCLC at Shandong Cancer Hospital between January 1, 2022, and December 31, 2023. The patients were stratified into three cohorts based on the first-line treatment received: chemoradiotherapy (cohort A), immunochemotherapy (cohort B), and immunochemotherapy followed by cTRT (cohort C). This study aims to demonstrate the efficacy and safety of various first-line treatment approaches for ES-SCLC in the real-world setting and to explore the potential benefits of incorporating cTRT into immunochemotherapy regimens.

The study included patients who met the following criteria: (I) confirmed diagnosis of SCLC through histopathology and aged 18 years or older; (II) confirmed ES-SCLC according to the Veterans Administration Lung Study Group (VALG) staging system; (III) patients in cohort A underwent 4–6 cycles of chemotherapy combined with cTRT, patients in cohort B received 4–6 cycles of immunochemotherapy followed by maintenance immunotherapy, and patients in cohort C were administered 4–6 cycles of immunochemotherapy along with concurrent cTRT during maintenance immunotherapy; (IV) the dose of cTRT was primarily determined based on the radiation physician’s comprehensive assessment of the patient’s lung lesions and general condition, with total radiation doses ranging from 30 to 60 Gy for patients enrolled in this study; (V) the chemotherapy regimen consisted of etoposide in combination with carboplatin or cisplatin (EP regimen). Exclusion criteria were: (I) patients with other concurrent primary tumors; (II) patients with histopathologically confirmed mixed histological types of SCLC; (III) patients with incomplete medical records. The study received approval from the Institutional Review Board of Shandong Cancer Hospital, with the approval number SDTHEC2024002011 and was conducted in accordance with the Helsinki Declaration (as revised in 2013). Informed consent was waived by our Institutional Review Board because of the retrospective nature of our study. All personal identifiers were removed from the datasets, and access to patient information was restricted to authorized personnel only, in compliance with applicable privacy regulations.

Data collection and outcome assessment

We collected the demographic and baseline characteristics of the patients from the electronic medical record system. These characteristics included age, sex, smoking status, Eastern Cooperative Oncology Group performance status (ECOG PS), comorbidities, and metastatic status. We also meticulously recorded details of the first-line treatment, such as the immunotherapeutic agents, adverse events (AEs), and survival outcomes.

The primary endpoints of the study were to describe the efficacy of various first-line treatment regimens across cohorts, including real-world progression-free survival (rwPFS) and OS. RwPFS is defined as the time from the initiation of the first-line treatment to disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria or death from any cause. OS is defined as the time from the date of diagnosis to the date of death from any cause. Secondary endpoints included the real-world safety profile of each cohort and evaluation of differences in rwPFS and OS across cohorts, following propensity score matching (PSM) to balance the baseline in treatment strategies. The real-world safety analysis focused on documenting AEs of specific interest, such as pneumonitis, hematologic toxicity, and gastrointestinal reactions. All AEs were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Exploratory endpoints included subgroup analyses of rwPFS and OS based on baseline clinical characteristics across all cohorts. These comprehensive assessments aim to provide a detailed understanding of the treatment outcomes and safety profiles of each therapeutic approach in a real-world setting.

Statistical analysis

Statistical analyses were conducted using R statistical software (version 4.0.2). Continuous variables were summarized by means and standard deviations (SD) or medians with range based on the distribution, whereas categorical variables were presented as frequencies and percentages. Differences in baseline characteristics among the cohorts (A, B, and C) were assessed using Chi-squared tests or Fisher’s exact test, as appropriate. PSM was used to adjust for the potential difference in the baseline characteristics between the cohorts. The Kaplan-Meier method was employed to estimate rwPFS and OS, which were then compared across the cohorts via the log-rank test. Cox proportional hazard (PH) models were used to adjust for potential confounders and estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for comparisons of rwPFS and OS among the cohorts following PSM. Subgroup analyses were subsequently conducted using Cox PH models to identify baseline characteristics of patients who could derive the maximum benefit from different treatment strategies by the PH hypothesis. Safety characteristics during treatment were descriptively summarized, and the severity of AEs was graded according to the CTCAE v 5.0. All statistical tests were two-sided with a significance level of P<0.05.

Results

Patient characteristics

We retrospectively reviewed the electronic medical records of 828 patients with ES-SCLC treated at Shandong Cancer Hospital between January 1, 2022, and December 31, 2023. A total of 374 patients were identified for further analysis: 170 in cohort A, 123 in cohort B, and 81 in cohort C (Figure 1). The majority of study participants were male (n=298, 79.7%), with a trend toward younger demographics (patients <65 years n=230, 61.5%) and a median age of 61 years (range, 36–82 years). A significant proportion of patients had a history of smoking (n=208, 55.6%) (Table 1).

Figure 1 Patient selection flowchart. ES-SCLC, extensive stage small cell lung cancer; EP, etoposide + carboplatin/cisplatin; cTRT, consolidative thoracic radiotherapy.

Baseline characteristics varied between cohorts, with patients in the radiotherapy cohorts (A and C) being generally younger (70% and 63% of patients were <65 years old, respectively) and having lower ECOG performance scores (91.2% and 87.7% of patients had ECOG scores of 0 or 1, respectively). Patients in the immunotherapy cohorts (B and C) had fewer brain and bone metastases (32.5% and 34.6% had brain metastases, respectively, and 24.4% and 27.2% had bone metastases, respectively) (Table 1). Given the potential safety implications of adding thoracic radiotherapy, clinicians’ tendency to select patients in better general condition for radiotherapy, suggests that such a baseline imbalance is justifiable in the real-world scenario. Furthermore, we observed that more than half of the patients in the immunotherapy cohorts (B and C) (53.9%) received serplulimab (an anti-PD-1 monoclonal antibody), with 49.6% in cohort B and 60.5% in cohort C treated with serplulimab. This preference may be attributed to the cost-effectiveness of this drug under China’s healthcare insurance policies (17-19).

Real-world efficacy and safety

In our analysis, median rwPFS across the three cohorts was observed as follows: 7.6 months (95% CI: 7.00–8.90) for cohort A, 8.0 months (95% CI: 6.90–9.97) for cohort B, and 10.9 months (IQR, 9.07–14.70 months) for cohort C. The 12-month rwPFS rate was 19% (95% CI: 14–26%) for cohort A, 34% (95% CI: 26–45%) for cohort B, and 41% (95% CI: 31–56%) for cohort C. The cohort C demonstrated numerical superiority in both rwPFS and the 12-month rwPFS rate compared to the cohorts A and B (Figure 2A). A similar trend was observed for OS, with cohorts B and C showing a numerical advantage over cohort A. Median OS (mOS) was 14.0 months in cohort A, 20.8 months in cohort B, and not yet reached in cohort C, with the lower limit of the 95% CI for cohort C being 17.80 months. The 18-month OS rates were 28% for cohort A, 62% for cohort B, and 63% for cohort C (Figure 2B). These results suggest that a first-line treatment strategy of cohort C may provide additional benefits to patients with ES-SCLC. However, further statistical testing was not conducted due to significant differences in baseline characteristics between the cohorts.

Figure 2 Kaplan-Meier survival curves for rwPFS and OS. (A) rwPFS Kaplan-Meier curves for all patients included in the study across the three cohorts; (B) OS Kaplan-Meier curves for all patients included in the study across the three cohorts; (C) rwPFS Kaplan-Meier curves for the three cohorts after PSM; (D) OS Kaplan-Meier curves for the three cohorts after PSM. rwPFS, real-world progression-free survival; OS, overall survival; PSM, propensity score matching; CI, confidence interval; cTRT, consolidative thoracic radiotherapy; HR, hazard ratio; NA, not available.

To examine the benefit of cohort C, we performed PSM to balance baseline characteristics between the three cohorts and further analyzed the survival differences between the three treatment strategies (see Table S1 for baseline characteristics after PSM). After PSM, the trends in rwPFS remained consistent with pre-matching results. The median rwPFS was 7.15 months (95% CI: 6.60–9.30) for cohort A, 7.50 months (95% CI: 6.70–9.93) for cohort B, and 10.37 months (95% CI: 8.93–13.47) for cohort C. Cohort C patients showed a significant improvement in rwPFS compared to cohort A (HR =1.88, 95% CI: 1.30–2.71, P=0.001). While the rwPFS for cohort C was numerically higher than that for cohort B, the difference was not statistically significant (HR =1.35, 95% CI: 0.91–2.00, P=0.14) (Figure 2C). Regarding OS among patients after PSM, cohorts B and C had similar mOS (HR =1.09, 95% CI: 0.59–2.00, P=0.78), which were 19.87 months [95% CI: 18.43–not reached (NR)] and 20.53 months (95% CI: 17.70–NR), respectively. Cohort A had a significantly lower mOS of 12.50 months (95% CI: 11.80–14.4) compared to cohort C (HR =3.21, 95% CI: 1.94–5.32, P<0.001) (Figure 2D). These findings suggest a potential survival advantage with the first-line treatment strategy that includes cohort C. However, further investigation is required to explore the benefit between cohorts B and C due to the lack of statistical significance.

Sub-group analysis for cohorts B and C

Based on the propensity score-matched results for rwPFS and OS benefit in cohorts B and C, we conducted subgroup analyses according to patient baseline characteristics and immunotherapy agents to identify subgroups most likely to benefit from these treatment strategies in the real world.

In cohort B, the univariate analysis of rwPFS revealed that patients with liver and bone metastases at baseline had a higher risk of progression compared to those without these metastases (liver metastasis, HR =2.01, 95% CI: 1.27–3.18, P=0.003; bone metastasis, HR =2.81, 95% CI: 1.75–4.51, P<0.001). The variable brain metastases violated the PH hypothesis, necessitating stratification for multivariate analysis. After adjusting for confounders and stratifying for brain metastases, the multivariate analysis confirmed worse rwPFS in patients with baseline liver and bone metastases (liver metastasis, HR =1.86, 95% CI: 1.09–3.17, P=0.02; bone metastasis, HR =2.35, 95% CI: 1.36–4.07, P=0.002) (Figure 3A).

Figure 3 Subgroup analysis of rwPFS and OS in Cohort B. (A) Subgroup analysis of rwPFS in Cohort B, stratified by clinical and treatment characteristics; (B) subgroup analysis of OS in Cohort B, stratified by clinical and treatment characteristics. Cohort B: immunochemotherapy alone. rwPFS, real-world progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval.

For the OS subgroup analysis, the univariate analysis within cohort B showed that patients with baseline bone metastases had an increased risk of death compared to those without bone metastases (HR =2.69, 95% CI: 1.27–5.68, P=0.009). Furthermore, patients who received 6 immunochemotherapy cycles showed better OS than those treated with 4 or 5 cycles (HR =0.28, 95% CI: 0.13–0.64, P=0.002). For brain metastasis not conforming to the PH hypothesis, stratification was applied in the multivariate analysis, which corroborated the finding that undergoing 6 cycles of immunochemotherapy was associated with a better OS prognosis (P=0.004) (Figure 3B).

In the subgroup univariate analysis for cohort C, it was found that never-smokers had a lower risk of progression compared to former/current smokers (HR =0.53, 95% CI: 0.29–0.96, P=0.04). Additionally, patients with liver and bone metastases at baseline had a higher risk of progression than those without these metastases (liver metastasis, HR =2.75, 95% CI: 1.5–5.04, P=0.001; bone metastasis, HR =2.53, 95% CI: 1.4–4.59, P=0.002) (Figure 4A).

Figure 4 Subgroup analysis of rwPFS and OS in Cohort C. (A) Subgroup analysis of rwPFS in Cohort C, stratified by clinical and treatment characteristics; (B) subgroup analysis of OS in Cohort C, stratified by clinical and treatment characteristics. Cohort C: immunochemotherapy with cTRT. rwPFS, real-world progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; cTRT, consolidative thoracic radiotherapy.

Surprisingly, subgroup analysis for cohort C revealed that patients aged ≥65 years had a lower risk of death compared to younger patients (HR =0.32, 95% CI: 0.11–0.95, P=0.04). Furthermore, the baseline liver metastasis patients had a higher risk of death (HR =2.48, 95% CI: 1.04–5.9, P=0.04) (Figure 4B). However, due to the failure of the brain metastasis variable to satisfy the PH hypothesis in the OS subgroup analysis of cohort C, and the limited sample size of this cohort, there exists a substantial challenge to the statistical reliability of the OS HRs post-stratification in the multivariate analysis. We avoid conducting overly stratified multivariate Cox regression analyses in cohort C OS subgroup analysis to prevent potentially misleading conclusions from the uneven distribution of sample sizes.

Safety

Due to the challenges of detailed treatment-related toxicity in the real world and the limitations of retrospective studies, we were unable to collect information on AEs with the same detailed granularity as prospective studies. Therefore, this study focuses on seven commonly observed AEs based on the known safety profiles of chemotherapy, radiotherapy, immunotherapy, and patient medical records. The AEs observed in the study were thrombocytopenia, leukopenia, gastrointestinal reactions, alopecia, pneumonitis, anemia, and myelosuppression.

The results showed that the incidence of these AEs of special interest was 97.06% (165/170) in cohort A, 97.56% (120/123) in cohort B, and 80.25% (65/81) in cohort C, with the incidence of grade ≥3 AEs being 88.24% (150/170), 82.93% (102/123), and 60.49% (49/81), respectively. The most common grade ≥3 AEs in all cohorts were myelosuppression, leukopenia, and gastrointestinal reactions, but those incidence rates varied numerically (Figure 5).

Figure 5 Incidence and severity of specific interested adverse events across the three cohorts. AEs, adverse events.

Discussion

The IMpower133 and CASPIAN studies have definitively revolutionized the first-line treatment paradigm for ES-SCLC by successfully introducing immunotherapy to the EP chemotherapy regimen. However, the addition of atezolizumab or durvalumab to chemotherapy has only extended OS in ES-SCLC patients by approximately two months (3,20). To improve the patient’s prognosis, the oncologists thoroughly investigated various immunotherapeutic agents in combination with the EP regimen (12,14,15). While these studies have shown that different immunotherapeutic agents can have a variable impact on patient survival, it has not overcome the early resistance observed in most patients. It is important to note that cTRT was not included in these prospective studies on first-line treatment for ES-SCLC. As early as 1999, Jeremic et al. demonstrated that patients with ES-SCLC who received cTRT in combination with chemotherapy had improved survival compared to chemotherapy alone (8). Furthermore, preclinical evidence suggests that radiotherapy can enhance antitumor effects by inducing a synergistic immune response with immunotherapy through the activation of both adaptive and innate immune responses (21). Clinical studies have identified an abscopal effect in immunotherapy-treated advanced cancer patients with additional radiotherapy leading to regression of metastatic lesions distant from the irradiation site (22,23). These findings provide a rationale, both theoretically and clinically, for incorporating cTRT into the first-line immunochemotherapy for ES-SCLC.

Our results suggest that in the real-world setting for patients with ES-SCLC, the addition of cTRT to first-line immunochemotherapy regimens results in numerically higher PFS and OS compared to cohort A and cohort B. This superiority of the immunochemotherapy plus cTRT regimen over cohort A was also confirmed after adjusting for patient characteristics using PSM. However, the results of post-PSM did not show a significant prognostic improvement of the immunochemotherapy regimen with the addition of cTRT, possibly due to the limited sample size in cohorts B and C. The question of whether the introduction of cTRT benefits patients with ES-SCLC has long been a topic of interest among oncologists, but conclusions remain inconsistent. Studies by Li et al. (24) and Hoffmann et al. (25) are consistent with our propensity score-matched findings of no statistically significant survival benefit with the addition of cTRT; however, other studies have shown clear benefits (26-29). A meta-analysis of 15 retrospective studies demonstrated that immunochemotherapy combined with cTRT significantly improved survival (HR =0.52, 95% CI: 0.39–0.68) with favorable 6-month (HR =0.89, 95% CI: 0.77–1.00) and 1-year (HR =0.77, 95% CI: 0.72–0.82) OS rates (30). Undeniably, the multiple confounding factors inherent in real-world studies may affect the statistical significance of the results. The prospective, randomized phase II/III RAPTOR trial (NCT04402788) (atezolizumab + chemotherapy ± radiotherapy) is currently in progress. This well-designed RCT is expected to provide more robust answers regarding the efficacy of integrating radiotherapy with chemo-immunotherapy in SCLC.

In the real-world treatment setting, our study observed an increased risk of disease progression in patients with liver or bone metastases at initial diagnosis when treated with first-line immunochemotherapy. However, for patients receiving immunochemotherapy combined with cTRT, the impact of liver and bone metastases on the risk of disease progression remains inconclusive due to inconsistent results between univariate and multivariate analyses. Overall, our results suggest that patients without distant metastases at baseline may benefit more from the addition of cTRT and potentially achieve a better rwPFS. Interestingly, subgroup analyses for OS suggested that patients aged ≥65 years potentially derive the most benefit from immunochemotherapy combined with cTRT, which may provide valuable insights for tailoring treatment strategies. Previous meta-analyses have concluded that serplulimab may offer the most favorable survival outcomes for patients with ES-SCLC, suggesting that different immunotherapeutic agents may contribute to survival benefits in varying degrees (31-34). Despite these insights, our retrospective study is limited by the inherent confounders of real-world settings and a relatively small sample size, which restricts the statistical power of our findings. Furthermore, more extensive prospective and/or retrospective studies focusing on this issue are warranted to definitively identify the optimal patient population that benefits most from treatment.

In our study, 55.6% of patients had a history of smoking, and the proportion of smokers in each cohort was also about 50%. This may be due to the recent smoking cessation education by our local government, which has led to a decrease in the number of smokers. However, even if nearly half of the patients are not smokers, it cannot be ruled out that they have no history of secondhand smoke exposure. Considering this situation, the proportion of patients who actually have a history of cigarette exposure may be higher. In fact, most studies have shown that smoking may be an independent and post factor for ES-SCLC (35-37), but there are also a few studies that suggest that smoking history has no significant effect on the treatment of ES-SCLC (38), and there are even cases where smoking patients have longer OS than non-smoking patients (35). This difference is mainly due to differences in region, sample size, treatment methods, prediction models, etc. In our results, smoking status is also an important prognostic factor for ES-SCLC.

Safety has always been a major concern in cancer treatment, and the clinical consensus has traditionally held that the introduction of immunotherapy and radiotherapy increases toxic risks for patients. However, our safety results indicate that the overall incidence and severity of AEs of special interest are similar across the three patient cohorts, with only slight variations in specific AEs. While myelosuppression, leukopenia, and gastrointestinal reactions were the most frequently observed AEs across all cohorts, the incidence of these events was numerically lower in cohorts B and C, which included immunotherapy, compared to cohort A. Importantly, the rate of grade 3 or higher pneumonitis was elevated among patients treated with immunochemotherapy, with or without cTRT, consistent with previous studies (39,40). However, in our study, the incidence and severity of pneumonitis in the patients receiving immunochemotherapy with cTRT (cohort C) were slightly better than in the patients treated with immunochemotherapy without cTRT (cohort B), diverging from the conclusions of some other studies (41,42). This difference may be due to the smaller sample size of cohort C in our study. The mechanisms by which the combination of immunotherapy and radiotherapy may increase the risk of lung injury have been reviewed in a comprehensive study (43). However, according to our data and clinical experience, patients with ES-SCLC generally tolerate immunochemotherapy combined with cTRT well and the associated safety concerns are manageable.

Undoubtedly, there are limitations in this study. We did not collect complete data on the tumor response of patients before and after treatment, so it is not possible to accurately evaluate ORR. This is because in the clinical treatment process, we cannot force patients to undergo regular imaging examinations, so there are obvious deficiencies and inconsistent evaluations in the relevant data, making it impossible to analyze. In addition, in order to minimize confounding factors in the real world, we limited the inclusion of patients who received and completed 4–6 cycles of first-line treatment, potentially excluding patients with refractory/primary drug resistance. Therefore, for this study design, reporting the tumor remission status of patients may actually confuse the ES-SCLC patient population.

Conclusions

It was conducted as a single-center retrospective analysis at Shandong Cancer Hospital, which resulted in a limited sample size. Additionally, the study only included patients with specific regional characteristics, which may not be representative of the broader ES-SCLC patient population. However, this study’s findings offer valuable real-world evidence on the efficacy and safety of combining immunochemotherapy with cTRT and, through subgroup analysis, identify patient characteristics most likely to benefit from this treatment approach. Radiotherapy is a backbone of lung cancer treatment, but the safety and efficacy of combination immunotherapy have not been fully established. Further research into this treatment strategy is warranted to maximize patient outcomes in ES-SCLC.

Acknowledgments

The abstract of this article has been presented at the European Society for Medical Oncology (ESMO) conference and was subsequently published in the journal Annals of Oncology.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1592/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1592/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1592/prf

Funding: This work was supported by the Clinical Research Capacity Building and Human Research Participants Protection Practice Platform (No. CCHRPP-ZL-2023-Q-003) and the Zhongguancun Precision Medicine Foundation (No. GX2DH03).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1592/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 received approval from the Institutional Review Board of Shandong Cancer Hospital, with the approval number SDTHEC2024002011 and was conducted in accordance with the Helsinki Declaration (as revised in 2013). Informed consent was waived by our Institutional Review Board because of the retrospective nature of our 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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