Efficacy and safety of camrelizumab in combination with S-1 plus oxaliplatin sequenced by camrelizumab-based maintenance therapy as a first-line treatment for advanced gastric or gastroesophageal junction adenocarcinoma: a retrospective cohort study

Introduction

Gastric or gastroesophageal junction (G/GEJ) adenocarcinoma is the fifth most common cancer and the third leading cause of cancer-related death worldwide (1-3). G/GEJ adenocarcinoma is commonly asymptomatic in the early stages, and due to the lack of specific screening methods, the vast majority of patients present with locally advanced or distant metastatic diseases at the initial diagnosis (4,5). The combination of a platinum drug (often cisplatin or oxaliplatin) and a fluoropyrimidine (usually fluorouracil, capecitabine, or S-1) still remain the mainstay of first-line palliative chemotherapy for patients with human epidermal growth factor receptor 2 (HER-2) negative status (5-7). Despite significant advancements in recent decades, the prognosis of such patients, who have a 5-year survival rate of approximately 10%, remains poor (6-10). Compared to cytotoxic chemotherapy, immune checkpoint inhibitors (ICIs) provide a novel and different mechanism for anti-tumor activity whereby malignant cells establish an immunosuppressive tumor microenvironment by releasing specific cytokines that can stimulate inhibitory immune checkpoints, which can be blocked by ICIs (11). Preclinical models of other malignant diseases have shown that the addition of chemotherapy to combination treatment can strengthen the anti-tumor response elicited by ICIs by inducing immune-mediated cell death (12,13).

Recently, the results of several double-blinded and randomized controlled trials have shown that combinations of ICIs and first-line chemotherapy significantly improved the survival of advanced or metastatic HER2-negative G/GEJ adenocarcinoma patients in comparison with standard chemotherapy alone (9,10,14). Notably, the phase-III CheckMate 649 trial showed that the addition of the programmed cell death protein 1 (PD-1) inhibitor nivolumab to standard chemotherapy significantly improved progression-free survival (PFS) and overall survival (OS) (15,16). A significant improvement in PFS was also confirmed in the phase-III ATTRACTION-4 trial of Asian patients (17). Similarly, the PD-1 inhibitor sintilimab plus first-line chemotherapy significantly improved OS compared to chemotherapy alone in the phase-III ORIENT-16 trial (18). Further, compared to placebo plus chemotherapy, tislelizumab in combination with chemotherapy was shown to significantly improve OS, PFS, and the objective response rate (ORR) in the phase-III RATIONALE-305 trial (19). Most recently, the phase-III KEYNOTE-859 trial reported that participants in the pembrolizumab plus chemotherapy group had significantly improved OS and PFS, and a significantly improved ORR compared to the placebo plus chemotherapy group (20).

Additionally, evidence from the past 5 years has shown that the combination of the PD-1 inhibitor camrelizumab with standard-of-care chemotherapy improves clinical outcomes and has manageable toxicity in unresectable, advanced, or metastatic HER2-negative G/GEJ adenocarcinoma (21-23). Moreover, both nivolumab combined with S-1 plus oxaliplatin (SOX) and pembrolizumab in combination with SOX have also demonstrated encouraging anti-tumor activity and a manageable safety profile (8-10), as well as in the perioperative and neoadjuvant settings of locally advanced G/GEJ adenocarcinoma (24,25), however, the improved PFS and OS were also limited, along with less access to these two ICIs. Therefore, we carried out this retrospective study to evaluate the efficacy and safety of camrelizumab plus SOX sequenced by camrelizumab-based maintenance therapy as a first-line treatment for patients with previously untreated HER2-negative and advanced G/GEJ adenocarcinoma. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-189/rc).

Methods

Study design and patients

This single-arm, retrospective study was conducted at the Department of Oncology, the First Affiliated Hospital of Anhui Medical University. To be eligible for inclusion in the study, the patients had to meet the following inclusion criteria: be aged 18 years or older; have histopathologically or cytologically confirmed advanced G/GEJ adenocarcinoma; have not previously undergone a systemic anti-cancer treatment; have an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1; have adequate organ function; have a HER-2 negative tumor; have a life expectancy of more than 3 months; and have at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 based on investigator assessment. Patients were excluded from the study if they met any of the following exclusion criteria: had previously received a systemic treatment with anti-PD-1 or programmed death-ligand 1 (PD-L1) monoclonal antibodies, had a HER2-positive status, had squamous cell gastric cancer, had active or a history of autoimmune diseases requiring relevant treatment, had a history of receiving chronic systemic immunosuppressant therapy, had a history of organ transplantation, had active hepatitis B or hepatitis C infection, had a known history of human immunodeficiency virus disease, had a serious cardiovascular or cerebrovascular disease, had an uncontrolled neurological or mental disorder, had active central nerve system (CNS) metastasis, or had other serious comorbidities.

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The protocol was approved by the independent Ethics Committees of the First Affiliated Hospital of Anhui Medical University (No. PJ 2024-06-69) and informed consent was taken from all the patients.

Treatment

All the included participants received at least 1 cycle of camrelizumab plus SOX treatment. In brief, they received camrelizumab (200 mg intravenously over 30 minutes on day 1 every 3 weeks) plus SOX (S-1, 40 mg orally twice daily if the patient’s body surface area was less than 1.25 m², 50 mg twice daily if it ranged from 1.25 to 1.5 m², and 60 mg twice daily if it was more than 1.5 m² on days 1 to 14 sequenced by one week off; and 130 mg/m² of oxaliplatin intravenously administered on the first day of each 3-week cycle) for 6–8 cycles. Those with no progressive disease (PD) after finishing the 6–8 cycles of camrelizumab in combination with SOX were treated with camrelizumab (as previously described) plus S-1 (at a specific dose, orally, twice daily for 14 days every 3 weeks).

Treatment was administered until intolerable toxicity, disease progression, death, investigator decision, withdrawal of consent, the completion of the maximum number of cycles, or other reasons (e.g., prohibited concomitant medication requiring withdrawal, and recurrent grade 2 pneumonitis). The participants who developed radiological PD could continue to receive previous treatment if they were tolerating it well and were deemed to be continuing to receive a clinical benefit. The dosage of camrelizumab could not be modified. However, the dosage of S-1 could be modified, and the oxaliplatin, camrelizumab, S-1, and oxaliplatin treatment could be interrupted due to treatment-related adverse events (TRAEs). The participants who discontinued S-1 and/or oxaliplatin due to treatment-related toxicities could continue to receive camrelizumab. If the participants could not recover from the toxicities within 6 weeks, chemotherapy was permanently terminated. Additionally, if a participant suffered from a grade 3 peripheral sensory neurotoxicity, oxaliplatin was permanently terminated. However, when grade 2 peripheral sensory neurotoxicity occurred, the administration of intravenous oxaliplatin was interrupted in the following cycle. When the neurotoxicity decreased to ≤ grade 1, the dosage of oxaliplatin was adjusted to three quarters of the prior dose.

Outcomes and assessments

The primary endpoint of the study was PFS, which was defined as the time interval from the start of treatment to the first confirmed disease progression as per the RECIST version 1.1, or death from any cause, whichever occurred first. The secondary endpoints were OS, which was defined as the time from the start of treatment to death due to any cause; the ORR, which was defined as the percentage of participants whose best overall response was a complete response (CR) or partial response (PR) according to the investigators’ assessment; the disease control rate (DCR), which was defined as the percentage of patients who had a CR, PR, or stable disease (SD) as their best overall response; and the duration of response (DoR), which was defined as the time from first documented evidence of CR or PR until disease progression or death from any cause, whichever occurred first; and safety profiles.

Tumor assessments were evaluated every 2–3 cycles of treatment according to the RECIST version 1.1 based on investigators’ review of enhanced computed tomography or magnetic resonance imaging scans. The participants were regularly followed up to assess their survival condition every 1–2 months until death due to any cause, consent withdrawal, or the end of study. The adverse events (AEs) were closely monitored for 90 consecutive days since the last administration, and were evaluated based on the National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAEs), version 4.0. The PD-L1 protein expression status of some of the enrolled participants was identified and examined by an anti-PD-L1 rabbit monoclonal antibody (clone SP142; Ventana, Tucson, AZ, USA). The cumulative positive score (CPS) was used to determine the PD-L1 expression level, which was defined as the number of PD-L1-positive cells (tumor cells, macrophages, and lymphocytes) divided by the total number of tumor cells multiplied by 100.

Statistical analysis

SPSS (IBM SPSS Statistics for Windows, Version 22.0, NY, USA) and GraphPad Prism (GraphPad Software for Windows, version 9.0.0, San Diego, CA, USA) were used for the statistical analysis. PFS, OS, and DoR were estimated using the Kaplan-Meier method, and the 95% confidence intervals (CIs) of the median were determined using the Brookmeyer and Crowley method. The median and range of time to response (TTR) were also calculated. The log-rank test was used to compare the survival differences. The ORR, DCR, PFS, OS, TTR, and DoR were classified by different PD-L1 expression levels for the subgroup analysis. Univariate and multivariate logistical regression analyses of PFS and OS were performed, and the hazard ratios (HRs) were calculated using Cox’s proportional hazard model. A two-sided P value less than 0.05 was considered statistically significant. The safety profiles of all the included patients who received at least one dose of treatment were evaluated by descriptive statistics.

Results

Baseline demographics and characteristics of patients

In total, 31 treatment-naive patients who were newly diagnosed with HER2-negative advanced G/GEJ adenocarcinoma and received camrelizumab in combination with SOX sequenced by camrelizumab-based maintenance therapy from February 1, 2020, to August 31, 2023, were enrolled in the study (Figure 1). As of December 31, 2023, 8 patients (25.8%) remained on treatment: 4 on camrelizumab/SOX and 4 on camrelizumab/S-1, while the remaining 23 (74.2%) patients had discontinued treatment [of whom, 17 (54.8%) had discontinued treatment during the camrelizumab combined with SOX stage, and 6 (19.4%) had discontinued treatment during the camrelizumab-based maintenance therapy stage]. The median follow-up time period was 14.9 months (range, 1.3–23.0 months). Disease progression was the major reason for treatment discontinuation (n=24, 45.2%), followed by AEs (n=4, 12.9%). One patient (3.2%) who had radiological PD continued to receive initial treatment at the investigators’ discretion.

Figure 1 Study flow diagram (n=31). SOX, S-1 plus oxaliplatin.

The participants had a median age of 68 years (range, 41–86 years), and the vast majority were male (n=25, 80.6%). Of the participants, 12 had an ECOG PS score of 0, and 19 (61.3%) had an ECOG PS score of 1. Further, 28 (90.3%) patients had a primary tumor originating from the stomach, and the remaining 3 (9.7%) had a primary tumor located at the GEJ. All the participants had at least one metastatic organ involved, and 11 (35.5%) participants had metastasis in more than two organ systems. Of the 31 patients, 5 (16.1%) had previously undergone curative gastrectomy (Table 1). Further, 23 (74.2%) participants had completed ≥4 cycles of camrelizumab plus SOX, and 8 (25.8%) had received <4 cycles of the first-line treatment. In total, 16 (76.2%) of the 21 patients who developed PD subsequently received second-line therapy or above.

Efficacy

Of the included 31 participants, 1 (3.2%) achieved a CR, 21 (67.7%) achieved a PR, and 5 (16.1%) had SD, resulting in an ORR of 71.0% (22/31) and a DCR of 87.1% (27/31) for the patients who received camrelizumab in combination with SOX sequenced by camrelizumab and S-1 maintenance therapy (Table 2). Overall, 26 (83.9%) participants showed tumor shrinkage of their target lesions from the baseline (Figure 2A). The decreased tumor burden was maintained for quite a long period over several assessments among several patients (Figure 2B). Tumor responses were identified at a median of 1.8 months (range, 1.3–3.1 months) (Table 2). Among the 22 participants who received the study treatment and achieved a CR/PR, 7 (31.8%) underwent subsequent camrelizumab plus S1 following camrelizumab plus SOX, and had a durable median DoR of 8.5 months (95% CI: 7.0–9.9, Figure 2C).

Figure 2 Treatment outcomes for patients treated with camrelizumab plus SOX followed by camrelizumab plus S-1. The responses of 28 evaluable patients were assessed by an investigator using the RECIST (version 1.1). (A) Best responses of target lesions from the baseline in each patient. (B) Longitudinal change from the baseline in the sum of the longest diameters of the target lesions. (C) Duration of the tumor response in 22 patients (1 CR and 21 PRs). CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; SOX, S-1 plus oxaliplatin.

As of the study data cut-off date, 21 (67.7%) participants had PFS, and a median PFS time of 7.3 months (95% CI: 3.0–11.6; Table 2 and Figure 3A), and 20 (64.5%) participants had died, and had a median OS time of 13.3 months (95% CI: 10.3–16.4; Table 2 and Figure 3B). The median DoR was 5.0 months (95% CI: 2.0–8.1; Table 2, and Figure 3C).

Figure 3 The PFS, OS, and DoR of all the patients. (A) Kaplan-Meier curves for PFS. (B) Kaplan-Meier curves for OS. (C) Kaplan-Meier curves for the DoR. PFS, progression-free survival; OS, overall survival; DoR, duration of response; CI, confidence interval.

PD-L1 expression status was evaluated in 19 (61.3%) patients, of whom 12 (38.7%) had PD-L1 CPS >1, and 7 (22.6%) had PD-L1 CPS ≤1 (Table 1). The ORR and DCR of the PD-L1 CPS >1 participants were 66.7% (8/12) and 100.0% (12/12), respectively, and those of the PD-L1 CPS ≤1 and unknown participants were 73.7% (14/19) and 78.9% (15/19), respectively (Table 3). The PD-L1 CPS >1 participants, and the PD-L1 CPS ≤1 and unknown participants had median PFS times of 7.3 months (95% CI: 6.6–7.9) and 9.3 (95% CI: 2.4–16.2), respectively (Table 3 and Figure 4A). The median OS time of the PD-L1 CPS >1 participants was 14.4 months (95% CI: 11.6–17.1) and that of the PD-L1 CPS ≤1 and unknown participants was 12.3 months (95% CI: 6.0–18.5) (Table 3 and Figure 4B).

Figure 4 Subgroup analysis of PFS and OS stratified by PD-L1 CPS expression (A,B), liver metastasis (C,F), serum albumin (D,G) and CA19-9 (E,H) levels. PD-L1, programmed death-ligand 1; CPS, combined positive score; UN, unknown; LM, liver metastasis; ALB, albumin; CA19-9, carbohydrate antigen 19-9; PFS, progression-free survival; OS, overall survival.

Post hoc analysis of median PFS and OS

The post hoc analysis showed that the participants with liver metastasis had unfavorable median mPFS (HR: 2.610; 95% CI: 1.073–6.352; P=0.03). In addition, decreased pre-treatment albumin (HR: 3.828; 95% CI: 1.231–11.902; P=0.02) and increased pre-treatment carbohydrate antigen 19-9 (CA19-9) (HR: 2.465; 95% CI: 1.013–5.997; P=0.047) levels were both associated with poor median PFS (Table S1). Patients without liver metastasis showed improved median PFS (9.3 versus 4.6 months, P=0.03, Figure 4C), as did those in the normal albumin group (18.1 versus 6.9 months, P=0.02, Figure 4D) and the normal CA19-9 group (11.5 versus 5.6 months, P=0.047, Figure 4E). Moreover, the multivariate analysis showed that the pre-treatment serum albumin level (HR: 3.683; 95% CI: 1.142–11.883; P=0.03) independently predicted median PFS (Table S1 and Figure 4D).

The univariate analysis of median OS indicated that the patients with liver metastasis tended to have decreased OS (HR: 2.459; 95% CI: 0.998–6.063; P=0.051) (Table S2 and Figure 4F). Participants in the normal albumin group (21.6 versus 12.5 months, P=0.04, Figure 4G) and the normal CA19-9 group (18.3 versus 10.4 months, P=0.04, Figure 4H) had a favorable median OS. Further, a multivariate analysis was then performed using a Cox proportional hazards model. Unfortunately, after adjusting for other confounding parameters, neither pre-treatment serum albumin nor CA19-9 levels were found to be independent predictors of median OS (Table S2, and Figure 4G,4H).

Safety

All 31 participants were enrolled in the final safety profile analysis. All participants (n=31, 100%) developed TRAEs (Table 4). In addition, the most frequent TRAEs of any grade were reactive cutaneous capillary endothelial proliferation (RCCEP) (n=23, 74.2%), a decreased platelet count (n=21, 67.7%), a decreased white blood cell count (n=20, 64.5%), decreased albumin (n=20, 64.5%), a decreased neutrophil count (n=17, 54.8%), increased aspartate aminotransferase (n=17, 54.8%), and increased alanine aminotransferase (n=16, 51.6%). Moreover, the most commonly observed grade ≥3 TRAEs were increased gamma-glutamyltransferase (GGT) (n=3, 9.7%) and a decreased neutrophil count (n=2, 6.5%). Other grade 3 TRAEs were decreased appetite (n=1, 3.2%), RCCEP (n=1, 3.2%), a decreased platelet count (n=1, 3.2%) and increased alkaline phosphatase (ALP, n=1, 3.2%). Of the 31 patients, 9 (29.0%) developed TRAEs leading to any dose reduction, 11 (35.5%) developed TRAEs leading to any treatment interruption, and 5 (16.1%) developed TRAEs leading to any treatment discontinuation (Table 5). The TRAEs that led to any treatment adjustments are detailed in Table 4. The most commonly observed TRAEs of special interest were grade 2 peripheral sensory neurotoxicity (n=2, 6.5%) and grade ≥3 RCCEP (n=6, 19.4%). No cases of serious TRAEs or treatment-related deaths were reported.

Discussion

Patients with HER2-negative advanced G/GEJ adenocarcinoma treated with a doublet or triplet platinum-fluoropyrimidine combination regimen have been shown to have a higher response rate and prolonged survival than those treated with single-agent therapy; however, the long-term usage of such regimens is strictly limited due to cumulative toxicity, worsened organ function, and deteriorated performance status (8-10). Therefore, maintenance treatment strategies with high efficiency and low toxicity, such as ipilimumab (an anti-cytotoxic T-lymphocyte associated protein 4 antibody) (26), avelumab (an anti-PD-L1 antibody) (27), camrelizumab plus apatinib (an antiangiogenic drug), following first-line platinum-fluoropyrimidine combination chemotherapy (21,23), are continuously being investigated (28). In the present study, camrelizumab was added to first-line SOX chemotherapy targeting to improve the treatment outcome, and a maintenance strategy with camrelizumab and S-1 was adopted to maximize the clinical benefits of the treatment and minimize the relevant toxicity. To the best of our knowledge, this study was the first to evaluate the efficacy of sequential camrelizumab plus S1 following combined camrelizumab and SOX therapy in HER2-negative advanced G/GEJ adenocarcinoma.

The 71.0% ORR of the participants who received camrelizumab in combination with SOX sequenced by camrelizumab and S-1 was higher than that previously reported for other first-line chemotherapy combined with anti-PD-1 agents, including nivolumab combined with SOX (57.1%) (17), pembrolizumab plus cisplatin and 5-fluorouracil/capecitabine (60.0%) (29), and camrelizumab plus capecitabine and oxaliplatin (CAPOX) followed by camrelizumab combined with apatinib (58.3%) (21). In addition, the 93.8% DCR was also similar to the results reported for patients who received a combination of nivolumab and SOX, pembrolizumab plus cisplatin and 5-fluorouracil/capecitabine, and camrelizumab plus CAPOX sequenced by camrelizumab combined with apatinib (80.0–93.8%) (17,21,29). Moreover, the median PFS and OS were 7.3 and 13.3 months, respectively, regardless of the PD-L1 expression level. The differences might be attributed to real-world setting, various ICIs and retrospective analysis in the present studies. While direct cross-trial comparisons could not be performed, the survival benefits of the combination treatments were more favorable than chemotherapy alone (median PFS: 3.7–5.6 months; median OS: 8.6–10.7 months) (4-7). Similar to our study, improved median PFS has also been reported in patients receiving pembrolizumab plus cisplatin and 5-fluorouracil/capecitabine (6.6 months) (29), nivolumab plus SOX (9.7 months) (17), as well as camrelizumab plus CAPOX sequenced by camrelizumab in combination with apatinib (6.8 months) (21). However, the median OS of the participants in the present study was slightly shorter than that of those who received pembrolizumab plus cisplatin and 5-fluorouracil/capecitabine in the KEYNOTE-059 study (13.8 months) (29), those who received nivolumab plus chemotherapy in the CheckMate-649 study (13.8 months) (17), and those who received camrelizumab combined with CAPOX followed by camrelizumab plus apatinib (14.9 months) (21). Above all, the promising ORR, DCR, PFS, and OS of the participants who received camrelizumab plus SOX followed by camrelizumab combined with S-1 suggest that this combination regimen could serve as a novel first-line treatment option for HER2-negative advanced G/GEJ adenocarcinoma.

Similarly, Liu and his colleagues showed that the median PFS and OS were 7.4 months (vs. 7.3 months) and 20.2 months (vs. 13.3 months), respectively, in untreated advanced HER-2 negative GC who received camrelizumab plus SOX as first-line treatment. Almost the same with our study, as well as the ORRs (36% vs. 71%) and DCRs (92% vs. 87.1%) and safety profiles (23).

Additionally, the occurrence rate and severity of TRAEs resulting from camrelizumab combined with SOX sequenced by camrelizumab and S-1 were similar to prior AEs related to chemotherapy alone, camrelizumab or S-1 (21,30). The most commonly observed grade ≥3 TRAEs were increased GGT (9.7%) and a decreased neutrophil count (6.5%), which is consistent with the findings of other studies (8-10). No new AEs were identified. Moreover, 74.2% of the entire cohort suffered RCCEP during the study treatment period, while the occurrence rate of RCCEP was reported to be 79.2% during the administration of camrelizumab in combination with CAPOX, which decreased to 17.9% during the subsequent maintenance treatment with camrelizumab and apatinib (21,31). Further, our study showed that the incidence of TRAEs leading to any treatment discontinuation was 16.1%, which was lower than that of camrelizumab plus chemotherapy sequenced by camrelizumab combined with apatinib (25.0%) (21), pembrolizumab plus chemotherapy (27.6%) (29), and nivolumab in combination with chemotherapy (36.3%) (17). In addition, unlike in previous studies of camrelizumab, no treatment-related deaths were observed in this study. For example, Peng et al. reported one (1/48, 2.1%) treatment-related death due to hepatic function deterioration and interstitial lung disease (21). Moreover, only 29.0% of the patients developed grade ≥3 TRAEs in this study, which is significantly lower than that reported in previous studies. Peng et al. reported that 68.8% of patients who received camrelizumab plus CAPOX sequenced by camrelizumab and apatinib suffered from grade ≥3 TRAEs (21), and 90.7% of patients receiving nivolumab plus paclitaxel and ramucirumab suffered from grade ≥3 TRAEs. Thus, this sequential treatment strategy had well-tolerated safety compared to concurrent chemotherapy, anti-PD-1 antibodies plus molecular antiangiogenic agents (32). Further, consistent with other studies, RCCEP, hepatotoxicity, and hematotoxicity were the most frequently observed TRAEs (21,31), while the occurrence of thyroid function abnormality and neurotoxicity was less observed in this combination regimen.

However, several limitations should be taken into account when interpreting the results of the present study. First, this study was carried out at only one institution; thus, the results might be influenced by patient selection bias. Second, the administration of camrelizumab in combination with SOX sequenced by maintenance treatment with camrelizumab and S-1 showed novelty and promising clinical utility, but a standard-of-care control group was lacking. Third, not all the included participants underwent PD-L1 expression evaluation, and no mismatch repair/microsatellite instability (MMR/MSI) status and tumor mutation burden (TMB) status evaluations were performed, and as a result no subgroup analyses of PD-L1, MMR/MSI, and TMB status were conducted. Thus, in the future, large cohort phase-III studies should examine whether the PD-L1 expression level, MMR/MSI status, or TMB status could serve as potential biomarkers for predicting the efficacy of this treatment strategy in this threatening disease.

Conclusions

As a first-line treatment for previously untreated patients with advanced G/GEJ adenocarcinoma, camrelizumab plus SOX followed by camrelizumab combined with S-1 is a novel treatment option with promising efficacy and good tolerance. This regiment could address a high unmet medical need for highly efficacious and safe therapies. However, further phase-III randomized trials need to be conducted.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-189/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-189/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-189/prf

Funding: This study was supported by grants from the 2021 Anhui Natural Science Foundation (No. 2108085QH345) and the 2023 Norman Bethune, Excelsior, Advanced Solid Tumor Research Program (No. STLKY2-072).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-189/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The protocol was approved by the independent Ethics Committees of the First Affiliated Hospital of Anhui Medical University (No. PJ 2024-06-69) and informed consent was taken from all the patients.

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)