Wang YC, Zhang CG, Wang YW, Guo C, Pan T, Yu PJ, Cai BJ, Ding RH, Qiang JL, Deng CQ, Hu CH, Xu YH. SOX plus sintilimab vs P-SOX vs SOX as neoadjuvant therapy in advanced gastric cancer: Efficacy and safety. World J Gastrointest Oncol 2025; 17(8): 109646 [DOI: 10.4251/wjgo.v17.i8.109646]
Corresponding Author of This Article
Peng-Jie Yu, PhD, Professor, Vice Director, Department of Gastrointestinal Oncology, The Affiliated Hospital of Qinghai University, No. 29 Tongren Road, Xining 810000, Qinghai Province, China. hnypj768@126.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Yi-Cong Wang, Can Guo, Ting Pan, Peng-Jie Yu, Bao-Jia Cai, Rui-Hua Ding, Yong-Huan Xu, Department of Gastrointestinal Oncology, The Affiliated Hospital of Qinghai University, Xining 810000, Qinghai Province, China
Co-first authors: Yi-Cong Wang and Chen-Guang Zhang.
Author contributions: Wang YC and Zhang CG contributed equally as co-first authors; Wang YC and Zhang CG conceived the study, designed experiments, and wrote the primary manuscript; Yu PJ supervised the project, performed critical data analysis, and revised the manuscript; Wang YW, Guo C, and Pan T contributed to data collection, validation, and visualization; Cai BJ, Ding RH, and Xu YH assisted in experimental execution and technical support; Qiang JL, Deng CQ, and Hu CH participated in literature review, methodology development, and preliminary analysis; all authors reviewed and approved the final manuscript.
Supported by Qinghai Provincial Science and Technology Plan, No. 2023-ZJ-787.
Institutional review board statement: The study was reviewed and approved by the Medical Ethics Committee of the Affiliated Hospital of Qinghai University, Approval number: P-SL-2024-421.
Informed consent statement: Written informed consent was obtained from all participants.
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: The datasets used and/or analyzed during the current study are not publicly available due to privacy or ethical restrictions.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Peng-Jie Yu, PhD, Professor, Vice Director, Department of Gastrointestinal Oncology, The Affiliated Hospital of Qinghai University, No. 29 Tongren Road, Xining 810000, Qinghai Province, China. hnypj768@126.com
Received: May 20, 2025 Revised: June 2, 2025 Accepted: July 1, 2025 Published online: August 15, 2025 Processing time: 89 Days and 11.9 Hours
Abstract
BACKGROUND
Gastric cancer (GC) remains a major global health burden, particularly in East Asia, due to its high incidence, aggressive progression, and poor prognosis in advanced stages. Although surgery is the mainstay of curative treatment, outcomes for locally advanced cases remain unsatisfactory despite perioperative chemotherapy. In recent years, immune checkpoint inhibitors, especially anti-PD-1 antibodies like sintilimab, have shown promise in improving survival when combined with chemotherapy. However, the comparative efficacy and safety of SOX plus sintilimab vs established regimens such as P-SOX and SOX alone in the neoadjuvant setting have not been fully explored.
AIM
To compare the efficacy and safety of three neoadjuvant chemotherapy regimens—SOX combined with sintilimab (SOX + PD-1), albumin-bound paclitaxel plus oxaliplatin and S-1 (P-SOX), and SOX—in patients with advanced GC.
METHODS
A retrospective analysis was conducted on 299 patients with advanced GC who received both neoadjuvant and adjuvant chemotherapy along with standard D2 radical gastrectomy. Among them, 81 patients received SOX plus sintilimab, 118 received the P-SOX regimen, and 100 received the SOX regimen. All patients were randomly assigned to training (70%) or validation (30%) cohorts using the R software sample function. Short-term efficacy, long-term survival outcomes, and adverse events were assessed across the three groups. Additionally, clinical factors associated with progression-free survival (PFS) were further investigated.
RESULTS
In terms of short-term efficacy, the SOX + sintilimab group had higher objective response rates [91.4% and 70.4% according to the tumor regression grade (TRG) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, respectively] than did the P-SOX (88.1% and 59.3%) and SOX groups (84.0% and 55.0%), although the intergroup differences were not statistically significant (P = 0.167). For long-term outcomes, the SOX + sintilimab group demonstrated significantly better OS rates at 1 year (98.8%), 18 months (92.6%), 2 years (84.0%), and 3 years (48.1%) than did the P-SOX (93.2%, 86.4%, 71.2%, 30.5%) and SOX (91.0%, 84.0%, 72.0%, 29.0%) groups, with the 3-year overall survival (OS) difference being statistically significant (P = 0.007). Similarly, PFS rates in the SOX + sintilimab group (1 year: 92.6%; 18 months: 77.8%; 2 years: 65.4%; 3 years: 35.8%) were significantly greater than those in the P-SOX (82.2%, 68.6%, 53.4%, 26.3%) and SOX (77.0%, 66.0%, 43.0%, 27.0%) groups, with significant differences at 1 year (P = 0.021) and 2 years (P = 0.011). In terms of safety, grade 1-2 gastrointestinal reactions, peripheral neuropathy, and alopecia were the main TRAEs across groups. The P-SOX group had a significantly greater incidence of alopecia (54.2% vs 53.0% vs 23.5%, P = 0.009) and more cases of grade 2 alopecia (6.8% vs 1.2%), potentially due to the accumulation of triple-agent toxicity. No significant intergroup differences were observed in hematologic toxicity or liver dysfunction (all P > 0.05).
CONCLUSION
Compared with the SOX and P-SOX regimens, the SOX plus sintilimab combination demonstrated significantly improved short- and long-term efficacy with favorable safety, with superior advantages in terms of 2- and 3-year OS and early PFS, suggesting that this combination is a more promising therapeutic option for patients with advanced GC. Patients who achieved good perioperative chemotherapy responses (meeting the TRG and RECIST 1.1 criteria) and had tumor diameters ≤ 2 cm, well-differentiated histology, earlier cTNM stages, and no lymph node metastasis had a better prognosis.
Core Tip: This study demonstrated that the SOX combined with sintilimab (PD-1 inhibitor) significantly improved long-term survival outcomes in patients with advanced gastric cancer (GC) compared with P-SOX (albumin-bound paclitaxel plus SOX) or SOX alone, with superior 3-year overall survival (48.1% vs 30.5% and 29.0%) and early progression-free survival rates. The regimen also maintains a favorable safety profile, suggesting that it is a promising perioperative treatment option. The key prognostic factors include a tumor diameter ≤ 2 cm, well-differentiated histology, and negative lymph node status. These findings support the integration of immunotherapy into neoadjuvant strategies for locally advanced GC.
Citation: Wang YC, Zhang CG, Wang YW, Guo C, Pan T, Yu PJ, Cai BJ, Ding RH, Qiang JL, Deng CQ, Hu CH, Xu YH. SOX plus sintilimab vs P-SOX vs SOX as neoadjuvant therapy in advanced gastric cancer: Efficacy and safety. World J Gastrointest Oncol 2025; 17(8): 109646
Gastric cancer (GC) is one of the most common malignant tumors worldwide and ranks as the third leading cause of cancer-related mortality. The overall prognosis for patients with metastatic GC remains poor, with a median overall survival (OS) of less than one year[1]. Globally, the highest incidence of GC is observed in East Asia, followed by Eastern and Central Europe[2]. The high incidence, mortality rate, and propensity for metastasis pose significant threats to human health and represent major burdens on global public health. Despite advances in diagnostic and therapeutic approaches in recent years, the overall prognosis for patients with GC remains suboptimal. Currently, surgical resection remains the only potentially curative treatment for GC. Most patients with early-stage GC can achieve favorable outcomes through endoscopic therapy, with a five-year survival rate exceeding 90%. However, for those with advanced disease, even comprehensive treatment centered on surgery yields a five-year survival rate of less than 30%[3,4]. Although multimodal treatment strategies, including surgery, radiotherapy, and chemotherapy, have provided some clinical benefits, the overall therapeutic efficacy remains limited. Conventional chemotherapy has not produced satisfactory outcomes in advanced cases, highlighting the urgent need for more effective adjunctive therapies. In recent years, immunotherapy has emerged as a promising strategy for advanced GC treatment because of its notable antitumor effects. A deeper understanding of the tumor microenvironment has further advanced the research and clinical application of immunotherapy in GC[5,6]. Currently available immunotherapeutic strategies for advanced GC include immune checkpoint inhibitors (ICIs), adoptive cell therapy, cancer vaccines, anti-VEGFA antibodies, and chimeric antigen receptor T-cell therapy[7]. Among them, anti-PD-1/PD-L1 antibodies have shown remarkable efficacy by activating the host immune system to target and eliminate cancer cells. Several ICIs—including pembrolizumab, avelumab, sintilimab, tislelizumab, and ipilimumab—have been approved for combination with targeted therapies in the treatment of advanced GC[8,9]. Notably, sintilimab was incorporated into the first-line treatment recommendations of the Chinese Society of Clinical Oncology (CSCO) guidelines for GC in 2021, making it the first PD-1 inhibitor approved for this indication in China[10]. Previous studies have demonstrated that sintilimab combined with chemotherapy provides both short- and long-term survival benefits in patients with GC[11]. Although preliminary evidence supports the efficacy and manageable toxicity of neoadjuvant therapy using SOX combined with sintilimab[12], no studies have yet systematically compared this regimen with albumin-bound paclitaxel plus SOX (P-SOX) and the standard SOX regimen in terms of both efficacy and safety. Therefore, this study aims to comprehensively evaluate the therapeutic outcomes and safety profiles of SOX plus sintilimab vs two commonly used neoadjuvant regimens in patients with advanced GC, thereby providing evidence to guide clinical decision-making and optimize treatment strategies.
MATERIALS AND METHODS
Patients
This retrospective study included 299 patients with advanced GC who were treated at the Department of Gastrointestinal Oncology, Affiliated Hospital of Qinghai University, from January 2019 to April 2022. Among them, 81 patients received the SOX plus sintilimab regimen, 118 received the P-SOX regimen, and 100 received the SOX regimen. All patients were randomly divided into training (70%) and validation (30%) cohorts using the R software sample function (see Supplementary Table 1). All patients underwent 2-4 cycles of chemotherapy before and after surgery (6-8 cycles in total) in combination with standard D2 radical gastrectomy, followed by regular follow-up for three years or until the endpoint was reached. Patients were enrolled based on the following inclusion criteria: (1) Pathologically confirmed stage II-IIIC primary gastric adenocarcinoma (based on the 8th edition of the AJCC TNM staging system of the UICC), without distant metastasis or other malignancies, and underwent R0 resection (no residual tumor macroscopically or microscopically); (2) Received 2-4 cycles of pre- and postoperative chemotherapy (6-8 cycles in total), with surgery performed at our institution according to the NCCN and CSCO guidelines; (3) Measurable primary tumor by computed tomography (CT) or magnetic resonance imaging and confirmed by postoperative pathology; and (4) Eastern Cooperative Oncology Group performance status ≤ 1, with adequate hepatic, renal, hematologic, and cardiopulmonary function to tolerate chemotherapy. The exclusion criteria were as follows: (1) Allergy to chemotherapeutic agents or contraindications to chemotherapy; severe comorbid conditions such as active infections, gastrointestinal bleeding, pyloric obstruction, or perforation; (2) History of prior radiotherapy, chemotherapy, immunotherapy, or surgery for other malignancies; (3) Incomplete clinical or imaging data or inability to accurately assess tumor size radiologically; and (4) HER2 (+++) status confirmed by immunohistochemistry. This study complied with the Declaration of Helsinki and was approved by the Ethics Committee of the Affiliated Hospital of Qinghai University (Study title: Biological Function and Molecular Mechanism of ZFP36 in Gastric Cancer). Written informed consent was obtained from all participants.
Treatment
The P-SOX regimen was as follows: On the first day, Nab-paclitaxel was injected at a dose of 135 mg/m² via intravenous infusion for 3 hours, and oxaliplatin was administered at a dose of 85 mg/m² via intravenous infusion for 2-4 hours. From day 1 to day 14, S-1 was orally administered. There were three dosing situations according to the body surface area (BSA). When the volume of BSA was less than 1.25 m², the dose per administration was 40 mg. When the BSA ranged from 1.25-1.5 m², the dose per administration was 50 mg. When the BSA concentration was greater than 1.5 m², the dose per administration was 60 mg. The regimen was administered twice a day, half an hour after breakfast and dinner. One cycle lasted for 21 days. The SOX regimen was as follows: On the first day, oxaliplatin was administered at a dose of 130 mg/m² via intravenous infusion for 2-4 hours. From day 1 to day 14, S-1 was orally administered with the same method as above, and one cycle lasted for 21 days. The SOX plus sintilimab regimen was as follows: On the first day, oxaliplatin was administered at a dose of 130 mg/m² via intravenous infusion for 2-4 hours, and sintilimab was simultaneously administered at a dose of 200 mg via intravenous infusion. From day 1 to day 14, S-1 (with the same administration method as before) was orally administered, and one cycle lasted for 21 days.
All patients underwent routine evaluations prior to treatment, including complete blood count, serum biochemistry, chest/abdominal/pelvic CT, and electrocardiography, to exclude patients with contraindications to chemotherapy. During intravenous infusion of albumin-bound paclitaxel, continuous electrocardiographic monitoring was performed for 3 hours. No prophylactic antiemetic or leukocyte-boosting therapy was administered unless patients developed grade 3 or higher adverse events, which were managed with appropriate symptomatic treatment in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Imaging assessments were performed every two chemotherapy cycles and again prior to surgery. After 2-4 cycles of preoperative chemotherapy, patients underwent upper gastrointestinal endoscopy and CT to evaluate tumor resectability. D2 radical gastrectomy was performed 3-4 weeks after the final cycle of neoadjuvant chemotherapy. All surgeries were performed by senior attending surgeons specializing in gastrointestinal oncology. Postoperatively, patients received regular chemotherapy, imaging evaluations, and follow-up.
Assessments
Short-term efficacy: The clinical response to chemotherapy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Complete response (CR) and partial response (PR) were defined as the effective group, whereas stable disease (SD) and progressive disease (PD) were defined as the ineffective group. Pathological response was assessed based on tumor regression grade (TRG) determined by postoperative pathological examination following the NCCN criteria. TRG 0-2 was considered effective, and TRG 3 was classified as ineffective. All evaluations were conducted with the assistance of experienced pathologists and radiologists. Chemotherapy efficacy was compared among the three treatment groups using both RECIST 1.1 and TRG assessments.
Long-term efficacy: The primary endpoint was OS, which was defined as the time from the initiation of chemotherapy to death from any cause or the date of last follow-up (up to 3 years). The secondary endpoint was progression-free survival (PFS), which was defined as the time from the initiation of chemotherapy to the recurrence of primary GC, the development of new GC, or death from any cause (up to 3 years).
Assessment of adverse events: Chemotherapy-related adverse events were graded according to the CTCAE, version 5.0, issued by the United States National Cancer Institute.
Statistical analysis
All the statistical analyses were conducted using R software version 4.4.1. Continuous variables are presented as the means ± SDs if normally distributed and were compared between groups using the independent samples t-test or one-way ANOVA for multiple groups. Nonnormally distributed data are expressed as medians (P25, P75) and were compared using the nonparametric rank-sum test. Categorical variables are described as frequencies (percentages), with group comparisons performed using the χ2 test or Fisher’s exact test when appropriate. All patients were randomly assigned to training (70%) and validation (30%) cohorts using the sample function in R. The training cohort was used to develop the prognostic model. First, univariate Cox regression analysis was conducted to identify potential predictors of PFS (P < 0.1). Variables with potential significance were then entered into a multivariate Cox regression model using stepwise bidirectional selection to identify independent predictors (P < 0.05).
A nomogram prediction model was constructed based on the final set of independent predictors. Internal validation was performed using bootstrap resampling, and calibration curves were plotted to assess model fitness. The model’s discriminative ability was evaluated using time-dependent receiver operating characteristic (ROC) curve analysis, with the concordance index (C-index) and area under the curve (AUC) calculated. Decision curve analysis (DCA) was conducted to assess the clinical utility of the model by quantifying the net benefit across different threshold probabilities. External validation of the nomogram was performed in the validation cohort. Risk scores were calculated for all patients based on the nomogram. In the training cohort, the optimal cutoff value (100 points) for risk stratification was determined using the surv_cutpoint function from the survminer package. Patients were then categorized into high- and low-risk groups, and Kaplan-Meier survival curves were generated. Survival differences between groups were evaluated using the log-rank test. Nomogram construction and calibration were performed using the rms package. Bootstrap validation was also carried out within this package. Time-dependent ROC curve analysis was conducted using the riskRegression, ggplot2, and ggprism packages. DCA was performed using the ggDCA package. Risk score calculations were performed using the nomogramFormula package, and survival analysis, including cutoff determination, was completed using the survminer package. All the statistical tests were two-sided, and a P value < 0.05 was considered statistically significant.
RESULTS
Basic patient characteristics
A total of 299 patients were included in this study, with 81 in the SOX plus sintilimab group, 118 in the P-SOX group, and 100 in the SOX group. As shown in Table 1, there were no statistically significant differences among the three groups in terms of baseline clinical characteristics, including sex, age, tumor differentiation, anesthesia classification, tumor location, Lauren classification, preoperative T stage, preoperative N stage, or clinical TNM stage (all P > 0.05).
Table 1 Basic patient characteristics and short-term efficacy, n (%).
Variables
Total (n = 299)
P-SOX (n = 118)
SOX (n = 100)
SOX + XDL (n = 81)
P value
Age
0.451
≤ 60
164 (54.8)
69 (58.5)
50 (50)
45 (55.6)
> 60
135 (45.2)
49 (41.5)
50 (50)
36 (44.4)
Gender
0.056
Male
240 (80.3)
102 (86.4)
79 (79)
59 (72.8)
Female
59 (19.7)
16 (13.6)
21 (21)
22 (27.2)
ASA
0.666
1 + 2
261 (87.3)
102 (86.4)
86 (86)
73 (90.1)
3
38 (12.7)
16 (13.6)
14 (14)
8 (9.9)
Differentiation
0.238
Well
82 (27.4)
33 (28)
28 (28)
21 (25.9)
Moderate
80 (26.8)
25 (21.2)
34 (34)
21 (25.9)
Poorly
137 (45.8)
60 (50.8)
38 (38)
39 (48.1)
cT stage
0.264
2
71 (23.7)
26 (22)
26 (26)
19 (23.5)
3
155 (51.8)
56 (47.5)
51 (51)
48 (59.3)
4
73 (24.4)
36 (30.5)
23 (23)
14 (17.3)
cN stage
0.066
Negative
92 (30.8)
41 (34.7)
22 (22)
29 (35.8)
Positive
207 (69.2)
77 (65.3)
78 (78)
52 (64.2)
cTNM
0.083
II
148 (49.5)
56 (47.5)
47 (47)
45 (55.6)
IIIA
28 (9.4)
13 (11)
11 (11)
4 (4.9)
IIIB
62 (20.7)
22 (18.6)
17 (17)
23 (28.4)
IIIC
61 (20.4)
27 (22.9)
25 (25)
9 (11.1)
RECIST 1.1
0.099
Ineffective
117 (39.1)
48 (40.7)
45 (45)
24 (29.6)
Effective
182 (60.9)
70 (59.3)
55 (55)
57 (70.4)
Lauren
0.616
Diffuse
107 (35.8)
42 (35.6)
39 (39)
26 (32.1)
Mixed
141 (47.2)
58 (49.2)
41 (41)
42 (51.9)
Intestinal
51 (17.1)
18 (15.3)
20 (20)
13 (16)
Tumor location
0.955
Upper
75 (25.1)
29 (24.6)
26 (26)
20 (24.7)
Middle
116 (38.8)
44 (37.3)
41 (41)
31 (38.3)
Lower
108 (36.1)
45 (38.1)
33 (33)
30 (37)
TRG
0.320
Effective
262 (87.6)
104 (88.1)
84 (84)
74 (91.4)
Ineffective
37 (12.4)
14 (11.9)
16 (16)
7 (8.6)
Tumor diameter
0.152
≤ 2
156 (52.2)
55 (46.6)
57 (57)
44 (54.3)
2-5
79 (26.4)
29 (24.6)
26 (26)
24 (29.6)
≥ 5
64 (21.4)
34 (28.8)
17 (17)
13 (16)
Efficacy and safety
Short-term efficacy: According to the TRG assessment, 91 patients (61.1%) in the P-SOX group achieved an effective response (TRG 0, 1, or 2), whereas 58 patients (38.9%) were classified as ineffective (TRG 3), resulting in an objective response rate (ORR) of 61.1%. In the SOX group, 37 patients (52.9%) achieved an effective response, and 33 patients (47.1%) achieved an ineffective response, yielding an ORR of 52.9%. In the SOX plus sintilimab group, 74 patients (91.4%) were classified as effective, and 7 patients (8.6%) were classified as ineffective, resulting in an ORR of 91.4%. However, the differences in TRG-based response rates among the three groups were not statistically significant (P = 0.320). Based on the RECIST 1.1 criteria, 70 patients in the P-SOX group (59.3%) achieved CR or PR, whereas 48 patients (40.7%) had SD or PD, resulting in an ORR of 59.3%. In the SOX group, 55 patients (55.0%) responded, and 45 (45.0%) did not, yielding an ORR of 55.0%. In the SOX plus sintilimab group, 57 patients (70.4%) achieved CR or PR, and 24 (29.6%) had SD or PD, with an ORR of 70.4%. However, the differences in RECIST 1.1-based response rates were not statistically significant among the three groups (P = 0.099). In summary, the ORRs based on TRG and RECIST 1.1 were 61.1% and 59.3% for the P-SOX group, 52.9% and 55.0% for the SOX group, and 91.4% and 70.4% for the SOX plus sintilimab group, respectively. Although these differences did not reach statistical significance, the SOX plus sintilimab regimen demonstrated a numerically superior ORR.
Long-term efficacy: In the long-term efficacy assessment, comparisons of the three treatment regimens in terms of OS and PFS revealed the following results. For OS, the median OS of the P-SOX group was 27.0 months (95%CI: 26.0-30.0), with 1-year, 18-month, 2-year, and 3-year survival rates of 93.2%, 86.4%, 71.2%, and 30.5%, respectively. The median OS of the SOX group was 29.0 months (95%CI: 27.0-32.0), with corresponding survival rates of 91.0%, 84.0%, 72.0%, and 29.0%, respectively. Notably, the SOX plus sintilimab group achieved a median OS of 32.0 months (95%CI: 30.0-NR), with significantly improved survival rates of 98.8%, 92.6%, 84.0%, and 48.1%, respectively. Statistically significant differences were observed in the 3-year OS rates among the three groups (P = 0.007; Figure 1A). The median PFS of the P-SOX group was 25.0 months (95%CI: 22.0-26.0), with 1-year, 18-month, 2-year, and 3-year PFS rates of 82.2%, 68.8%, 53.4%, and 26.3%, respectively. The median PFS of the SOX group was 22.5 months (95%CI: 19.0-26.0), with corresponding PFS rates of 77.0%, 66.0%, 43.0%, and 27.0%, respectively. The SOX plus sintilimab group had a median PFS of 30.0 months (95%CI: 27.0-33.0), with significantly elevated PFS rates of 92.6%, 77.8%, 65.4%, and 35.8%, respectively. Statistically significant differences were noted in the 1- and 2-year PFS rates among the three groups (P = 0.021 and P = 0.011; Figure 1B). Overall, the SOX plus sintilimab regimen exhibited superiority in prolonging OS and delaying disease progression, particularly demonstrating significant clinical benefits in terms of the 3-year OS rate and early PFS rates.
Figure 1 Comparison of overall survival and progression-free survival among the three groups.
A: Overall survival; B: Progression-free survival. OS: Overall survival; PFS: Progression-free survival.
Safety
As summarized in Table 2, most adverse events across the three treatment groups were grade 1-2 in severity. The incidence rates of grade 3 or higher adverse events were low across all groups, with no evident clustering of severe toxicities. This may be partially attributed to the reduced dose of oxaliplatin used in the three-drug P-SOX chemotherapy regimen. The most common toxicities included gastrointestinal reactions, peripheral neuropathy, and alopecia. Notably, the incidence of alopecia was significantly greater in the P-SOX group than in the SOX and SOX plus sintilimab groups (54.2% vs 53.0% vs 23.5%, respectively; P = 0.009). Moreover, the incidence of grade 2 alopecia was also greater in the P-SOX group (6.8% vs 1.2%), which may be attributed to the cumulative toxicity associated with the triple-drug regimen. Apart from alopecia, there were no statistically significant differences among the three groups in the incidence of other adverse events, including hematologic toxicity and liver function abnormalities (all P > 0.05).
Table 2 Side effects associated with three groups treatment, n (%).
Variables
Total (n = 299)
P-SOX (n = 118)
SOX (n = 100)
SOX + XDL (n = 81)
P value
Nausea and vomiting
0.786
0
63 (21.1)
24 (20.3)
20 (20)
19 (23.5)
1
171 (57.2)
65 (55.1)
62 (62)
44 (54.3)
2
58 (19.4)
27 (22.9)
16 (16)
15 (18.5)
3
7 (2.3)
2 (1.7)
2 (2)
3 (3.7)
Liver toxicity
0.912
0
254 (84.9)
100 (84.7)
83 (83)
71 (87.7)
1
39 (13)
15 (12.7)
15 (15)
9 (11.1)
2
6 (2)
3 (2.5)
2 (2)
1 (1.2)
Alopecia
0.009
0
178 (59.5)
64 (54.2)
53 (53)
61 (75.3)
1
107 (35.8)
46 (39)
42 (42)
19 (23.5)
2
14 (4.7)
8 (6.8)
5 (5)
1 (1.2)
Peripheral sensory neuropathy
0.426
0
143 (47.8)
51 (43.2)
54 (54)
38 (46.9)
1
124 (41.5)
50 (42.4)
40 (40)
34 (42)
2
27 (9)
15 (12.7)
5 (5)
7 (8.6)
3
5 (1.7)
2 (1.7)
1 (1)
2 (2.5)
Fewer neutrophils
0.231
0
218 (72.9)
88 (74.6)
70 (70)
60 (74.1)
1
52 (17.4)
23 (19.5)
17 (17)
12 (14.8)
2
18 (6)
3 (2.5)
7 (7)
8 (9.9)
3
10 (3.3)
3 (2.5)
6 (6)
1 (1.2)
4
1 (0.3)
1 (0.8)
0 (0)
0 (0)
Fewer white blood cells
0.838
0
196 (65.6)
80 (67.8)
65 (65)
51 (63)
1
66 (22.1)
23 (19.5)
21 (21)
22 (27.2)
2
26 (8.7)
9 (7.6)
10 (10)
7 (8.6)
3
7 (2.3)
3 (2.5)
3 (3)
1 (1.2)
4
4 (1.3)
3 (2.5)
1 (1)
0 (0)
Fewer platelets
0.457
0
215 (71.9)
87 (73.7)
72 (72)
56 (69.1)
1
54 (18.1)
19 (16.1)
20 (20)
15 (18.5)
2
25 (8.4)
10 (8.5)
5 (5)
10 (12.3)
3
5 (1.7)
2 (1.7)
3 (3)
0 (0)
Anemia
0.794
0
152 (50.8)
63 (53.4)
49 (49)
40 (49.4)
1
106 (35.5)
39 (33.1)
37 (37)
30 (37)
2
26 (8.7)
10 (8.5)
7 (7)
9 (11.1)
3
15 (5)
6 (5.1)
7 (7)
2 (2.5)
Univariate and multivariate Cox regression analyses
Univariate Cox regression analysis was performed on 12 variables in the training cohort, including baseline characteristics and early treatment responses (RECIST 1.1 and TRG). Seven variables were identified as potential predictors of PFS (P < 0.1): Differentiation, T stage, lymph node status, TNM stage, RECIST 1.1 response, TRG, and pretreatment tumor diameter (Table 3). These factors were entered into a multivariate model, which revealed the following independent prognostic factors: (1) Patients with RECIST 1.1-defined response (grade 1) had a significantly lower risk of progression than nonresponsive patients did (grade 0; HR = 0.574, 95%CI: 0.411-0.802, P = 0.001); (2) TRG nonresponders (grade 0) had a 2.008-fold greater risk than responders did (grade 1; 95%CI: 1.182-3.410, P = 0.010); (3) Patients with low differentiation had a significantly greater risk than did those with high differentiation (HR = 1.848, 95%CI: 1.179-2.896, P = 0.007); (4) Tumor diameters > 2-5 cm and ≥ 5 cm were associated with 1.974-fold (95%CI: 1.342-2.903, P = 0.001) and 3.145-fold (95%CI: 2.056-4.811, P < 0.001) greater risk, respectively, than were found in patients with tumors ≤ 2 cm; (5) Lymph node-positive patients had a 79.4% greater risk than did those without nodal involvement (HR = 1.794, 95%CI: 1.204-2.672, P = 0.004); and (6) Compared with stage II, stages IIIB and IIIC were associated with 2.477-fold (95%CI: 1.625-3.778, P < 0.001) and 3.750-fold (95%CI: 2.405-5.846, P < 0.001) increased risks of progression, respectively (Table 4).
As shown in Figure 2, a predictive model for PFS was developed based on the six independent risk factors identified in the prior univariate and multivariate Cox analyses. The top axis represents the individual point score ("Points") assigned to each variable, reflecting its relative contribution to PFS risk. For clinical use, each patient's status across the included factors is projected upward to the Points axis to determine the corresponding score. These scores are then summed to yield a "Total Points" value, which is used to estimate the probabilities of 18-month, 2-year, and 3-year PFS by aligning downward to the probability scales. This nomogram enables individualized risk assessment, where a lower total score indicates greater potential benefit from neoadjuvant chemotherapy with SOX plus sintilimab. Specifically, patients who exhibit favorable perioperative treatment responses (RECIST 1.1 response and TRG grade 1), a tumor diameter ≤ 2 cm, high differentiation, absence of lymph node metastasis, and stage II disease demonstrate the highest predicted PFS probabilities, suggesting a greater long-term survival benefit.
The predictive performance of the nomogram was assessed using time-dependent ROC curves, with the AUC and C-index calculated at multiple time points in both the training and validation cohorts (Figure 3). In the training cohort, the AUCs at 18 months, 24 months, and 36 months were 0.837 (95%CI: 0.731-0.943), 0.804 (95%CI: 0.712-0.897), and 0.788 (95%CI: 0.618-0.958), respectively. In the validation cohort, the AUCs at the same time points were 0.846 (95%CI: 0.787-0.906), 0.808 (95%CI: 0.750-0.866), and 0.868 (95%CI: 0.795-0.942). All the AUC values exceeded 0.7, indicating good discriminative ability, with the highest value observed at 36 months in the validation cohort. The overall C-indices for the model were 0.75 (95%CI: 0.70-0.80) in the training cohort and 0.73 (95%CI: 0.67-0.79) in the validation cohort, further confirming the model’s stability and predictive strength across datasets and supporting its potential clinical utility. Calibration of the nomogram was evaluated using bootstrap resampling (Figure 4). At 18 months, 24 months, and 36 months, the predicted PFS probabilities closely aligned with the observed outcomes in both cohorts, particularly at 18 months, where the predicted and observed curves nearly overlapped, demonstrating strong calibration. Clinical utility was assessed using DCA (Figure 5). In the training cohort, the model showed clear net benefits across threshold probabilities of 0.0-0.6, 0.7-0.6, and 0.9-1.0 at 18 months; 0.0-0.5, 0.6-0.8, and 0.8-1.0 at 24 months; and 0.0-0.5, 0.6-0.9, and 0.9-1.0 at 36 months—all outperforming the "treat-all" or "treat-none" strategies. The validation cohort showed consistent results: Net benefit was evident across 0.0-0.7, 0.8-0.9, and 0.9-1.0 at 18 months; 0.0-0.6, 0.7-0.9, and 0.9-1.0 at 24 months; and 0.0-0.6, 0.7-0.9, and 0.9-1.0 at 36 months. Collectively, these results demonstrate that the nomogram performs well across 18-month, 2-year, and 3-year prediction intervals, with reliable calibration and strong clinical applicability in both datasets. Individual risk scores were calculated for all patients based on the nomogram. With PFS as the outcome, the optimal cutoff value of 100 points was determined using the surv_cutpoint function in the survminer package. Patients were stratified into low- and high-risk groups accordingly. In the training cohort, the low-risk group had significantly better PFS than the high-risk group did (P < 0.001, HR = 4.13, 95%CI: 2.22-7.69); this trend was similar to that observed in the validation cohort (P < 0.001, HR = 5.11, 95%CI: 3.53-7.38; Figure 6). These findings confirm the ability of the nomogram to distinguish risk levels effectively in patients with advanced GC.
Figure 3 Progression-free survival receiver operating characteristic curve.
A: Training set; B: Validation set; C: Concordance index over time. AUC: Area under the curve.
Figure 6 Kaplan-Meier survival curves for the verification of risk stratification.
A: Training set; B: Validation set; C: Total set. PFS: Progression-free survival.
DISCUSSION
The search for effective yet low-toxicity chemotherapy regimens remains a central focus in GC research. Both SOX and SOX plus sintilimab are widely used first-line treatments in Asia, whereas albumin-bound paclitaxel is a standard second-line agent. To compare treatment strategies, our study evaluated the efficacy of the triplet P-SOX regimen (albumin-bound paclitaxel + oxaliplatin + S-1) vs the doublet SOX regimen, with or without immunotherapy. Consistent with previous reports, we found that intensifying chemotherapy with albumin-bound paclitaxel (P-SOX) improved certain efficacy endpoints compared with those of SOX alone; for example, Wang et al[13] reported that P-SOX improved both the objective response and disease control rates over those of SOX. In the postoperative adjuvant setting following D2 resection, P-SOX showed a trend toward improved 3-year disease-free survival (approximately 78.2% vs 74.0% after matching), along with a reduced risk of peritoneal metastasis. However, in our analysis, the SOX plus sintilimab regimen demonstrated superior PFS and OS compared with either P-SOX or SOX alone. Rather than simply increasing the cytotoxic intensity, the addition of immunotherapy resulted in greater survival benefit. Importantly, P-SOX relies solely on chemotherapy, whereas the combination of SOX and sintilimab involves both cytotoxic and immune-mediated antitumor mechanisms. This mechanistic distinction likely underlies the superior long-term outcomes observed with the chemoimmunotherapy regimen. Several preclinical studies have supported this concept, showing that chemotherapy can induce immunogenic cell death and thereby enhance the efficacy of PD-1 blockade[14,15]. Therefore, this study comprehensively compared the short-term efficacy, long-term outcomes, and safety of SOX plus sintilimab vs P-SOX and SOX alone, investigated PFS-related prognostic factors, and developed a nomogram for individualized risk prediction.
The results of this study, evaluated according to the TRG and RECIST 1.1 criteria, demonstrated that the ORRs of the P-SOX group were 88.1% and 59.3%, respectively; those of the SOX group were 84.0% and 55.0%, whereas those of the SOX plus sintilimab group reached 91.4% and 70.4%, respectively. Although the differences among the three groups were not statistically significant (P = 0.167), the SOX plus sintilimab group exhibited a greater remission rate advantage in terms of short-term efficacy. In the perioperative treatment of advanced GC patients, the SOX combined with sintilimab regimen showed superior performance in both short- and long-term efficacy. During the neoadjuvant phase, the combination of the anti-PD-1 antibody sintilimab significantly increased the pathological CR (pCR) rate, indicating a notable increase in preoperative tumor regression. This trend aligns with the findings of the 3-year follow-up in the CheckMate 649 study by Janjigian et al[16], which confirmed that the combination of PD-1 inhibitors and chemotherapy significantly improved the initial remission rate and pCR rate, highly consistent with the short-term efficacy trends observed in this study. Although the differences did not reach statistical significance, the limited sample size may have reduced the statistical power to detect true differences. Notably, the SOX plus sintilimab group demonstrated a consistent advantage across two independent evaluation criteria (TRG and RECIST 1.1). Moreover, the observed trend in efficacy aligns with the findings of previous studies, suggesting the potential clinical value of this regimen. These findings warrant further investigation in larger, well-powered clinical trials. In terms of long-term efficacy, the SOX plus sintilimab group also demonstrated a significant advantage. For OS, the 1-year, 18-month, 2-year, and 3-year survival rates of the P-SOX group were 93.2%, 86.4%, 71.2%, and 30.5%, respectively; those of the SOX group were 91.0%, 84%, 72.0%, and 29.0%, respectively; whereas those of the SOX plus sintilimab group were 98.8%, 92.6%, 84.0%, and 48.1%, respectively, with statistically significant differences in the 3-year OS rates among the three groups (P = 0.007). In terms of PFS, the 1-year, 18-month, 2-year, and 3-year PFS rates of the P-SOX group were 82.2%, 68.6%, 53.4%, and 26.3%, respectively; those of the SOX group were 77.0%, 66%, 43.0%, and 27.0%, respectively; and those of the SOX plus sintilimab group reached 92.6%, 77.8%, 65.4%, and 35.8%, respectively, with 1-year and 2-year PFS rates significantly superior to those of the other two groups (P = 0.021 and P = 0.011). These results suggest that the SOX plus sintilimab regimen has the most significant clinical advantage in prolonging survival, especially in terms of the 3-year OS and early PFS rates. Similar efficacy advantages have been demonstrated in large-scale clinical studies, such as CheckMate 649 and ORIENT-16, supporting the broad applicability of immunotherapy combinations in improving long-term prognosis[17,18]. This is crucial for the goals of perioperative treatment, namely, increasing the cure rate and reducing the risk of recurrence. Our data support that the SOX plus sintilimab regimen can significantly improve the long-term prognosis of patients with advanced GC, which is consistent with the results of Xu et al[19], who reported that, compared with the placebo, the SOX plus sintilimab regimen significantly prolonged OS (15.2 months vs 12.3 months; HR = 0.77, 95%CI: 0.63-0.94; P = 0.009).
Importantly, these therapeutic benefits were not achieved at the expense of increased toxicity. In our study cohort, the SOX plus sintilimab regimen demonstrated a favorable toxicity profile, with overall tolerability comparable to that of chemotherapy alone. This finding is supported by previous studies, including KEYNOTE-859 and multiple meta-analyses, which reported that immunochemotherapy does not significantly increase toxicity risk in the first-line treatment of GC[20,21]. In our study, the most common adverse events were hematologic and gastrointestinal toxicities, all of which were effectively managed with supportive care, and no new safety signals were observed. These results are consistent with safety data from large phase III trials. For example, in the KEYNOTE-585 study, the incidence rates of grade ≥ 3 adverse events were similar between the immunochemotherapy group and the chemotherapy-only group (78% vs 74%)[22]. Similarly, the ORIENT-16 trial revealed no significant differences in the incidence of common toxicities such as neutropenia, thrombocytopenia, and anemia between the sintilimab combination group and the control group[23]. Taken together, our findings confirm that SOX plus sintilimab enhances short-term response and long-term survival while maintaining an acceptable safety profile, supporting its potential as a viable perioperative treatment strategy.
This study highlights the potential transformative role of SOX plus sintilimab in the perioperative management of advanced GC. This immunochemotherapy regimen induces deeper tumor regression preoperatively and prolongs PFS and OS postoperatively, thereby achieving dual improvements in short-term efficacy and long-term outcomes. Its favorable safety profile further supports its feasibility in clinical practice. Supported by multicenter studies and randomized controlled trials, our findings suggest that incorporating PD-1 inhibitors into perioperative treatment strategies may establish a new standard of care for selected patients[13]. Compared with simple intensifying chemotherapy, the SOX plus sintilimab regimen offers a superior balance of efficacy and safety, as evidenced by its significant improvements in both PFS and OS. The addition of sintilimab to SOX not only enhances the short-term tumor response but also translates into meaningful survival benefits, representing a promising advancement in the comprehensive treatment of locally advanced GC.
Nonetheless, several limitations of this study should be acknowledged. Variations in geographic regions, sample sources, and data handling may affect the consistency of prognostic outcomes. Prior studies have suggested that GC prognosis is also closely associated with factors such as age, tumor location, lymph node involvement, ASA score, abnormal BMI, number of dissected lymph nodes, number of chemotherapy cycles, and postoperative complications[24-30], many of which have also been incorporated into nomogram-based prediction models[31,32]. This study has several limitations. First, owing to its retrospective design, some patients were excluded because of incomplete clinical data, which limited the inclusion of individuals who did not complete both preoperative and postoperative chemotherapy in combination with curative surgery. As a result, the analysis included only patients who completed the full perioperative regimen, potentially introducing selection bias. Additionally, the exact surgical resection rate following perioperative chemotherapy could not be accurately determined. Second, the study was conducted at a single center with a relatively small sample size, which may limit the generalizability and statistical power of the findings. Future large-scale, multicenter phase III trials are warranted to validate and expand upon these results. Therefore, future efforts should focus on refining risk prediction models through multicenter, large-scale studies to develop more accurate and generalizable prognostic tools, thereby providing stronger support for individualized treatment decisions in patients with GC.
CONCLUSION
Compared with the SOX and P-SOX regimens, the SOX+ sintilimab regimen can improve short- and long-term efficacy, and the adverse reactions are tolerable. The SOX+ sintilimab regimen demonstrated long-term survival advantages over the other regimens in this study, especially in terms of 2- and 3-year OS and 1-year, 18-month and 2-year PFS, which were more prominent. These findings provide more promising treatment options for patients with advanced GC. 2. Patients with advanced GC with effective perioperative chemotherapy (RECIST 1.1, TRG), a tumor diameter ≤ 2 cm, a high degree of differentiation, an early cTNM stage and no lymph node metastasis have a better prognosis.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade A, Grade C
Novelty: Grade C, Grade C
Creativity or Innovation: Grade C, Grade C
Scientific Significance: Grade B, Grade B
P-Reviewer: Dai P; Liu ZC S-Editor: Lin C L-Editor: A P-Editor: Zhang XD
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