Clinical efficacy and safety of apatinib plus S-1 combined with oxaliplatin (SOX) in postoperative stage III gastric cancer patients with high VEGFR-2 expression

Introduction

Gastric cancer (GC) is the third most common tumor worldwide, with the third highest mortality rate (1). China accounts for approximately 40% of the world’s 1.2 million new cases of stomach cancer each year. The proportion of patients with early GC in China is very low, only approximately 20%; most patients are in the advanced stage, and stage III GC patients account for 40–50% (2). At present, surgery is the only possible cure for GC, and chemotherapy is the important means to improve the prognosis of GC after radical gastrectomy (3,4). S-1 combined with oxaliplatin (SOX) is currently the recommended class IA chemotherapy regimen for patients with stage III GC in China. However, the 5-year survival rate is only 30–40%, mainly due to the strong heterogeneity of GC (5). Therefore, the focus of current research is to actively develop more effective treatment methods. Studies have shown that tumor angiogenesis is a multifactorial, global and dynamic process involving vascular endothelial growth factor (VEGF) and its receptor vascular endothelial growth factor receptor 2 (VEGFR-2). In particular, the signalling pathway mediated by VEGFR-2 is a key pathway that can regulate the proliferation, migration, survival, and permeability changes of vascular endothelial cells and plays an important role in promoting angiogenesis. Apatinib is an oral medicine for the treatment of GC. It is a small molecular targeted drug that can be combined with the specificity of VEGFR-2 for competitive inhibition and subsequent phosphorylation of VEGFR-2 to inhibit tumor angiogenesis growth and exert definite antitumor effects. Studies have shown that apatinib can improve overall survival (OS) and progression-free survival (PFS) in patients with unresectable or metastatic adenocarcinoma of the stomach or gastroesophageal junction (GEJ) carcinoma (6,7). Moreover, studies have also demonstrated that apatinib combined with SOX as neoadjuvant therapy can further downstage the tumor and improve the R0 resection rate in locally advanced GC (8,9). Multiple studies have confirmed that the efficacy of apatinib is positively correlated with VEGFR-2 expression (10,11). However, there are no reports on the clinical efficacy and side effects of postoperative adjuvant chemotherapy combined with apatinib in stage III GC patients at present.

Therefore, this study aimed to evaluate the efficacy and safety of SOX + apatinib in postoperative stage III GC patients with high VEGFR-2 messenger RNA (mRNA) expression. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0370/rc).

Methods

Patient selection

A retrospective study was conducted on 112 patients with postoperative stage III GC with high VEGFR-2 mRNA expression at The Affiliated Hospital of Guizhou Medical University from January 2015 to June 2021. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval was obtained from the Ethics Committee of The Affiliated Hospital of Guizhou Medical University (No. 2021-672). Informed consent was waived by the ethics committee due to the retrospective nature of the study. The inclusion criteria were as follows: (I) age 18–80 years old; (II) D2 radical gastrectomy and stage III according to American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) staging (8^th edition) (11); (III) no history of preoperative radiotherapy, chemotherapy, targeted therapy or immunotherapy; (IV) high expression of the VEGFR-2 gene after operation; (V) negative human epidermal growth factor receptor 2 (HER-2) expression; (VI) exclusion of distant metastasis by chest and abdominal computed tomography (CT) examination; (VII) no serious heart, lung, kidney or other complications and could tolerate targeted therapy; (VIII) Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0–1, and predicted survival was more than 3 months; and (IX) complete clinical data and follow-up. The exclusion criteria were as follows: (I) pregnant and lactating women <18 years old; (II) gross or microscopic margin cancer cells remaining (R1/R2 excision); (III) severe organ dysfunction (liver, kidney, lung, heart), bleeding tendency, or serious infection; and (IV) incomplete clinical data or lost to follow-up.

Clinical case collection

A total of 112 patients with stage III GC were included: 68 males (60.7%) and 44 females (39.3%). The age ranged from 26 to 80 years (57.5±11.6 years). There were 55 patients in the SOX group and 57 patients in the SOX + apatinib group.

Age, gender, clinical symptoms, ECOG PS, previous surgical history, gastroscopy + biopsy, imaging data, tumor location, Borrmann classification, preoperative treatment, preoperative Nutritional Risk Screening 2002 (NRS-2002) nutritional score, surgical data, postoperative pathological stage, vascular invasion, nerve invasion, VEGFR-2 expression, postoperative treatment and follow-up data were collected.

VEGFR-2 gene detection procedures and judgement criteria

The experimental procedure was as follows: (I) appropriate amounts of paraffin sections of tumor tissues were taken, lysate was added, and samples were lysed at 56 ℃ for 2 h. The purity of total mRNA in the lysate was detected by a NanoDrop nucleic acid protein analyser. (II) The sample lysates were transferred to the incubation plate; support probe microsphere, support extension probe, and buffer were added; and samples were incubated overnight at 55 ℃ with shock. (III) The next day, the incubation plate was placed on the magnetic rack for 1 min, at which time the magnetic microspheres gathered at the bottom, and the supernatant was absorbed and discarded. (IV) The washing solution was added, the samples were shock washed for 1 min, the incubation plate was placed on the magnetic rack for 1 min, and the discarded supernatant was absorbed. The washing step was repeated 3 times. (V) Amplification extension probe and labelling probe were added, and the samples were shaken at 50 ℃ for 1 h. (VI) The incubation plate was placed on the magnetic rack for 1 min, and the discarded supernatant was absorbed. The plate was washed 2 times with washing liquid. (VII) Streptavidin-phycoerythrin was added, and the samples were shaken at 50 ℃ for 30 min. (VIII) The incubation plate was placed on the magnetic rack for 1 min, and the discarded supernatant was absorbed. The plate was washed 2 times with washing liquid. (IX) Washing liquid was added, the plate was shaken for 5 min, and the data were read on the Luminex reader.

The statistical quartile method was used as the determination standard of gene mRNA expression results, which were classified as low expression (<25%), medium expression (25–75%), and high expression (>75%).

Postoperative adjuvant therapy

A total of 112 patients with postoperative stage III GC with high VEGFR-2 mRNA expression were included in this retrospective study. We fully informed the patient about the treatment protocols and underlying evidence for the SOX regimen and the SOX plus apatinib regimen. Patients were divided into the SOX group (receiving the SOX regimen without oral apatinib) and the SOX + apatinib group (taking oral apatinib on the basis of the SOX regimen) according to whether they took apatinib or not. Both the SOX + apatinib group and the SOX group received six cycles of treatment 4 weeks after operation, with 21 days for one cycle.

SOX group: oxaliplatin 130 mg/m² was given intravenously on the first day. S1 was administered orally at 40–80 mg twice daily for 1–14 days, followed by the next cycle of treatment.

SOX + apatinib group: in addition to the SOX regimen, 250 mg apatinib (Jiangsu Hengrui Pharmaceutical Co., Ltd., Lianyungang, China) was given orally once a day approximately 30 min after breakfast.

Endpoints and assessments

The primary endpoints of this study were disease-free survival (DFS) and OS. The secondary end point was side effects.

The DFS and OS of the patients were estimated according to the time of recurrence and death. The 3- and 5-year DFS and OS of the patients were calculated, and the prognoses of the two groups were compared. Adverse reactions during chemotherapy were recorded.

• DFS: DFS was defined as the time from the date of the postoperative pathology report to the date of documented local recurrence, metastasis, death from any cause, or last follow-up, whichever occurred first;
• OS: OS was defined as the time from the date of the postoperative pathology report to death from any cause or last follow-up;
• Toxicity and adverse effects: according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0. The adverse effects were recorded in detail.

Follow-up

The last follow-up date of 112 patients was December 31, 2025. Follow-up was mainly carried out by telephone, outpatient review, and inpatient examination. The postoperative recurrence, survival, and drug toxicity data were recorded.

Statistical analysis

All statistical analyses were conducted with SPSS software, version 26.0. Measurement data are expressed as the mean ± standard deviation (SD), and a t-test was used. Enumeration data are expressed as absolute numbers and percentages, and comparisons were performed by the Chi-squared test or Fisher’s exact probability method. The log-rank test was used for univariate survival analysis. A Cox survival regression model was used for multivariate survival analysis. Kaplan-Meier survival curves were drawn (log-rank test was used for comparison of factors). P<0.05 was considered statistically significant.

Results

Expression of VEGFR-2 in stage III GC patients

A total of 439 patients with stage III disease underwent VEGFR-2 mRNA detection, and 123 (28.0%) had low expression, 181 (41.2%) had medium expression, and 135 (30.8%) had high expression. Of the 135 patients with high expression, 112 were included in our study according to the inclusion and exclusion criteria.

Patient characteristics

Chi-squared analysis showed that there were no significant differences in age, gender, ECOG PS, tumor site, Borrmann classification, nutritional risk, surgical method, vascular invasion, nerve invasion, pathologic tumor (pT) stage, or pathologic nodal (pN) stage between the SOX group and the SOX + apatinib group (Table 1).

Survival prognosis of patients with stage III GC postoperative follow-up and prognosis of patients

All 112 patients had complete follow-up records, and the follow-up time was 59.3±24.2 months (range, 13–115 months). Postoperative recurrence or distant metastasis occurred in 62 patients, including local recurrence in 24 patients and distant metastasis in 38 patients (liver in 17 patients; peritoneum in 6 patients; bone in 5 patients; lungs in 4 patients; pelvic in 3 patients; distant lymph nodes in 3 patients). Sixty-one of the patients died. During follow-up, the 3-year DFS of the SOX group vs. the SOX + apatinib group was 41.8% vs. 70.2%, P=0.002; the 5-year DFS was 32.1% vs. 62.5%, P=0.002; the 3-year OS was 74.5% vs. 86.0%, P=0.13; and the 5-year OS was 34.0% vs. 64.6%, P=0.002.

Univariate survival analysis

Univariate survival analysis showed that age (P=0.42), gender (P=0.07), ECOG PS (P=0.46), tumor location (P=0.30), surgical type (P=0.11), vascular invasion (P=0.87), nerve invasion (P=0.27), and pT stage (P=0.95) were not correlated with DFS. However, nutritional risk (P=0.04), Borrmann classification (P=0.003), pN stage (P=0.01) and postoperative therapy (P<0.001) were correlated with DFS. In addition, age, gender, ECOG PS, tumor location, surgical type, vascular invasion, nerve invasion and pT stage were not correlated with OS (P>0.05). However, nutritional risk (P=0.02), Borrmann classification (P<0.001), pN stage (P=0.01) and postoperative therapy (P<0.001) were correlated with OS.

Cox multivariate regression analysis

Cox multivariate regression analysis showed that age (P=0.35), gender (P=0.30), ECOG PS (P=0.17), tumor location (P=0.56), nutritional risk (P=0.35), surgical method (P=0.37), vascular invasion (P=0.45), and nerve invasion (P=0.28) were not correlated with DFS. However, Borrmann classification (P=0.003), pT stage (P=0.03), pN stage (P<0.001), and postoperative therapy (P<0.001) were correlated with DFS. In addition, age, gender, ECOG PS, tumor location, nutritional risk, surgical method, vascular invasion, and nerve invasion were not correlated with OS (P>0.05). However, Borrmann classification (P=0.002), pT stage (P=0.006), pN stage (P<0.001), and postoperative therapy (P<0.001) were correlated with OS.

Kaplan-Meier survival analysis

The Kaplan-Meier survival analysis revealed that DFS was affected by Borrmann classification, pN stage, and postoperative treatment, which were correlated with both univariate and multivariate factors. Higher Borrmann classification was associated with lower DFS (P<0.001). Higher pN stage was associated with lower DFS (P=0.01). And SOX + apatinib improved DFS compared to the SOX group (P<0.001) (Figure 1). Kaplan-Meier survival analysis demonstrated that OS decreased with increasing Borrmann classification (P<0.001). Higher pN stage was associated with lower OS (P=0.02). Furthermore, SOX + apatinib improved OS compared to the SOX group (P<0.001) (Figure 2).

Figure 1 Kaplan-Meier curves of DFS. (A) DFS according to Borrmann type; (B) DFS according to pN stage; (C) DFS of the SOX group and the SOX + apatinib group. DFS, disease-free survival; pN, pathologic nodal; SOX, S-1 combined with oxaliplatin.

Figure 2 Kaplan-Meier curves of OS. (A) OS according to Borrmann type; (B) OS according to pN stage; (C) OS of the SOX group and the SOX + apatinib group. OS, overall survival; pN, pathologic nodal; SOX, S-1 combined with oxaliplatin.

Adverse effects

The two groups of patients mainly experienced adverse effects of bone marrow suppression (a decrease in white blood cells, platelets, and anaemia), high blood pressure, gastrointestinal tract reaction syndrome (nausea, vomiting, and diarrhoea) and hand-foot syndrome (Table 2). The adverse effects were mainly grade I–II, which were relieved after symptomatic treatment, and there were no deaths caused by adverse effects.

Discussion

GC remains a major health challenge worldwide, with nearly one million new cases annually contributing to more than 650,000 deaths (12). At present, the prognosis of advanced GC is still poor, especially for stage III GC patients after radical resection, and the 5-year survival rate is less than 40% (13,14). In this study, VEGFR-2, the target gene of apatinib, was screened among 439 patients with stage III disease, and 30.8% of patients had high expression of VEGFR-2, which was higher than the less than 20% positive rate of HER-2 expression, the target gene of trastuzumab. In the enrolled 112 patients, we studied the clinical efficacy and toxicity of SOX + apatinib, which is still rarely reported at home and abroad. In this study, univariate analysis and Cox multivariate analysis showed that SOX + apatinib could improve DFS and OS, and the difference was statistically significant. The 3- and 5-year DFS of patients in the SOX + apatinib group were 70.2% and 62.5%, respectively, and the 3- and 5-year OS were 86.0% and 64.6%, which were all better than those in the SOX group. The DFS and OS of patients in the SOX + apatinib group were better than those in the SOX group. In addition, the main toxic side effects of the SOX + apatinib group were bone marrow suppression, hypertension, and hand-foot syndrome, most of which were grade I–II, with few toxic side effects and high safety.

Some studies suggest that the factors causing the recurrence and metastasis of GC after radical resection are related to pathological pT stage, pN stage, concomitant disease and tumor site (15,16). Both univariate and Cox multivariate regression analyses in our study showed that Borrmann classification, pN stage, and postoperative therapy were correlated with DFS and OS in stage III patients. It is worth noting that although the current staging is TNM staging, several studies have suggested that the Borrmann classification is an independent prognostic factor (17,18). Our study also showed that Borrmann classification was associated with prognosis, and Borrmann type IV patients had the worst prognosis.

In Asian countries, GC patients are mainly treated with D2 radical surgery combined with postoperative adjuvant chemotherapy (19,20). The RESOLVE study published by the European Society for Medical Oncology (ESMO) in 2019 showed that for patients with locally advanced cT4a/N + M0 or cT4b/NxM0 disease, five cycles of SOX adjuvant therapy and three cycles of S-1 monotherapy after D2 radical resection could significantly improve 3-year DFS compared with the XELOX regimen (7). The ARTIST-2 study published in Ann Oncol 2021 by Park et al., showed that in patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX was effective in prolonging DFS, when compared with S-1 monotherapy (21). The above two studies established SOX as an adjuvant treatment for GC after surgery, and it has been gradually popularized in clinical practice with good curative effects. SOX has become a grade I recommendation for GC after surgery in China (22). Although chemotherapy can delay disease progression and improve patients’ quality of life, there are still some differences in its clinical effects, especially for stage III patients. The current prognosis is still poor, and the 5-year survival rate is less than 40%. In our study, the 3- and 5-year DFS rates of the SOX group were 41.8% and 32.1%, respectively. The 3- and 5-year OS rates were 74.5% and 34.0%, respectively, which were consistent with the above results. It is worth noting that the 5-year DFS (32.1%) and OS (34.0%) in the SOX group in our study appeared lower than the 5-year DFS (50.6%) and OS (60.3%) reported in the JACCRO GC-07 trial (23). We have carefully analyzed the possible reasons for this discrepancy. Besides the limited sample size, the most probable reason may be attributed to the fact that patients received at least six cycles of the SOX regimen without subsequent S-1 monotherapy maintenance therapy for up to one year in our study. The shorter duration of chemotherapy most likely led to poorer DFS and OS outcomes compared to the JACCRO GC-07 trial. However, taking into consideration that our patients were enrolled between 2015 and 2021 in our study, when the results of JACCRO GC-07 had not been published and thus could not be referenced. But when the results and treatment regimen of the JACCRO GC-07 trial were published in 2023, we had carefully analyzed and adopted its study protocol. In the subsequent treatment, patients were given S-1 maintenance therapy for up to one year after SOX chemotherapy, aiming to optimize their prognosis.

Several studies have demonstrated that multidrug resistance is the leading cause of death in patients undergoing chemotherapy and that cancer of the stomach is not sensitive to chemotherapy drugs, mainly due to tumor cells producing resistance to drugs used previously. Additionally, the chemical structure and mechanism of action of drugs are not the same, indicating that tumours have a common mechanism of drug resistance, which is still unclear (24). Therefore, finding more effective treatments is the focus of current research. In recent years, the main research direction in malignant tumours has been targeted therapy, which has shown fewer adverse reactions, high tolerance, light drug resistance, and other advantages (25). HER-2 is a vital driver gene of GC. The ToGA study established the efficacy of trastuzumab in GC patients with HER-2 overexpression, but unfortunately, only 20% of GC patients exhibit HER-2 overexpression. Thus, exploring novel therapeutic targets which can benefit more patients has become a research hotspot in GC treatment. Antivascular component drugs have become an important direction of targeted therapy in recent years. Folkman first proposed that tumor growth and metastasis mainly depend on the generation of new blood vessels, and tumor treatment can be achieved by inhibiting the formation of tumor neovascularization. Antitumor angiogenesis therapy has become the target of solid tumor treatment. Li et al. (6) had confirmed that apatinib targets the VEGF/VEGFR-2 signaling pathway in advanced GC. It can block downstream signal transduction and inhibit tumor neoangiogenesis, thereby prolonging the survival of patients with advanced GC. In our study, VEGFR-2 expression was detected in 439 patients with stage III GC. Our study showed that the proportion of patients with high VEGFR-2 expression was 30.8%, higher than that of HER-2 expression. Meanwhile, SOX + apatinib therapy could improve prognosis compared to SOX therapy in patients with high VEGFR-2 expression in our study. These findings indicated that VEGFR-2 and apatinib may act as promising targets and therapeutic drug to benefit more patients with GC. However, in consideration of the small sample size of the present study, large-scale data from further researches are still required. In the exploration of the treatment of metastatic GC, the results of a phase II clinical trial showed that the median PFS and OS were significantly longer in the apatinib group than in the placebo group, indicating a survival benefit. Compared with placebo, apatinib prolonged survival in advanced GC or adeno-oesophageal junction cancer patients after systemic chemotherapy failure in a multicentre, randomized, double-blind trial. The median OS (mOS) and median nonprogressive survival were observed, and the adverse reactions were controllable (26). On the basis of this study, apatinib was approved by the National Medical Products Administration of China at the end of 2014, becoming the first small-molecule targeted therapy drug that can be used in cases of failure of second-line chemotherapy and above in advanced GC, and it is also a single drug that can significantly prolong the survival time of advanced GC patients after the failure of standard chemotherapy. Through highly selective competition for the adenosine triphosphate (ATP) binding site of VEGFR-2, the drug blocks downstream signal transduction and inhibits neoangiogenesis in tumor tissues. Subsequently, to further validate the clinical efficacy of apatinib in GC, 267 patients with advanced GC or GEJ adenocarcinoma were randomly divided into an apatinib group and a placebo group in a phase III clinical trial conducted by Li et al. in 2016 (6). The mOS of the two groups was 6.5 and 4.7 months, respectively (P=0.01). The median PFS of the two groups was 2.6 and 1.8 months (P<0.001), which confirmed the efficacy of apatinib in advanced GC and adenocarcinoma at the junction of the gastric feeding tube. The prospective, single-arm, open-arm phase IV trial of apatinib was officially launched in 2015 and plans to enrol at least 2,000 patients to further evaluate the safety and efficacy of apatinib in clinical use, which will provide more reference data. Since China Food and Drug Administration (CFDA) approval in November 2014, it has achieved gratifying results in the treatment of advanced GC.

In terms of neoadjuvant therapy, Zheng et al. reported a phase II clinical study of the apatinib +SOX regimen as neoadjuvant chemotherapy of locally advanced GC, which confirmed that the neoadjuvant therapy regimen of SOX + apatinib followed by radical gastric surgery for locally advanced GC has controllable safety and good efficacy. The objective response rate (ORR) and disease control rate (DCR) of neoadjuvant therapy were 76.9% and 96.1%, respectively (8). A multicentre, single-arm, prospective clinical study led by Professor Huang prospectively explored the safety and efficacy of apatinib combined with the SOX regimen in the neoadjuvant treatment of locally advanced GC for the first time and confirmed that the neoadjuvant chemotherapy regimen was safe and controllable, with good clinical efficacy (9). The above two studies fill the gap in the field of molecular targeted therapy combined with chemotherapy in the preoperative treatment of locally advanced GC, which is additional powerful evidence of the application of molecular targeted therapy in the treatment of GC and provides a valuable preliminary research basis for further research in the future.

The above studies on metastatic GC and neoadjuvant therapy in locally advanced GC have demonstrated that apatinib has achieved satisfactory results in metastatic GC and the neoadjuvant treatment of locally advanced GC. Apatinib is a small molecular targeted drug that can be combined with the specificity of VEGFR-2 for competitive inhibition and subsequent phosphorylation of VEGFR-2 to inhibit tumor angiogenesis growth. Some studies have confirmed that the efficacy of apatinib is positively correlated with high VEGFR-2 expression (10,11). However, no studies have been explored its efficacy in postoperative stage III GC patients at present. So, we preliminarily selected patients with VEGFR-2 overexpression to evaluate the efficacy and safety. Based on our finding that SOX + apatinib therapy could improve DFS and OS and had an acceptable safety in patients with high VEGFR-2 expression, subsequent studies will be conducted to evaluate the efficacy of apatinib in patients without VEGFR-2 overexpression in the future. Long-term chemotherapy alone frequently induces drug resistance in tumor cells, which commonly leads to compromised therapeutic effects in clinical practice. The classic cytotoxic SOX regimen, consisting of oxaliplatin plus S-1, works via cytotoxic pathways. Apatinib is an oral small-molecule anti-angiogenic agent mainly targeting VEGFR-2. Combined use of SOX and apatinib realizes complementary anti-tumor actions. SOX directly kills solid tumor cells by inhibiting DNA synthesis and replication and quickly reduces tumor size. Apatinib specifically targets tumor vascular endothelial cells to inhibit angiogenesis and inhibit tumor growth. Therefore, the combined therapy produces prominent synergistic anti-tumor effects through different mechanisms. In our study, univariate analysis suggested that SOX + apatinib could improve DFS (P<0.001) and OS (P<0.001). Cox multivariate regression also showed that SOX + apatinib was an independent prognostic factor for improving DFS (P<0.001) and OS (P<0.001), which confirmed that for stage III patients with high VEGFR-2 expression, the conventional SOX regimen combined with apatinib could further improve their prognosis. The 3- and 5-year DFS rates reached 70.2% and 62.5%, respectively. The 3- and 5-year OS were 86.0% and 64.6%, respectively, which were higher than those of the SOX group. Our study provides some theoretical support for the use of apatinib in postoperative stage III GC patients. However, due to the small number of cases in this study, further validation is still needed in the future through randomized and large-sample controlled studies to provide more evidence support and improve the prognosis of patients with GC.

In addition, we observed the adverse effects of SOX + apatinib. Considering the poor tolerance of chemotherapy in patients with advanced GC, we used low-dose apatinib in the design of the combination regimen to ensure the smooth progress of the combination therapy as much as possible. As previously reported, a number of phase II and III clinical studies have shown that the adverse reactions of apatinib are predictable, controllable, and tolerable (8,9,27,28). The common adverse effects of apatinib were high blood pressure (17.5–28.0%), proteinuria (8.1–31.0%) and hand and foot skin reaction (HFSR) (8.1–30.0%). In our study, haematological toxicity, including leukopenia, haemoglobin, and thrombocytopenia, in the SOX + apatinib group was comparable to that in the SOX group, with no increase in significant adverse effects. Nonhematological toxicity included hypertension and HFSR. In our group, the incidence of hypertension and HFSRs were 28.0% and 29.8%, respectively. The incidence of hypertension and HFSRs was basically suppressed by the above studies. In our study, it was higher than in the SOX group, and the difference was statistically significant (P=0.02, P=0.03), but most adverse effects were grade I–II, which improved after treatment, and no death due to toxicity or adverse effects occurred. The study suggested that hypertension during apatinib treatment could be attributed to its downregulation of the bioavailability of nitric oxide, a vasodilator that causes vasoconstriction. It also reduces renal sodium excretion, resulting in water and sodium retention. Antivascular therapy itself inhibits vascular endothelial function, resulting in vascular sparseness and increased blood pressure. HFSR pathogenesis is not very clear and may be related to VEGFR and platelet-derived growth factor receptor (PDGFR) signal transduction pathways (16). Tyrosine kinase inhibitors (TKIs) inhibit VEGF, leading to capillary damage. HFSR accompanied by inflammatory symptoms can occur when the hands and feet are subjected to mechanical damage such as stress in daily activities. In general, in the SOX + apatinib group, the toxicity and adverse effects were relatively small and controllable, and patient compliance was good, which may be due to its fast metabolism.

Conclusions

In conclusion, our study showed that VEGFR-2 mRNA overexpression occurred in 30.8% of stage III GC patients, which was higher than the rate of HER-2 overexpression. For patients with stage III GC, the effect of postoperative chemotherapy is still poor. Our study showed that SOX + apatinib could further improve DFS and OS compared with the SOX group. This result indicated that apatinib may potentially become another targeted drug in the postoperative treatment of stage III GC. SOX + apatinib also showed acceptable adverse effects. However, this study is still controversial, mainly because of the small sample size of the study, which still needs to be verified by large-scale randomized prospective clinical trials in the future.

Acknowledgments

We would like to thank all patients involved in the study and their family members.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0370/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0370/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0370/prf

Funding: This work was supported by the Science and Technology Fund Project of Guizhou Provincial Health Commission (No. gzwkj2022-081) and the Guizhou Provincial Science and Technology Planning Project [No. Qiankehejichu-ZK (2022) General 444].

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0370/coif). All authors report that this work was supported by the Science and Technology Fund Project of Guizhou Provincial Health Commission (No. gzwkj2022-081) and the Guizhou Provincial Science and Technology Planning Project [No. Qiankehejichu-ZK (2022) General 444]. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval was obtained from the Ethics Committee of The Affiliated Hospital of Guizhou Medical University (No. 2021-672). Informed consent was waived by the ethics committee due to the retrospective nature of the 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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