In the present prospective, cohort study, a total of 25 patients with LAGC, who were about to receive apatinib combined with tegafur/gimeracil/oteracil potassium SOX chemotherapy as neoadjuvant therapy, were consecutively enrolled between March 2018 and May 2020. The patients were treated in the Second People's Hospital of Liaocheng (Liaocheng, Shandong, China) and the People's Hospital of Xiajin Affiliated to Shandong First Medical University (Xiajin, Shandong, China). The enrollment criteria were as follows: i) Patients with confirmed gastric adenocarcinoma both pathologically and histologically; ii) aged >18 years; iii) with clinical tumor-node-metastasis (cTNM) stage III (cT3-cT4a, cN1-cN3 and cM0) according to the 8th edition of TNM classification; iv) Eastern Cooperative Oncology Group (ECOG) score of 0-1(16); v) with a resectable tumor as determined via tumor resectability assessment; and vi) patients who were about to receive apatinib combined with SOX chemotherapy as neoadjuvant therapy. The exclusion criteria were the followings: i) Patients with a history of other types of cancer or malignancies; ii) with an allergy to the drugs used in the present study; iii) who were unwilling to be followed up regularly; and iv) pregnant or lactating women. All 25 patients were included in the apatinib + SOX group. The current study was approved by the Institutional Review Board of The Second People's Hospital of Liaocheng [approval no. (2018)0203; Linqing, China] and all patients provided written informed consent.

Patients with gastric carcinoma in the apatinib + SOX group were treated with apatinib combined with SOX chemotherapy as neoadjuvant therapy. At 3-5 weeks following neoadjuvant therapy, the tumor resectability was assessed by three independent surgeons with >10 years of experience in operating gastric cancer, in accordance with the Japanese classification of gastric carcinoma (17), then the surgical resections were operated on the patients whose tumor was deemed resectable (n=24). At 4-8 weeks after surgery, the patients continued to be treated by SOX chemotherapy as adjuvant therapy for 3-5 cycles (18). The detailed regimen of neoadjuvant therapy was as follows: Apatinib was orally administered at a dose of 500 mg/day for two consecutive cycles (21 days per cycle), followed by one cycle of withdrawal (18). Subsequently, patients were treated with SOX chemotherapy for three cycles (21 days per cycle). The detailed regimen of SOX chemotherapy was as follows: Oxaliplatin was intravenously administered at a dose of 130 mg/m² on day 1 for three cycles. S-1 was orally administered for two continuous cycles, followed by one cycle of withdrawal. The dose of S-1 dependent on body surface area (BSA): BSA <1.25 m², 80 mg/day; BSA 1.25-1.50 m², 100 mg/day; BSA >1.50 m², 120 mg/day, as previously described (12). Dose adjustment was allowed depending on the response and tolerance of patients.

At 4 weeks after the end of the last neoadjuvant therapy cycle, clinical response was evaluated in all patients using computed tomography (CT), according to the Response Evaluation Criteria in Solid Tumors (RECIST) (19). During surgery, the pathological response was assessed in patients undergoing surgical resection based on intraoperative pathological examinations, according to the Japanese classification of gastric carcinoma (17). Based on the aforementioned classification system, gastric carcinoma was classified into the following four grades: Grade 0, no evidence of effect; grade 1, viable tumor cells in >1/3 of the tumor area; grade 2, viable tumor cells in <1/3 of the tumor area; and grade 3, no viable tumor cells in the tumor area. Viable tumor cells were considered as the cells judged to be capable of proliferating. After surgery, R0 resection was evaluated in patients undergoing surgical resection using formalin-fixed paraffin-embedded tumor specimens. R0 resection was defined as the resection without remaining macroscopic or microscopic residual lesions. Furthermore, the adverse events were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0; https://ctep.cancer.gov).

All patients were followed up regularly until March 31, 2022. The median follow-up duration was 24.4 months, and the range was from 9.5 to 38.1 months. Based on follow-up information, and disease-free survival (DFS) and overall survival (OS) were calculated. DFS was defined as the time between the date of surgery to disease relapse or death. In addition, OS was defined as the time between the date of surgery and to patient's death.

During the same period, a total of 35 patients with LAGC, who were treated with SOX neoadjuvant chemotherapy, were also reviewed. The screening criteria were as follows: i) Patients diagnosed with gastric adenocarcinoma; ii) >18 years old; iii) with cTNM stage III; iv) ECOG score 0-1; v) with a resectable tumor as determined by tumor resectability assessment, and vi) treated with SOX chemotherapy as a neoadjuvant therapy. The patients who met any of the exclusion criteria set for patients in the apatinib + SOX group were also not eligible for the study. All 35 patients were included in the SOX group. The recommended regimen for patients in the SOX group was as follows: Patients were treated with SOX neoadjuvant chemotherapy for three cycles. After tumor resectability reassessment, surgical resection was performed in patients with resectable tumors (n=33). At 4-8 weeks after surgery, patients were treated with SOX adjuvant chemotherapy for three to five cycles (29 patients received three cycles, one patient received four cycles and three patients received five cycles). The dose of SOX administration was the same as previously described for patients in the apatinib + SOX group. To evaluate clinical outcomes, the clinical response rate was measured in all patients. In addition, pathological response rate, R0 resection rate, DFS and OS were determined in all patients who had undergone surgical resection. The median follow-up duration was 20.1 months, and the range was from 6.4 to 36.8 months. Additionally, adverse events were also recorded.

All statistical analyses and figure plotting were performed using SPSS 26.0 (IBM Corp.) and GraphPad Prism version 7.02 (GraphPad Software Inc.), respectively. Count data are expressed as percentages, while measurement data are expressed as the mean ± SD. The differences between two groups were compared using a unpaired Student's t-test, a χ² test or a Wilcoxon rank sum test. DFS and OS were analyzed using Kaplan-Meier curves and compared using log-rank test. P<0.05 was considered to indicate a statistically significant difference.

A total of 35 and 25 patients were included in the SOX and apatinib + SOX groups, respectively. The mean age of patients in the SOX group, including nine females (25.7%) and 26 males (74.3%), was 58.2±9.9 years. Accordingly, six females (24.0%) and 19 males (76.0%) patients were enrolled in the apatinib + SOX group, with a mean age of 55.2±10.0 years. No differences in the demographic characteristics, chronic diseases, helicobacter pylori infection, tumor location, tumor differentiation and clinical T, N or TNM stage were observed between the two groups (all P>0.05; Table I).

In the SOX group, none of the patients achieved complete response (CR), while 13 (37.1%) patients achieved partial response (PR), 18 (51.4%) stable disease (SD) and four (11.4%) had progressive disease (PD). In addition, the objective response (ORR) and disease control rates (DCR) were 37.1 and 88.6%, respectively. In the apatinib + SOX group, one (4.0%), 15 (60.0%), eight (32.0%) and one (4.0%) patients achieved CR, PR, SD and PD, respectively, while the ORR and DCR were 64.0 and 96.0%, accordingly. Furthermore, comparative analyses revealed that the general response rate (P=0.030) and ORR (64.0% vs. 37.1%; P=0.040) were increased in the apatinib + SOX group compared with the SOX group. However, no differences in DCR (96.0 vs. 88.6%) were revealed between the apatinib + SOX and SOX groups (P=0.580; Table II).

Tumor resectability reassessment was conducted at 4 weeks after the end of the last neoadjuvant therapy cycle. The results showed that 2/4 patients with PD in the SOX group and 1 patient with PD in the apatinib + SOX group could not be treated by surgery. Therefore, R0 resection rate, pathological response rate, DFS and OS were not determined in these patients. Finally, the data form 33 patients in the SOX group and 24 patients in the apatinib + SOX group were analyzed. In the SOX group, the R0 resection rate was 90.9%. In terms of pathological response, three (9.1%) patients were of grade 0, 13 (39.4%) of grade 1, 14 (42.4%) of grade 2 and three (9.1%) of grade 3. In the apatinib + SOX group, R0 resection rate was 95.8%, while 0 (0.0%), 5 (20.8%), 15 (62.5%) and 4 (16.7%) patients were of pathological response grade of 0, 1, 2 and 3, respectively. Overall, the pathological response rate was higher in the apatinib + SOX group compared with the SOX group (P=0.030), while no differences in the R0 resection rate (95.8 vs. 90.9%) were observed between the two groups (P=0.847; Table III).

During a median follow-up period of 21.0 months (range, 6.4-38.1 months), median DFS and OS were not reached in both groups (Fig. 1A and B). More specifically, the 1-, 2- and 3-year DFS rates in the SOX group were 71.8, 59.6 and 44.7%, respectively. Additionally, in the apatinib + SOX group, the 1-, 2- and 3-year DFS rates were 91.7, 75.2 and 75.2%, respectively. However, no statistical differences were observed in DFS between the two groups (P=0.094; Fig. 1A). In the SOX group, the 1-, 2- and 3-year OS rates were 90.3, 69.2 and 55.4%, respectively, while those in the apatinib + SOX group were 100.0, 89.6 and 78.4%, accordingly. Consistently, no differences in OS were obtained between both groups (P=0.155; Fig. 1B).

The main adverse events of SOX chemotherapy included leukopenia (42.9%), fatigue (34.3%), anemia (31.4%), hand-foot syndrome (28.6%), elevated transaminase (28.6%) and pruritus (28.6%). The grade 3-4 adverse events included leukopenia (2.9%), elevated transaminase (2.9%), neutropenia (2.9%), nausea and vomiting (2.9%), fatigue (2.9%) and anemia (2.9%). The rest of the adverse events were of grade 1-2. Accordingly, the most common adverse events recorded in patients treated with neoadjuvant apatinib plus SOX chemotherapy were leukopenia (44.0%), hypertension (44.0%), thrombocytopenia (36.0%) and hand-foot syndrome (32.0%), and elevated transaminase (32.0%). The grade 3-4 adverse events were hypertension (8.0%), thrombocytopenia (4.0%), hand-foot syndrome (4.0%), elevated transaminase (4.0%), neutropenia (8.0%), nausea and vomiting (4.0%) and anemia (4.0%). Finally, the rest of the adverse events were of grade 1-2 (Table IV).