{'fraction_non_alphanumeric': 0.04564670932358318, 'fraction_numerical': 0.029250457038391225, 'mean_word_length': 5.080236193122612, 'pattern_counts': {'":': 0, '<': 3, '<?xml version=': 0, '>': 6, 'https://': 1, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Neoadjuvant apatinib plus tegafur/gimeracil/oteracil potassium (S‑1)/oxaliplatin chemotherapy vs. chemotherapy alone in patients with locally advanced gastric carcinoma

The current study aimed to evaluate the efficacy and safety of neoadjuvant apatinib plus tegafur/gimeracil/oteracil potassium (S-1) plus oxaliplatin (SOX) chemotherapy in patients with locally advanced gastric carcinoma (LAGC). Therefore, patients with LAGC treated with neoadjuvant apatinib plus SOX chemotherapy (apatinib + SOX group; n=25) or SOX chemotherapy (SOX group; n=35) were enrolled in the present study. Subsequently, the objective response (ORR) and disease control rates (DCR), pathological response, disease-free survival (DFS), overall survival (OS) and adverse events were recorded. The results showed that patients in the apatinib + SOX group exhibited a higher ORR (64.0 vs. 37.1%; P=0.040), but a similar DCR (96.0 vs. 88.6%; P=0.580), compared with those in the SOX group. The pathological response rates in patients with grade 0, 1, 2 and 3 LAGC were 0.0, 20.8, 62.5 and 16.7%, respectively, in the apatinib + SOX group, while in those treated with SOX alone they were 9.1, 39.4, 42.4 and 9.1%, respectively. By contrast, the pathological response was elevated in the apatinib + SOX group compared with the SOX group (P=0.030). During a median follow-up period of 21.0 months (range, 6.4-38.1 months), median DFS and OS were not reached. More specifically, the 1-, 2- and 3-year DFS rates were 91.7, 75.2 and 75.2% in the apatinib + SOX group and 71.8, 59.6 and 44.7% in the SOX group, respectively. In addition, the 1-, 2- and 3-year OS rates were 100.0, 89.6 and 78.4% in the apatinib + SOX group, while those in the SOX group were 90.3, 69.2 and 55.4%, respectively. However, no differences in DFS (P=0.094) or OS (P=0.155) were observed between the two groups. Additionally, the most common adverse events in the SOX group were mild leukopenia (42.9%) and fatigue (34.3%), while those in the apatinib + SOX group were tolerable leukopenia (44.0%) and hypertension (44.0%). In conclusion, the present study suggested that neoadjuvant apatinib plus SOX chemotherapy could be more effective and tolerable compared with SOX chemotherapy alone in patients with LAGC.


Introduction
Gastric carcinoma is one of the most common types of cancer and the 3rd leading cause of cancer-associated mortality worldwide (1). It has been reported that China accounted for 45% of all global gastric carcinoma cases in 2019 (2)(3)(4). Currently, the treatment approaches for early-stage gastric carcinoma include surgery, chemotherapy and targeted treatments, which provide favorable survival rates (5). However, patients with locally advanced gastric carcinoma (LAGC) exhibit limited treatment options and poor prognoses (2,4,6). Currently, neoadjuvant chemotherapy is recommended for patients with LAGC in China to decrease tumor volume and stage, as well as improve R0 resection rate, thus increasing survival (3,7,8). However, there remains a group of patients who do not benefit from neoadjuvant chemotherapy, partially due to the heterogeneity of tumors and chemotherapy resistance (9)(10)(11). Therefore, identifying more effective neoadjuvant therapies for patients with LAGC is of clinical value.
Recently, molecular targeted therapy has attracted increasing attention for patients with advanced gastric carcinoma owing to favorable efficacy and satisfactory safety (12)(13)(14). In this field, apatinib is the first oral VEGFR tyrosine kinase inhibitor developed in China, which provides obvious survival benefits and tolerable toxicity in patients with advanced gastric carcinoma (3,6,15). Notably, two previous trials demonstrated that apatinib combined with S-1 plus oxaliplatin (SOX) chemotherapy as neoadjuvant therapy exhibited favorable clinical and pathological response rates, as well as mild and manageable adverse events in patients with LAGC (12,13). However, the survival profile and data under real clinical settings were not evaluated in the aforementioned two single-armed trials (12,13). Therefore, studies on the survival profile of patients in real-world settings are needed.
Overall, the current study aimed to evaluate the efficacy and safety of neoadjuvant apatinib plus SOX chemotherapy in patients with LAGC by comparing treatment response, survival, and adverse events between neoadjuvant apatinib plus SOX and SOX chemotherapy alone.

Materials and methods
Subjects. 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.
Treatment procedures. 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/m 2 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 m 2 , 80 mg/day; BSA 1.25-1.50 m 2 , 100 mg/day; BSA >1.50 m 2 , 120 mg/day, as previously described (12). Dose adjustment was allowed depending on the response and tolerance of patients.
Outcome assessment. 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.
Control cohort. 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.
Statistical analysis. 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 χ 2 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.

Results
Clinical characteristics. 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).

Discussion
A previous study revealed that ORR, DCR and R0 resection rates are 60.0, 84.4 and 64.4%, respectively, in patients with LAGC treated with neoadjuvant SOX chemotherapy (20). Additionally, another study showed that the R0 resection and pathological response rates are 87.2 and 59.5%, respectively, in SOX chemotherapy-treated patients (21). However, several patients with LAGC fail to show obvious survival benefits from neoadjuvant SOX chemotherapy mainly due to chemoresistance (9,12,22). Therefore, several clinical trials have investigated the effect of antiangiogenic drugs combined with chemotherapy as neoadjuvant therapies to improve treatment responses in patients with LAGC (12,13,23). Notably, two single-arm trials suggest that neoadjuvant apatinib plus SOX chemotherapy exhibits promising efficacy in patients with LAGC (12,13). More specifically, regarding treatment response, ORR and DCR in patients treated with apatinib combined with SOX chemotherapy are 79.3 and 96.6%, respectively. Furthermore, the grade 3 pathological response rate is 13.8% in the aforementioned patients (12). Another study has demonstrated that CR, PR, SD and PD are 5, 70, 20 and 5%, respectively, in patients   with LAGC treated with apatinib plus chemotherapy (13). In the current study, the results indicated that ORR was 64%. In addition, grade 0, 1, 2, and 3 pathological responses were 0.0, 20.8, 62.5 and 16.7%, respectively, in patients treated with neoadjuvant apatinib combined with SOX chemotherapy, which was superior compared with SOX chemotherapy alone. The possible reasons could be the following: i) Apatinib could suppress VEGFR2 activation and subsequently inhibit the VEGFR2 downstream pathways involved in angiogenesis, such as the PI3K/AKT/mTOR and MAPK pathways, consequently inhibiting tumor activity in LAGC (13,15,24); and ii) the synergistic effect of anti-angiogenetic drugs with chemotherapy could display improved efficacy (25). At present, the survival rate of patients with LAGC remains unsatisfactory (7,20,21,26). For instance, a study revealed that the 3-year RFS and OS rates in patients with LAGC treated with neoadjuvant SOX chemotherapy are 53.2 and 62.9%, respectively (21). Additionally, another study showed that the 3-and 5-year OS rates are 55.1 and 25.8%, respectively, in patients treated with neoadjuvant SOX chemotherapy alone (20). However, the data regarding the survival of patients treated with neoadjuvant apatinib combined with SOX chemotherapy are obscure. Therefore, the current study aimed to explore the survival rate of the above patients.
The results showed that during a median follow-up period of 21.0 months (range, 6.4-38.1 months), the 1-, 2-and 3-year DFS rates were 91.7, 75.2 and 75.2%, respectively, while the 1-, 2-and 3-year OS rates were 100.0, 89.6, and 78.4%, respectively, in patients receiving neoadjuvant apatinib plus SOX chemotherapy. DFS and OS were increased in patients treated with neoadjuvant apatinib combined with SOX chemotherapy compared with those treated with SOX chemotherapy alone. However, the trend did not reach statistical significance. The above finding could be due to the following reasons: i) The favorable treatment response of apatinib combined with SOX chemotherapy could result in satisfactory survival; ii) apatinib could synergize with the chemotherapeutic drug, eventually leading to improved efficacy of the neoadjuvant therapy (25); iii) the short-term follow-up period and the limited sample size could lead to reduced events of disease recurrence and death. Therefore, it could be difficult to observe statistically significant differences in survival between the two cohorts; and iv) surgery and adjuvant chemotherapy could affect survival, which in turn could affect the differences in survival between the two groups.
Emerging evidence has suggested that the most common adverse events associated with apatinib are mild hand-foot syndrome, hypertension, proteinuria and neutropenia (27,28). Furthermore, it has been also reported that the main neoadjuvant SOX chemotherapy-related toxic effects in patients with LAGC are grade 1-2 leukopenia, neutropenia, thrombocytopenia, and amenia (29). Herein, the main adverse events of SOX chemotherapy included leukopenia, fatigue and anemia, while those of neoadjuvant apatinib combined with SOX chemotherapy were leukopenia, hypertension, thrombocytopenia, hand-food syndrome and neutropenia. The majority of the adverse events belonged to grades 1-2. Interestingly, the adverse events of neoadjuvant apatinib combined with SOX chemotherapy were not more severe than those reported for SOX chemotherapy in a previous study (29). Therefore, the results of the current study further supported the safety profile of neoadjuvant apatinib combined with SOX chemotherapy in patients with LAGC.
However, the present study has several limitations. Firstly, the sample size was relatively small; thus, in order to clarify the influence of the small sample size, the confidence level and margin of error of group difference in ORR, DCR, R0 resection and the pathological response were calculated and presented in Table SI. Additionally, in the present study, the quality of life in patients with LAGC after apatinib combined with SOX chemotherapy and SOX chemotherapy alone was not assessed. Therefore, further studies are needed.
In conclusion, the present study demonstrated that neoadjuvant apatinib plus SOX chemotherapy was more effective and well-tolerated compared with SOX chemotherapy alone in patients with LAGC.