The following XELOX regimen was applied for chemotherapy: capecitabine was administered at 1,000 mg/m² twice daily for 14 days (day 1 to day 14); oxaliplatin was intravenously administered at 130 mg/m² on day 1, and all subjects were treated for two cycles. Two cycles of chemotherapy were administered prior to surgery, and six cycles were administered after surgery. Eight cycles were administered after surgery in the control group.

(1) Radiotherapy planning CT scans were obtained with the patient in the supine position in a body mold to ensure setup reproducibility.

(2) CT simulation with intravenous (IV) contrast was performed to help guide the gross tumor volume (GTV) target, particularly for lymph nodes.

(3) The treating physicians utilized the following information to delineate active disease: barium meal, esophagoscopy/gastroscopy, and magnetic resonance imaging (MRI) scanning.

(4) Radiation targets included AEG, any perigastric extension, and lymph nodes (perigastric, celiac, portal hepatis, splenic hilar) with adequate margins. The standard GTV-t to clinical target volume (CTV)-t expansions were 2 cm in the superior-inferior direction and 0.8 cm laterally and anteroposteriorly. CTV-nd included CTV-nd and involved the field; 0.8–1.0 cm was added so that CTV+ 0.8–1.0 cm = planning target volume (PTV).

(5) Intensity-modulated radiation therapy (IMRT) was used and delivered by a linear accelerator as multiple shaped beams of 6 MV X-rays in five daily fractions of 1.8 Gy per week for 5 weeks (total PTV dose: 45 Gy).

Therapeutic efficacy was determined according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). The response was made up of four classifications: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). The total efficacy [response rate (RR)] was calculated as the sum of CR and PR, and the tumor control rate was calculated as the sum of CR, PR, and SD. Tumor-node-metastasis (TNM) staging was performed according to the criteria developed by the AJCC (7th edition).

A tumor volume reduction rate of 12.5% was measured by CT as an effective threshold for evaluating neoadjuvant therapy (8).

Tumor volume reduction rate after chemotherapy = (tumor volume before chemotherapy − tumor volume after chemotherapy)/tumor volume before chemotherapy × 100%.

Laparoscopic exploration was performed 6–8 weeks after the end of concurrent chemoradiotherapy. Surgical treatment involved total gastrectomy and subsequent extended lymph node dissection (D2 resection). Reconstruction of the digestive tract involved Roux-en-Y esophagojejunostomy.

The treated group started with 500 ml of the enteral nutrition (EN) suspension (total protein fiber, TPF) (Nutrison Fiber^®), an oral nutrition supplementation (ONS) (500 ml per bottle containing energy 500 kcal, protein 20 g, fat 19.45 g, and carbohydrate 61.5 g), 7 days before surgery in addition to a routine preoperative diet (35 kcal/kg/day) according to dietary guidance. Patients in this group also received TPF 48 h after surgery via a nasojejunal tube placed during surgery. The feeding speed increased from the initial 30 ml/h according to the tolerance of the patients’ intestinal tracts. In general, nutritional support was shifted to the total EN 3–5 days after surgery, where patients were expected to start a semiliquid diet 4 days later. Consequently, the amounts of energy and protein were 25–30 kcal/kg/day and 1.0–1.5 g/kg/day, respectively, with the insufficient component supplemented with parenteral nutrition (9).

The pathological examination included the detection of tumor size, depth of invasion, number of metastatic lymph nodes, surgical margins, HER-2 expression, and tumor regression grade (TRG).

TRG was defined as follows: grade 0 (complete remission), no cancer cells; grade 1 (partial remission), single cells or a small group of cancer cells; grade 2 (low efficacy), residual cancer outgrown by fibrosis; and grade 3 (poor efficacy), minimum or no treatment effect with extensive residual cancer cells.

During the first year after treatment completion, patients received regular check-ups every 3 months. In the second year, regular follow-ups took place every 6 months and annually thereafter until 5 years after treatment. Additional interim visits were scheduled if complaints, such as renewed dysphagia and unexplained weight loss or pain, arose before the next scheduled visit. Diagnostic investigations were only undertaken as necessary measures during follow-up. No data on adverse events were collected beyond the initial report of this trial.

Statistical analysis was performed with SPSS version 19.0 software and GraphPad Prism version 7. Quantitative data were compared using the chi-square test. Qualitative data were compared using the t-test and are expressed as the mean ± standard deviation. The Kaplan–Meier method was used to calculate overall survival (OS) and disease-free survival (DFS). A p-value < 0.05 was considered statistically significant.

A total of 149 patients with AEG who were admitted to the Fourth Hospital of Hebei Medical University between August 2012 and January 2016 were enrolled in this study. Patients were randomized at a 1:1 ratio using a stratified method (HER2 expression): a concurrent chemoradiotherapy group (n = 76) or a surgery group (n = 73). Patients in the concurrent chemoradiotherapy group (68 males and 8 females, median age 64 years, range: 43–75 years) received concurrent chemoradiotherapy and subsequent surgery. Patients in the surgery group (63 males and 10 females, median age 65 years, range: 42–74 years) were treated with surgery without chemoradiotherapy preoperatively. The general clinical characteristics of the patients in the two groups are shown in Table 1 . After the end of concurrent chemoradiotherapy, 11 patients did not undergo surgery, 3 patients due to disease progression and 8 patients due to poor tolerance or economic reasons ( Figure 1 ).

In the treated group, evaluation according to RECIST 1.1 revealed CR in 0 patients, PR in 31 patients, SD in 42 patients, and PD in 3 patients. The RR in the treated group was 40.8% (31/76), and the tumor control rate was 96.1% (73/76).

The tumor volume was 53.23 ± 21.57 cm³ before nCRT, and the tumor volume was 45.26 ± 22.39 cm³ after nCRT. Based on CT measurements of tumor volume reduction, the effective rate was 47.4%.

The hematologic toxic effects included leukopenia, neutropenia, anemia, thrombocytopenia, and abnormal liver function. The incidence of neutropenia in the treated group was greater than that in the control group, and the difference was statistically significant (65.8% vs. 38.4%, p = 0.034). The nonhematologic toxic effects included nausea, vomiting, diarrhea, constipation, hand–foot syndrome, and fatigue. These toxic effects were mainly graded 1–2. The incidence of nausea in the treated group was greater than that in the control group, and the difference was statistically significant (67.1% vs. 47.9%, p = 0.032). The incidence of fatigue in the treated group was greater than that in the control group, and the difference was statistically significant (61.8% vs. 39.7%, p = 0.022). The incidences of grade 3–4 hematologic and nonhematologic toxicities were low in the two groups, and the difference was not statistically significant (p > 0.05). Radiation gastritis/esophagitis and pneumonitis were unique to the treated group, with incidence rates of 43.4% and 13.2%, respectively, and these toxic effects were mainly grade 1–2 ( Table 2 ).

The incidence of wound infection, anastomotic bleeding, anastomotic leakage, abdominal infection, and intestinal obstruction was low, and the difference between groups was not statistically significant (p > 0.05). The incidence of pleural effusion in the treated group was higher than that in the control group, and this difference was statistically significant (23.08% vs. 6.85%, p = 0.007). The incidence of lung infection in the treated group was higher than that in the control group, and this difference was statistically significant (24.62% vs. 8.22%, p = 0.009). One patient in the treated group died during the perioperative period due to severe pulmonary infection ( Tables 3 , 4 ). In the intention-to-treat analysis, the incidences of pleural effusion and pneumonia were also significantly different between the two groups (19.74% vs. 6.85%, p = 0.021; 21.05% vs. 8.22%, p = 0.027).

The R0 resection rates in the treated group and the control group were 97% (63/65) and 87.7% (64/73), respectively, and this difference was statistically significant (χ ² = 4.012, p = 0.045). In the treated group, the pathological complete response (pCR) rate was 16.9% (11/65), and the total pathological response rate (grade 1 + grade 0) was 47.7% (31/65). The pathological lymph node metastasis rate and positivity rate were 43.1% and 3.9%, respectively, in the treated group and 76.7% and 20.9%, respectively, in the control group ( Table 5 ). In the intention-to-treat analysis, there was no significant difference in the R0 resection rate between the two groups (86.3% vs. 87.7%, p = 0.806).

The median follow-up time was 52 months (27–77) in all patients, and the median DFS times in the treated group and the control group were 33 and 27 months, respectively (HR 0.68, [95% confidence interval (CI) 0.44–1.05], p = 0.08) ( Figure 2 ). In the treated group, 30 patients had recurrence and metastasis, 8 patients had local recurrence, 27 patients had distant metastasis, and 5 patients had two or more recurrent metastases; therefore, the rate of total recurrence/distant metastases was 39.5% (30/76). In the control group, 39 patients had recurrence and metastasis, 20 patients had local recurrence, 26 patients had distant metastasis, and 7 patients had two or more recurrent metastases. Therefore, the rate of total recurrence/distant metastases was 53.4% (39/73) ( Table 6 ). The median OS times were 39 and 30 months (HR 0.59, [95% CI 0.38–0.91], p = 0.01) ( Figure 3 ), and the survival rates were 43.94% and 36.92% (χ ² = 0.83, p = 0.362).

The median DFS times of patients with positive or negative HER-2 expression in the treated group were 13 and 43 months, respectively (HR 0.36, [95% CI 0.09–1.33], p = 0.01), and the median OS times were 27 and 41 months, respectively (HR 0.35, [95% CI 0.09–1.30], p = 0.01) ( Figures 4 , 5 ). The median DFS times of patients with positive and negative HER-2 expression in the control group were 22 and 30 months, respectively (HR 0.57, [95% CI 0.24–1.39], p = 0.17), and the median OS times were 24 and 31.5 months, respectively (HR 0.59, [95% CI 0.23–1.49], p = 0.16) ( Figures 6 , 7 ).