Objective: To investigate the effectiveness, safety, and prognosis of neoadjuvant chemoradiotherapy (nCRT) for Siewert type II and III adenocarcinomas of the esophagogastric junction (AEG). Methods: This study is a prospective randomized controlled clinical study (NCT01962246). AEG patients who were treated at the Third Department of Surgery of the Fourth Hospital of Hebei Medical University from February 2012 to June 2016 were included. All of the enrolled patients were diagnosed with type II or III locally advanced AEG gastric cancer (T2-4N0-3M0 or T1N1-3M0) by gastroscopy and CT before operation; the longitudinal axis of the lesion was ≤ 8 cm; no anti-tumor treatment was previously given and no contraindications of chemotherapy and surgery were found. Case exclusion criteria: serious diseases accompanied by liver and kidney, cardiovascular system and other vital organs; allergy to capecitabine or oxaliplatin drugs or excipients; receiving any form of chemotherapy or other research drugs; pregnant or lactating women; patients with diseases resulting in difficulty to take capecitabine or with concurrent tumors. Based on sample size estimation, a total of 150 AEG patients were enrolled. Using the random number table method, the enrolled patients were divided into the nCRT group and the direct operation group with 75 cases in each group. The nCRT group received XELOX chemotherapy (capecitabine+ oxaliplatin) before surgery and concurrent radiotherapy (45 Gy, 25 times, 1.8 Gy/d, 5 times/week). Clinical efficacy of the nCRT group was evaluated by the solid tumor efficacy evaluation standard (RECIST1.1) and the tumor volume reduction rate was measured on CT. After completing the preoperative examination in the direct operation group, and 8-10 weeks after the end of nCRT in the nCRT group, surgery was performed. Laparoscopic exploration was initially performed. According to the Japanese "Regulations for the Treatment of Gastric Cancer", a transabdominal radical total gastrectomy combined with perigastric lymph node dissection was performed. The primary outcome was the 3-year overall survival (OS) and disease-free survival rate (DFS); the secondary outcomes were R0 resection rate, the toxicity of chemotherapy, and surgical complications. The follow-up ended on December 31, 2019. The postoperative recurrence, metastasis and survival time of the two groups were collected. Results: After excluding patients with incomplete clinical data, patients or family members requesting to withdraw informed consent, and those failing to follow the treatment plan, 63 cases in the nCRT group and 69 cases in the direct operation group were finally enrolled in the study. There were no statistically significant differences in baseline characteristics of the two groups (all P>0.05). Sixty-three patients in the nCRT group were evaluated by RECIST1.1 after treatment, the image based effective rate was 42.9% (27/63), and the stable disease rate was 98.4% (62/63); the tumor volume before and after nCRT measured on CT was (58.8±24.4) cm(3) and (46.6±25.7) cm(3), respectively, the effective rate of tumor volume reduction measured by CT was 47.6% (30/63). Incidences of neutrophilopenia [65.1% (41/63) vs. 40.6% (28/69), χ(2)=7.923, P=0.005], nausea [81.0% (51/63) vs. 56.5% (39/69), χ(2)=9.060, P=0.003] and fatigue [74.6% (47/63) vs. 42.0% (29/69), χ(2)=14.306, P=0.001] in the nCRT group were significantly higher than those in the direct surgery group. Radiation gastritis/esophagitis and radiation pneumonia were unique adverse reactions in the nCRT group, with incidences of 52.4% (33/63) and 15.9%(10/63), respectively. The classification of tumor regression of 63 patients in nCRT group presented as 11 cases of grade 0 (17.5%), 20 cases of grade 1 (31.7%), 28 cases of grade 2 (44.4%), and 5 cases of grade 3 (7.9%). Eleven (17.5%) patients achieved pathologic complete response. Sixty-one (96.8%) patients in the nCRT group underwent R0 resection, which was higher than 87.0% (60/69) in the direct surgery group (χ(2)=4.199, P=0.040). The mean number of harvested lymph nodes in the specimens in the nCRT group and the direct operation group was 27.6±12.4 and 26.8±14.6, respectively, and the difference was not statistically significant (t=-0.015, P=0.976). The pathological lymph node metastasis rate and lymph node ratio in the two groups were 44.4% (28/63) vs. 76.8% (53/69), and 4.0% (70/1 739) vs. 21.9% (404/1 847), respectively with statistically significant differences (χ(2)=14.552, P<0.001, and χ(2)=248.736, P<0.001, respectively). During a median follow-up of 52 (27-77) months, the 3-year DFS rate in the nCRT group and the direct surgery group was 52.4% and 39.1% (P=0.049), and the 3-year OS rate was 63.4% and 52.2% (P=0.019), respectively. According to whether the tumor volume reduction rate measured by CT was ≥ 12.5%, 63 patients in the nCRT group were divided into the effective group (n=30) and the ineffective group (n=33). The 3-year DFS rate of these two subgracps was 56.6% and 45.5%, respectively without significant difference (P=0.098). The 3-year OS rate was 73.3% and 51.5%,respectively with significant difference (P=0.038). The 3-year DFS rate of patients with the tumor regression grades 0, 1, 2 and 3 was 81.8%, 70.0%, 44.4%, and 20.0%, repectively (P=0.024); the 3-year OS rate was 81.8%, 75.0%, 48.1% and 40.0%, repectively (P=0.048). Conclusion: nCRT improves treatment efficacy of Siewert type II and III AEG patients, and the long-term prognosis is good.
目的： 探讨新辅助同步放化疗（nCRT）在治疗SiewertⅡ、Ⅲ型食管胃结合部腺癌（AEG）中的有效性、安全性及预后。 方法： 本研究为随机对照临床研究（Clinical Trials注册号为NCT01962246）。纳入2012年2月至2016年6月期间，于河北医科大学第四医院外三科接受治疗的AEG患者，所有患者术前均经胃镜、CT等检查确定为Ⅱ型或Ⅲ型AEG且为进展期胃癌（T(2~4)N(0~3)M(0)或T(1)N(1~3)M(0)），病变纵轴长径≤8 cm，未接受抗肿瘤治疗且无化疗及手术禁忌；排除伴随有肝肾、心血管系统等重要脏器严重疾病，对卡培他滨或奥沙利铂药物及其辅料过敏，接受过任何形式的化疗或者其他研究药物，妊娠或哺乳期妇女，伴有致口服卡培他滨有困难的疾病以及合并其他肿瘤的患者。通过样本量估算，共纳入150例AEG患者，采用随机数字表法，将入组患者分为nCRT组和直接手术组各75例。nCRT组术前接受XELOX方案（卡培他滨+奥沙利铂）进行化疗，同期进行放疗（45 Gy，25次，1.8 Gy/d，5次/周）。以实体瘤疗效评价标准（RECIST1.1）及CT测量肿瘤体积减少率分别对nCRT组进行临床疗效评判。直接手术组完善术前检查后、nCRT组于nCRT结束后8~10周后行手术治疗，先行腹腔镜探查，如腹腔脱落细胞学阴性或无腹腔种植转移，则行开腹手术，根据日本《胃癌处理规约》行经腹根治性全胃切除术联合胃周淋巴结清扫。主要观察指标为两组患者的3年总体生存率（OS）和无病生存率（DFS）；次要观察指标为R(0)切除率、围手术期化疗的毒性分析和手术相关并发症发生情况。随访截止2019年12月31日，收集两组术后复发转移及生存时间，分析各项指标及相互间关系。 结果： 剔除临床资料不完整、患者或家属要求撤回知情同意书以及未按方案进行治疗者后，最终nCRT组63例、直接手术组69例被纳入本研究，两组一般临床特征的比较差异无统计学意义（均P>0.05）。63例nCRT组患者治疗后进行RECIST1.1评价，影像学评估有效率为42.9%（27/63），疾病稳定率为98.4%（62/63）；CT测量nCRT前后肿瘤体积分别为（58.8±24.4）cm(3)和（46.6±25.7）cm(3)，CT测量肿瘤体积减小有效率为47.6%（30/63）。nCRT组中性粒细胞数减少[65.1%（41/63）比40.6%（28/69），χ(2)=7.923，P=0.005]、恶心[81.0%（51/63）比56.5%（39/69），χ(2)=9.060，P=0.003]和乏力[74.6%（47/63）比42.0%（29/69），χ(2)=14.306，P=0.001]的发生率均高于直接手术组。放射性胃炎/食管炎、放射性肺炎是nCRT组特有的不良反应，发生率分别为52.4%（33/63）和15.9%（10/63）。63例nCRT组患者肿瘤退缩分级为：0级11例（17.5%），1级20例（31.7%），2级28例（44.4%），3级5例（7.9%）；17.5%（11/63）的患者获得病理完全缓解。96.8%（61/63）的nCRT组患者达到R(0)切除，高于直接手术组（87.0%，60/69），差异有统计学意义（χ(2)=4.199，P=0.040）。nCRT组与直接手术组每例患者标本淋巴结检出分别为（27.6±12.4）枚和（26.8±14.6）枚，差异无统计学意义（t=-0.015，P=0.976），术后病理淋巴结转移率和淋巴结阳性率分别为44.4%（28/63）比76.8%（53/69），4.0%（70/1 739）比21.9%（404/1 847），差异均有统计学意义（χ(2)=14.552，P<0.001；χ(2)=248.736，P<0.001）。中位随访52（27~77）个月，nCRT组与直接手术组3年DFS分别为52.4%与39.1%（P=0.049），3年OS分别为63.4%与52.2%（P=0.019），差异均有统计学意义。根据CT测量肿瘤体积减少率是否≥12.5%，将63例nCRT组患者分为有效组（30例）与无效组（33例），两组3年DFS分别为56.6%与45.5%（P=0.098），3年OS为73.3%与51.5%，差异有统计学意义（P=0.038）。肿瘤退缩分级为0级、1级、 2级及3级患者的3年DFS分别为81.8%、70.0%、44.4%和20.0%（P=0.024）；3年OS分别为81.8%、75.0%、48.1%和40.0%（P=0.048），差异均有统计学意义。 结论： nCRT联合手术治疗改善了SiewertⅡ、Ⅲ型AEG患者的治疗效果，患者远期预后良好。.
Keywords: Adenocarcinoma of esophagogastric junction, Siewert II and III; Adenocarcinoma of esophagogastric junction, advanced; Neoadjuvant chemoradiotherapy; Prognosis.