紫杉醇联合卡铂的新辅助同步放化疗方案应用于Ⅲ期食管胃结合部腺癌的近期疗效及安全性分析

Short-term efficacy and safety of the synchronous neoadjuvant chemoradiotherapy with paclitaxel plus carboplatin in stage Ⅲ adenocarcinoma of esophagogastric junction

目的探讨紫杉醇联合卡铂的新辅助同步放化疗方案应用于Ⅲ期食管胃结合部腺癌（AEG）中的近期疗效及安全性。方法前瞻性纳入河北北方学院附属第一医院胃肠肿瘤外科2014年12月至2017年11月收治的40例临床确诊为Ⅲ期AEG患者，其中男27例，女13例，采用随机数字表法将患者分至新辅助治疗组（20例）和直接手术组（20例）。病例入组标准为：（1）胃镜活组织检查确诊为AEG腺癌，且根据超声内镜及螺旋CT等确定分期为Ⅲ期；（2）体力评分≥70，年龄≤75岁；（3）无放化疗及手术禁忌证。剔除标准为：（1）自动退出或拒绝治疗；（2）发生化疗药物严重过敏反应；（3）治疗过程中出现了急性不可控的情况而无法继续治疗；（4）治疗期间发现肿瘤明显进展的患者。新辅助治疗组的术新辅助同步放化疗方案为：采用TP方案化疗，紫杉醇80mg／m2，卡铂药时曲线下面积（AUC）=1．5mg·ml-1·min-1，每周1次（共9周）；在第2周开始放疗，剂量为40Gy／20F／4周。两组手术方式均为贲门癌根治术（D2）。术后辅助化疗方案均为单药口服替吉奥。观察新辅助治疗组同步放化疗不良反应、新辅助治疗过程中患者进食状态的变化、新辅助治疗前后胃镜图像变化，依据美国国家癌症研究所（NCI）实体瘤疗效评价标准评价新辅助治疗疗效；比较新辅助治疗组与直接手术组两组的手术相关指标。结果新辅助治疗组中有1例患者在化疗7周后出现病灶处穿孔行急诊手术剔除本研究。19例完成新辅助放化疗患者的不良反应主要为脱发和骨髓抑制，3-4级不良反应主要为脱发（8例，42．1％）、白细胞减少（3例，15．8％）及中性粒细胞减少（3例，15．8％）。新辅助治疗疗效评价：完全缓解4例，部分缓解13例，疾病稳定2例，无疾病进展病例；有效率89．5％（17／19），疾病控制率100％。新辅助治疗前16例患者进流食困难，3例患者仅能进流食，治疗12周后19例患者全部可正常进食。新辅助治疗后胃镜检查见贲门处溃疡趋于愈合，肿块消失可见新生正常黏膜。两组患者基线资料的比较，差异无统计学意义（均P〉0．05）。与直接手术组比较，新辅助治疗组淋巴结阳性数较少[（4．9±3．6）枚比（8．8±2．8）枚，t=3．676，P=0．001]，R0切除率更高[94．7％（18／19）比50．0％（10／20），P=0．003]。两组问清扫淋巴结数量的比较，差异无统计学意义[（19．1±2．5）枚比（18．6±7．0）枚，t=0．326，P=0．746]。两组均未出现术后死亡病例，直接手术组1例术后出现术后早期炎性肠梗阻，新辅助治疗组术后未出现手术相关并发症。结论紫杉醇联合卡铂的新辅助同步放化疗方案可以提高Ⅲ期AEG患者的R0切除率，且并不增加手术病死率及术后并发症发生率。

Objective To evaluate the short-term efficacy and safety of neoadjuvant synchronous chemoradiotherapy （paclitaxel plus carboplatin regimen） in stage Ⅲ adenocarcinoma of esophagogastric junction （AEG）. Methods Forty cases clinically diagnosed as stageⅢ AEG were prospectively enrolled at the Department of Gastrointestinal Oneology Surgery, the First Affiliated Hospital of Hebei North University from December 2014 to November 2017 and then were randomly divided into paclitaxel plus carboplatin combined with synchronous radiotherapy group （neoadjuvant group） and direct operation group. Inclusion criteria was as follows ： （ 1 ） AEG was diagnosed by gastroscopic biopsy and Ⅲ stage was confirmed by ultrasound endoscopy and spiral CT; （2） physical strength score ≥70, and age ≤75 years old; （3） no contraindications of chemoradiotherapy and operation. Exclusion criteria was as follows：（1 ） patients voluntarily withdrew or refused the treatment; （2） occurrence of severe anaphylaxis; （3） uncontrollable events happened during treatment and treatment was unable to continue; （4） tumor developed obviously during treatment. Preoperative neoadjuvant synchronous chemoradiotherapy used TP regimen： paclitaxel 80 mg/m2, drug concentration-time area under curve of carboplatin= 1.5 mg·ml-1 min-1, once per week tor 9 weeks; radiotherapy began at the second week, 40 Gy/20 F, completed within 4 weeks. Operative procedure of both groups was radical resection of cardiac cancer （D2）. Postoperative chemotherapy regimen was oral Tegaiur （Gimeracil and Oteracil potassium）. The side effects, diet situation, change of gastroscopic image after treatment in patients of neoadjuvant group were observed and efficacy evaluation of chemotherapy was performed according to solid tumor efficacy evaluation criteria of US National Cancer Institute. Operation-associated parameters, including R0 resection rate, lymph node metastasis, operative mortality and postoperative complications, were compared between two groups. Results There were no significant differences in baseline information between the two group （all P〉0.05）. One case in neoadjuvant group was excluded because of perforation at lesion site 7 weeks after chemotherapy. The side effects of 19 cases in neoadjuvant group were mainly alopecia （100%） and marrow inhibition （68.4%）, while 3-4 degree side effects were alopecia （8/19,42.1%）, leukopenia （3/19, 15.8%） and neutropenia（3/19, 15.8%）. Complete remission was observed in 4 cases; partial remission was observed in 13 cases and stable disease in 2 cases, with an objective response rate of 89.5% and a disease control rate of 100%. Before neoadjuvant chemotherapy, 16 cases were difficult to take liquid diet and 3 eases reeeived liquid diet only, while after 12 weeks of neoadjuvant chemotherapy, all the 19 cases received normal diet. Besides, after neoadjuvant chemotherapy, gastroscopic examination showed close healing of cardiac ulcer, disappearance of swelling, and renewal of normal mucosa. Compared to direct operation group, neoadjuvant group had less number of positive lymph node （4.9±3.6 vs. 8.8±2.8, P〈0.05） and higher R0 resection rate （94.7% vs. 50.0%, P〈O.05）. Total number of harvested lymph node was not significantly different between two groups （19.1±2.5 vs. 18.6±7.0, t=0.326, P=0.746）. There was no surgical death in either group. One case in direct operation group developed postoperative intlammatory obstruction. No associated complication was found in neoadjuvant group. Conclusion Paclitaxel plus carboplatin combined with synchronous radiotherapy ean elevate the R0 resection rate of patients with stage Ⅲ esophagogastric junction adenoearcinoma, without increasing operative mortality and postoperative eomplications.