新辅助化疗联合免疫治疗后腹腔镜胃癌根治术的安全性分析

Safety and efficacy of laparoscopic surgery in locally advanced gastric cancer patients with neoadjuvant chemotherapy combined with immunotherapy

目的探究SOX化疗联合PD-1抑制剂新辅助治疗局部进展期胃癌后行腹腔镜下胃癌根治手术的应用效果与安全性。方法前瞻性入组2020年10月至2021年4月间华中科技大学同济医学院附属协和医院收治的30例局部进展期胃癌患者的临床病理资料。病例纳入标准:(1)充分了解本研究后并自愿签署知情同意书;(2)年龄18~75岁;(3)肿瘤临床分期为cT3~4N+M0期;(4)体力状况美国东部肿瘤协作组(ECOG)评分为0~1分;(5)预计生存期≥6个月,具有进行以治愈为目的的R0切除术的可能;(6)入组前7 d内患者有充足器官和骨髓功能;(7)完成胃癌D2根治术。排除标准:(1)抗PD-1或PD-L1抗体治疗、化疗史;(2)治疗前14 d内使用皮质类固醇或其他免疫抑制剂治疗;(3)自身免疫性疾病或间质性肺病活动期;(4)其他恶性肿瘤病史;(5)治疗前28 d内有外科手术史;(6)对本研究药物成分过敏。采用门诊和电话方式进行随访,术前SOX化疗联合PD-1抑制剂免疫治疗期间每3周随访1次,了解患者不良反应发生情况;手术治疗1个月后随访1次,了解患者不良反应与生存情况。本研究观察指标:(1)入组患者情况;(2)术前治疗情况及评估与手术完成情况;(3)术后情况及病理结果。评价标准:(1)手术标本按第8版美国癌症联合委员会(AJCC)TNM分期系统进行分期;(2)肿瘤退缩分级(TRG)参考AJCC标准评估;(3)治疗相关不良反应根据常见不良反应评价标准5.0版进行评估;(4)治疗前后CT采用RECIST V1.1标准评估肿瘤反应;(5)术后采用Clavien-Dindo并发症分级系统进行并发症评估。结果筛选出符合条件的患者30例,其中男25例,女5例;中位年龄60.5(35.0~74.0)岁;初诊肿瘤位置位于食管胃结合部12例、胃上部8例、胃中部7例、胃下部3例;治疗前30例患者临床分期均为Ⅲ期。30例患者新辅助化疗联合免疫治疗过程中,21例患者出现不良反应,其中4例CTCAE 3~4级不良反应,主要表现为骨髓抑制及胸主动脉血栓形成。所有不良反应经过积极对症处理后均减轻或者消失。30例患者接受腹腔镜胃癌根治术,其完成新辅助治疗至手术中位时间为28(23~49)d,其中10例全腔镜下胃癌根治术,20例腹腔镜辅助胃癌根治术,合并脾脏切除1例,合并胆囊切除1例。手术时间(239.9±67.0)min,术中中位出血量为84(10~400)ml,中位手术切口长度7(3~12)cm。术后病理证实30例均完成R0切除。肿瘤低分化18例,中分化12例,神经浸润11例,脉管浸润6例,清扫淋巴结30(17~58)枚,30例患者完成手术后首次肛门排气时间、术后首次排便时间、术后流质饮食时间、术后住院时间分别为3(2~6)d、3(2~13)d、5(3~12)d、10(7~27)d。23例患者发生术后并发症,Clavien-Dindo分级Ⅲa级以上并发症7例,6例患者经治疗后均好转顺利出院,1例患者因粒细胞缺乏、贫血、双肺感染和呼吸窘迫综合征,经抢救无效术后27 d死亡。余29例患者出院30 d内未出现手术相关并发症及死亡。30例患者TRG 0、1、2、3级分别为8、9、4、9例,术后病理分期0、Ⅰ、Ⅱ、Ⅲ分别为8、7、8、7例,8例患者获得病理完全缓解。结论新辅助化疗联合免疫治疗后腹腔镜下胃癌根治术可达到根治性切除目的,但新辅助化疗联合免疫治疗后化疗相关不良反应值得关注,早期发现并及时治疗相关并发症十分重要。

Objective To investigate the safety and efficacy of laparoscopic surgery in locally advanced gastric cancer patients with neoadjuvant SOX chemotherapy combined with PD-1 inhibitor immunotherapy.Methods Between November 2020 and April 2021,patients with locally advanced gastric cancer who were admitted to the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology were prospectively enrolled in this study.Inclusion criteria were:(1)patients who signed the informed consent form voluntarily before participating in the study;(2)age ranging from 18 to 75 years;(3)patients staged preoperatively as cT3-4N+M0 by the TNM staging system;(4)Eastern Collaborative Oncology Group score of 0-1;(5)estimated survival of more than 6 months,with the possibility of performing R0 resection for curative purposes;(6)sufficient organ and bone marrow function within 7 days before enrollment;and(7)complete gastric D2 radical surgery.Exclusion criteria were:(1)history of anti-PD-1 or PD-L1 antibody therapy and chemotherapy;(2)treatment with corticosteroids or other immunosuppre-ssants within 14 days before enrollment;(3)active period of autoimmune disease or interstitial pneumonia;(4)history of other malignant tumors;(5)surgery performed within 28 days before enrollment;and(6)allergy to the drug ingredients of the study.Follow-up was conducted by outpatient and telephone methods.During preoperative SOX chemotherapy combined with PD-1 inhibitor immunotherapy,follow-up was conducted every 3 weeks to understand the occurrence of adverse reactions of the patients;follow-up was conducted once after 1 month of surgical treatment to understand the adverse reactions and survival of patients.Observation indicators were:(1)condition of enrolled patients;(2)reassessment after preoperative therapy and operation received(3)postoperative conditions and pathological results.Evaluation criteria were:(1)tumor staged according to the 8th edition of the American Joint Committee on Cancer(AJCC)TNM staging system;(2)tumor regression grading(TRG)of pathological results were evaluated with reference to AJCC standards;(3)treatment-related adverse reactions were evaluated according to version 5.0 of the Common Terminology Criteria for Adverse Events;(4)tumor response was evaluated by CT before and after treatment with RECIST V1.1 criteria;and(5)Clavien-Dindo complication grading system was used for postoperative complications assessment.Results A total of 30 eligible patients were included.There were 25 males and 5 females with a median age of 60.5(35-74)years.The primary tumor was located in the gastroesophageal junction in 12 cases,in the upper stomach in 8,in the middle stomach in 7,and in the lower stomach in 3.The preoperative clinical stage of 30 cases was III.Twenty-one patients experienced adverse reactions during neoadjuvant chemotherapy combined with immunotherapy,including four cases of CTCAE grade 3–4 adverse reactions resulting in bone marrow suppression and thoracic aortic thrombosis.All cases of adverse reactions were alleviated or disappeared after active symptomatic treatment.Among the 30 patients who underwent surgery,the time from chemotherapy combined with immunotherapy to surgery was 28(23-49)days.All 30 patients underwent laparoscopic radical gastrectomy,of which 20 patients underwent laparoscopic-assisted radical gastric cancer resection;10 patients underwent total gastrectomy for gastric cancer,combined with splenectomy in 1 case and cholecystectomy in 1 case.The surgery time was(239.9±67.0)min,intraoperative blood loss was 84(10-400)ml,and the length of the incision was 7(3-12)cm.The degree of adenocarcinoma was poorly differentiated in 18 cases,moderately differentiated in 12 cases,nerve invasion in 11 cases,and vascular invasion in 6 cases.The number lymph nodes that underwent dissection was 30(17-58).The first of gas passage,the first postoperative defecation time,the postoperative liquid diet time,and the postoperative hospitalization time of 30 patients was 3(2-6)d,3(2-13)d,5(3-12)d,and 10(7-27)d,respectively.Postoperative complications occurred in 23 of 30 patients,including 7 cases of complications of Clavien–Dindo grade IIIa or above.Six patients improved after treatment and were discharged from hospital,while 1 patient died 27 days after surgery due to granulocyte deficiency,anemia,bilateral lung infection,and respiratory distress syndrome.The remaining 29 patients had no surgery-related morbidity or mortality within 30 days of discharge.Postoperative pathological examination showed TRG grades 0,1,2,and 3 in 8,9,4,and 9 cases,respectively,and the number of postoperative pathological TNM stages 0,I,II,and III was 8,7,8,and 7 cases,respectively.The pCR rate was 25.0%(8/32).Conclusion Laparoscopic surgery after neoadjuvant SOX chemotherapy combined with PD-1 inhibitor immunotherapy for locally advanced gastric cancer is safe and feasible,with satisfactory short-term efficacy.Early detection and timely treatment of related complications are important.