短程放疗序贯化疗联合抗PD-1抗体治疗后腹腔镜手术对局部进展期直肠癌短期疗效的前瞻性研究

Short-term efficacy of laparoscopic surgery after short-course radiotherapy followed by sequential chemotherapy combined with anti-PD-1 antibody therapy for locally advanced rectal cancer:a prospective study

目的探讨短程放疗序贯化疗联合抗程序性死亡[蛋白]-1(PD-1)抗体治疗后腹腔镜手术对局部进展期直肠癌的短期疗效。方法采用前瞻性研究方法。选取2019年11月至2020年9月华中科技大学同济医学院附属协和医院收治的30例局部进展期直肠癌患者的临床病理资料。患者经短程放疗序贯化疗联合抗PD-1抗体治疗后,再行腹腔镜手术治疗。观察指标:(1)入组患者情况。(2)短程放疗序贯化疗联合抗PD-1抗体治疗及不良反应情况。(3)术前评估与手术完成情况。(4)术后情况及病理学检查结果。(5)术后辅助化疗及随访情况。采用门诊和电话方式进行随访。短程放疗序贯化疗联合抗PD-1抗体治疗期间每3周随访1次,了解患者不良反应发生情况;手术治疗后2年内每3个月随访1次,此后每6个月随访1次,了解患者肿瘤复发和生存情况。随访时间截至2022年3月。正态分布的计量资料以x±s表示,偏态分布的计量资料以M(范围)表示,计数资料以绝对数或百分比表示。采用Kaplan-Meier法计算生存率并绘制生存曲线。结果(1)入组患者情况。筛选出符合条件的患者30例;男17例,女13例;年龄为(57±16)岁;术前原发肿瘤分期cT3期、cT4期分别为22、8例;术前淋巴结转移分期cN0期、cN1期、cN2期分别为4、16、10例;术前患者临床分期Ⅱ期、Ⅲ期分别为4、26例。30例患者中,术前影像学评估环周切缘阳性21例、直肠壁外血管侵犯12例。30例患者肿瘤下缘距肛缘距离为4.7(1.9~9.0)cm,肿瘤长径为5.4(2.1~10.0)cm。30例患者中,肿瘤组织错配修复完整28例、错配修复缺陷1例,1例因治疗前未成功行活组织病理学检查缺失肿瘤组织错配修复资料。(2)短程放疗序贯化疗联合抗PD-1抗体治疗及不良反应情况。30例患者术前均完成短程放疗,其中3例未行化疗联合抗PD-1抗体治疗,24例完成2个疗程化疗联合抗PD-1抗体治疗,3例完成1个疗程化疗联合抗PD-1抗体治疗。27例患者放疗结束至开始化疗联合抗PD-1抗体治疗时间为12(4~18)d。30例患者行短程放疗序贯化疗联合抗PD-1抗体治疗期间发生白细胞减少、皮肤毛细血管内皮增生、放射性直肠炎、贫血、外周神经毒性、中性粒细胞减少、血小板降低、疲乏、食欲减退、肝功能异常、甲状腺功能减退分别为24、22、21、20、18、16、16、13、10、9、2例,均经对症治疗后好转。(3)术前评估与手术完成情况。30例患者经术前多学科评估,7例达到临床完全缓解,23例未达到临床完全缓解。30例患者中,27例行腹腔镜直肠癌根治术,3例未完成化疗联合抗PD-1抗体治疗患者未行手术治疗。27例患者完成化疗联合抗PD-1抗体治疗至行手术时间为14(5~141)d,术前美国东部肿瘤协作组体力状况评分0、1分分别为13、14例,手术方式采用低位直肠前切除术、腹会阴联合切除术分别为24、3例,手术时间为(182±36)min,术中出血量为30(10~150)mL。27例患者中,16例行保护性回肠造口,24例保留肛门。(4)术后情况及病理学检查结果。27例完成手术患者术后首次肛门排气时间、术后首次进食流质食物时间、术后住院时间分别为2(1~4)d、3(2~5)d、8(7~16)d。27例患者中,5例发生术后并发症,均为Ⅰ~Ⅱ级,其中2例发生切口感染,腹腔感染、切口出血、左下肢肌间静脉血栓形成各1例,均经对症治疗后好转。27例患者术后病理学检查病理学完全缓解率为48.1%(13/27),肿瘤退缩分级0、1、2、3级分别为13、5、7、2例,肿瘤病理学T分期T0期、Tis期、T2期、T3期分别为13、1、5、8例,肿瘤病理学N分期N0期、N1期、N2期分别为19、6、2例,肿瘤病理学TNM分期0期、Ⅰ期、Ⅱ期、Ⅲ期分别为14、0、5、8例,淋巴结清扫数目为15(3~29)枚,环周切缘阳性1例,R0切除26例,无二次手术或围手术期死亡。(5)术后辅助化疗及随访情况。27例完成手术患者中,21例行术后辅助化疗,疗程为4(1~6)个周期。27例患者均获得术后随访,随访时间为20(20~29)个月。随访期间,14例未达到病理学完全缓解患者中,3例发生肿瘤复发,无患者死亡。27例患者无病生存率为88.9%。结论短程放疗序贯化疗联合抗PD-1抗体治疗后腹腔镜手术对局部进展期直肠癌安全、可行,短期疗效较好。

Objective To investigate the short-term efficacy of laparoscopic surgery after short-course radiotherapy followed by sequential chemotherapy combined with anti-programmed death-1(PD-1)antibody therapy for locally advanced rectal cancer.Methods The prospective study was conducted.The clinicopathological data of 30 locally advanced rectal cancer patients who were admitted to the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology from November 2019 to September 2020 were selected.Patients underwent laparos-copic surgery after short-course radiotherapy followed by sequential chemotherapy combined with anti-PD-1 antibody therapy.Observation indicators:(1)situations of the enrolled patients;(2)situations of short-course radiotherapy followed by sequential chemotherapy combined with anti-PD-1 antibody therapy and adverse events;(3)preoperative evaluation and surgical situations;(4)postoperative situations and pathological examinations;(5)postoperative adjuvant chemo-therapy and follow-up.Follow-up was conducted using outpatient examination and telephone interview up to March 2022.Patients were followed up once every 3 weeks during the period of short-course radiotherapy followed by sequential chemotherapy combined with anti-PD-1 antibody therapy to detect the adverse events and patients were followed up once every 3 months during the first postoperative 2 years and once every 6 months thereafter to detect tumor recurrence and survival of patients.Measurement data with normal distribution were represented as Mean±SD,and measurement data with skewed distribution were represented as M(range).Count data were described as absolute numbers or percentages.The Kaplan-Meier method was used to calculate survival rates and draw survival curves.Results(1)Situations of the enrolled patients.A total of 30 patients were selected for eligibility.There were 17 males and 13 females,aged(57±16)years.Cases with preoperative primary tumor in stage cT3 and cT4 were 22 and 8,respectively.Cases with preoperative clinical lymph node metastasis in stage cN0,cN1,cN2 were 4,16,10,respectively.Cases in preoperative clinical stageⅡandⅢwere 4 and 26,respectively.Of the 30 patients,there were 21 cases with positive circumferential margin and 12 cases with vascular invasion in extramural of rectum in the preoperative imaging evaluation.Distance from the distal margin of tumor to anal margin and tumor diameter of the 30 patients were 4.7(range,1.9-9.0)cm and 5.4(range,2.1-10.0)cm,respectively.There were 28 cases with mismatch repair proficient and 1 case with mismatch repair deficiency in tumor tissues.There was 1 case missing the data of mismatch repair in tumor tissues as failed in biopsy of pathological examination before the treatment.(2)Situations of short-course radiotherapy followed by sequential chemotherapy combined with anti-PD-1 antibody therapy and adverse events.All the 30 patients completed preoperative short-course radiotherapy successfully.Of the 30 patients,there were 3 cases not undergoing the sequential chemotherapy combined with anti-PD-1 antibody therapy and there were 24 cases undergoing 2 courses of the sequential chemotherapy combined with anti-PD-1 antibody therapy and 3 cases undergoing 1 course of the sequential chemotherapy combined with anti-PD-1 antibody therapy.The time interval between ending of radiotherapy and starting of chemotherapy combined with anti-PD-1 antibody therapy of the 27 patients was 12(range,4-18)days.Cases with leukopenia,cases with endothelial hyperplasia of skin capillaries,cases with radiation proctitis,cases with anemia,cases with peripheral neurotoxicity,cases with neutropenia,cases with thrombocytopenia,cases with fatigue,cases with anorexia,cases with abnormal liver function,cases with hypothyroidism were 24,22,21,20,18,16,16,13,10,9,2 in the 30 patients during the preoperative short-course radiotherapy followed by sequential chemotherapy combined with anti-PD-1 antibody therapy.Cases with the above adverse events were improved after symptomatic treatment.(3)Preoperative evaluation and surgical situations.Seven of the 30 patients were in clinical complete remission after preoperative multidisciplinary evaluation and the other 23 patients were not in clinical complete remission.Twenty-seven of the 30 patients underwent laparoscopic radical resection of rectal cancer and 3 patients not undergoing the sequential chemotherapy combined with anti-PD-1 antibody therapy did not undergo surgery.The time interval between ending of chemotherapy combined with anti-PD-1 antibody therapy and the surgery of the 27 patients were 14(range,5-141)days.Of the 27 cases,there were 13 cases and 14 cases with 0 and 1 of the preoperative Eastern Cooperative Oncology Group score,respectively,and there were 24 cases undergoing low anterior proctectomy and 3 cases undergoing abdominoperineal excision.The operation time and volume of intra-operative blood loss of the 27 cases were(182±36)minutes and 30(range,10-150)mL,respectively.Of the 27 cases,there were 16 cases with protective ileostomy and 24 cases with anal preservation.(4)Postoperative situations and pathological examinations.The time to postoperative first flatus,time to postoperative initial liquid food intake and duration of postoperative hospital stay of the 27 patients undergoing surgery were 2(range,1-4)days,3(range,2-5)days and 8(range,7-16)days,respectively.Five of the 27 patients had postoperative gradeⅠ-Ⅱcomplications,including 2 cases with incision infection,1 case with abdominal infection,1 case with incision hemorrhage and 1 case with venous thrombosis in left lower limb intermuscular.Cases with postoperative complica-tions were improved after symptomatic treatment.Results of postoperative pathological examina-tion showed that the rate of pathologic complete response in 27 patients was 48.1%(13/27).Of the 27 cases,cases in grade 0,grade 1,grade 2,grade 3 of the tumor regression grading were 13,5,7,2,respectively,cases in stage T0,stage Tis,stage T2,stage T3 of the tumor T staging were 13,1,5,8,respectively,cases in stage N0,stage N1,stage N2 of the tumor N staging were 19,6,2,respectively,cases in stage 0,stageⅠ,stageⅡ,stageⅢof the tumor TNM staging were 14,0,5,8,respectively.The number of lymph node dissected of the 27 patients was 15(range,3-29).Of the 27 patients,there was 1 case with positive circumferential margin and 26 cases achieving R0 resection.None of the 27 patients underwent secondary operation or perioperative death.(5)Postoperative adjuvant chemotherapy and follow-up.Of the 27 patients undergoing surgery,21 cases underwent post-operative adjuvant chemotherapy,with the cycles of 4(range,1-6).All the 27 patients were followed up for 20(range,20-29)months.During the follow-up,3 cases not achieving pathological complete response had tumor recurrence and no patient died.The disease free survival rate of the 27 patients was 88.9%.Conclusion Laparoscopic surgery after short-course radiotherapy followed by sequential chemotherapy combined with immunotherapy for locally advanced rectal cancer is safe and feasible,with satisfied short-term efficacy.