直肠癌新辅助免疫治疗相关不良反应分析:一项全国多中心回顾性研究

Adverse events of neoadjuvant immunotherapy for rectal cancer:a nationwide multicenter retrospective study

目的分析直肠癌病人接受新辅助免疫检查点抑制剂(ICIs)治疗发生免疫相关不良反应(irAEs)情况,并探讨其管理策略。方法回顾性分析2020年9月至2024年3月全国7家中心收治的100例接受新辅助免疫治疗后发生irAEs的直肠癌病人的临床资料。收集并分析基线资料、新辅助治疗方案、irAEs诊断及治疗情况、手术情况及随访资料。结果新辅助治疗期间,irAEs的总发作次数为141次,32例(32%)病人发生irAEs次数>1次。irAEs主要发生在内分泌系统、肝脏、皮肤、胃肠道和骨关节与肌肉,分别为41次、33次、29次、17次和7次,中位发生时间分别为31、18、12、32.5、29 d。Ⅰ、Ⅱ级irAEs发生131次(92.9%),经保守治疗、对症处理后好转;≥Ⅲ级的irAEs发生10次(7.1%),经多学科综合治疗协作组(MDT)评估后,予糖皮质激素、免疫抑制剂等治疗后好转,其中7例病人永久停止ICIs治疗,3例病人继续ICIs治疗。irAEs严重程度与是否联合放疗无关(P=0.858)。5例(5%)病人出现延迟性irAEs。新辅助治疗后3例(3%)临床完全缓解病人行等待观察策略,97例(97%)病人行手术治疗。发生手术相关并发症11例(11.3%)。术后中位随访时间为12个月,97例(97%)病人无病生存,1例(1%)病人出现肿瘤复发,2例(2%)病人出现肿瘤远处转移。结论直肠癌新辅助免疫治疗中存在发生1次或多次irAEs的可能,且内分泌系统、肝脏和皮肤是最常受累的系统或器官。多数irAEs可通过对症治疗缓解。对于发生≥Ⅲ级irAEs的病人,应通过MDT讨论制定诊疗计划,且多数病人需永久停用ICIs。另外,irAEs严重程度与是否联合放疗无关,经过治疗后的irAEs并不影响病人手术安全,但须警惕irAEs延迟发生。

To analyze the immune-related adverse events(irAEs)and their management strategies in patients with rectal cancer receiving neoadjuvant immune checkpoint inhibitors(ICIs)therapy.Methods We conducted a retrospective study,including 100 rectal cancer patients who underwent irAEs after neoadjuvant immune therapy between September 2020 and March 2024 at seven centers nationwide.Baseline data,neoadjuvant treatment regimens,irAEs diagnosis and treatment,surgical outcomes,and follow-up information were collected.Results During neoadjuvant treatment,there were a total of 141 episodes of irAEs,with 32 patients(32%)experiencing more than one irAE.irAEs mainly occurred in the endocrine system,liver,skin,gastrointestinal tract,and musculoskeletal system,with 41,33,29,17and 7 times,respectively,and the median time of irAEs occurrence in each system was 31,18,12,32.5 and 29 days,respectively.Grade I andⅡirAEs occurred 131 times(92.9%),which could be managed with conservative treatment and symptomatic management.Grade III and above irAEs occurred 10 times(7.1%),and after evaluation by a multi-disciplinary team(MDT),applying treatment such as glucocorticoids,immunosuppressants,and so on,ameliorated irAEs.Among them,7 patients permanently discontinued ICIs treatment,and 3 patients continued ICIs treatment.The severity of irAEs was not associated with whether patients received combined radiotherapy(P=0.858).Delayed irAEs occurred in 5 cases(5%).3 patients(3%)with clinical complete remission after neoadjuvant treatment opted for Watch&Wait strategy,while 97 patients(97%)underwent surgical treatment.11 cases(11.3%)had surgery-related complications.The median follow-up time after surgery was 12 months.Among the cases,97 patients(97%)achieved disease-free survival,1 patient(1%)experienced tumor recurrence,and 2 patients(2%)developed distant metastases.Conclusion There is a possibility of one or multiple irAEs occurring in neoadjuvant immunotherapy for rectal cancer,with the endocrine system,liver,and skin being the most commonly affected systems.Most irAEs can be alleviated with symptomatic treatment.For grade III and above irAEs,a MDT should be consulted to develop a diagnosis and treatment plan and most of them need to permanently discontinue ICIs.The severity of irAEs is not related to the usage of combined radiotherapy.After treatment,irAEs did not affect the safety of patients undergoing surgery,but vigilance is needed for delayed onset of irAEs.