短程放疗联合CAPOX和PD-1单抗用于局部进展期直肠癌全程新辅助治疗的前瞻性多中心随机二期临床研究(TORCH)——单中心初步结果分析  

Short-course radiotherapy combined with CAPOX and PD-1 inhibitor for the total neoadjuvant therapy of locally advanced rectal cancer:the preliminary single-center findings of a prospective,multicentre,randomized phase II trial(TORCH)

作　　者：王雅琪[1,2,3,4] 申丽君 万觉锋[1,2,3,4] 张慧 王雁 吴显[1,2,3,4] 王靖雯 王人杰[2,5] 孙轶群 童彤 黄丹 王磊 盛伟琪[2,7] 张迅 蔡国响[2,5] 徐烨 蔡三军[2,5] 章真 夏凡[1,2,3,4] Wang Yaqi;ShenLijun;Wan Juefeng;Zhang Hui;WanYgan;Wu Xian;Wang Jingwen;Wang Renjie;Sun Yiqun;Tong Tong;Huang Dan;Wang Lei;Sheng Weiqi;Zhang Xun;Cai Guoxiang;Xu Ye;Cai Sanjun;Zhang Zhen;Xia Fan(Department of Radiation Oncology,Fudan University Shanghai Cancer Center,Shanghai 200032,China;Department of Oncology,Shanghai Medical College,Fudan University,Shanghai 200032,China;Shanghai Key Laboratory of Radiation Oncology,Shanghai 200032,China;Shanghai Clinical Research Center for Radiation Oncology,Shanghai 200032,China;Department of Colorectal Surgery,Fudan University Shanghai Cancer Center,Shanghai 200032,China;°Department of Radiology,Fudan University Shanghai Cancer Center,Shanghai 200032,China;Department of Pathology,Fudan University Shanghai Cancer Center,Shanghai 200032,China;Department of Ultrasound,Fudan University Shanghai Cancer Center,Shanghai 200032,China)

机构地区：[1]复旦大学附属肿瘤医院放射治疗中心,上海200032 [2]复旦大学上海医学院肿瘤学系,上海200032 [3]上海市放射肿瘤学重点实验室,上海200032 [4]上海市放射治疗临床医学研究中心,上海200032 [5]复旦大学附属肿瘤医院大肠外科,上海200032 [6]复旦大学附属肿瘤医院放射诊断科,上海200032 [7]复旦大学附属肿瘤医院病理科,上海200032 [8]复旦大学附属肿瘤医院超声科,上海200032

出　　处：《中华胃肠外科杂志》2023年第5期448-458,共11页Chinese Journal of Gastrointestinal Surgery

基　　金：国家自然科学基金(82003229)。

摘　　要：目的对于局部进展期直肠癌(LARC,T3~4或N+M0)患者,全程新辅助治疗(TNT)已被证实可提高肿瘤退缩率,尽早控制远处转移。取得临床完全缓解(cCR)的患者有机会采取等待观察策略,实现器官功能保留(保肛)。相较于常规分割放疗,大分割放疗和免疫治疗具有更好的协同作用,有助于增加微卫星稳定(MSS)结直肠癌对免疫治疗的敏感性。因此,本研究旨在探索短程放疗为基础的TNT模式联合免疫治疗,是否能进一步提高LARC患者的肿瘤退缩。方法这是一项前瞻性多中心随机二期临床研究(TORCH研究注册号:NCT04518280)的单中心初步结果分析,纳入肿瘤距肛缘10 cm的LARC患者,随机分为巩固组和诱导组。巩固组先行短程放疗(25 Gy/5 Fx),再进行6程CAPOX化疗(奥沙利铂+卡培他滨)和特瑞普利单抗治疗;诱导组先行2程CAPOX化疗和特瑞普利单抗治疗,再行短程放疗,再行4程上述化疗+免疫治疗,最后行全直肠系膜切除(TME)术,达到cCR的患者可选择等待观察策略。主要研究终点是完全缓解(CR)率,即病理完全缓解率(pCR率)+持续超1年的cCR率。次要研究终点为不良反应发生情况。结果截至2022年9月30日,复旦大学附属肿瘤医院前瞻性入组62例患者(巩固组34例,诱导组28例);中位年龄53(27~69)岁;MSS或错配修复完整(pMMR)型59例(95.2%),仅3例为微卫星高度不稳定(MSI-H)或错配修复缺陷(dMMR);肿瘤Ⅲ期患者55例(88.7%)。肿瘤距肛缘距离≤5 cm者占77.4%(48/62),cT4期者占11.3%(7/62),肿瘤侵犯直肠系膜筋膜者占27.4%(17/62),cN2期者占41.9%(26/62)和肿瘤侵犯壁外血管浸润者占17.7%(11/62)。全部62例患者均完成短程放疗和≥5程的化疗免疫治疗,6程化疗免疫完成率为83.9%(52/62)。疗效评估显示,共29例患者达到了cCR(46.8%,29/62),其中18例采取了等待观察策略。共32例接受了TME手术,其中18例pCR,4例TRG 1分,10例TRG 2~3分。3例MSI-H患者均获得cCR;其中1例术后病理为pObjective Total neoadjuvant therapy has been used to improve tumor responses and prevent distant metastases in patients with locally advanced rectal cancer(LARC).Patients with complete clinical responses(cCR)then have the option of choosing a watch and wait(W&W)strategy and organ preservation.It has recently been shown that hypofractionated radiotherapy has better synergistic effects with PD-1/PD-L1 inhibitors than does conventionally fractionated radiotherapy,increasing the sensitivity of microsatellite stable(MSS)colorectal cancer to immunotherapy.Thus,in this trial we aimed to determine whether total neoadjuvant therapy comprising short-course radiotherapy(SCRT)combined with a PD-1 inhibitor improves the degree of tumor regression in patients with LARC.Methods TORCH is a prospective,multicenter,randomized,phase II trial(TORCH Registration No.NCT04518280).Patients with LARC(T3-4/N+M0,distance from anus≤10 cm)are eligible and are randomly assigned to consolidation or induction arms.Those in the consolidation arm receive SCRT(25Gy/5 Fx),followed by six cycles of toripalimab plus capecitabine and oxaliplatin(ToriCAPOX).Those in the induction arm receive two cycles of ToriCAPOX,then undergo SCRT,followed by four cycles of ToriCAPOX.Patients in both groups undergo total mesorectal excision(TME)or can choose a W&W strategy if cCR has been achieved.The primary endpoint is the complete response rate(CR,pathological complete response[pCR]plus continuous cCR for more than 1 year).The secondary endpoints include rates of Grade 3–4 acute adverse effects(AEs)etc.Results Up to 30 September 2022,62 patients attending our center were enrolled(Consolidation arm:34,Induction arm:28).Their median age was 53(27–69)years.Fifty-nine of them had MSS/pMMR type cancer(95.2%),and only three MSI-H/dMMR.Additionally,55 patients(88.7%)had Stage III disease.The following important characteristics were distributed as follows:lower location(≤5 cm from anus,48/62,77.4%),deeper invasion by primary lesion(cT47/62,11.3%;mesorectal fascia

关 键 词：直肠肿瘤 局部进展期 短程放疗 免疫治疗 全程新辅助治疗 肿瘤完全退缩 等待观察 不良反应 

分 类 号：R735.37[医药卫生—肿瘤]