[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)].

Objective: 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 (cT4 7/62, 11.3%; mesorectal fascia involved 17/62, 27.4%), and high risk of distant metastasis (cN2 26/62, 41.9%; EMVI+ 11/62, 17.7%). All 62 patients completed the SCRT and at least five cycles of ToriCAPOX, 52/62 (83.9%) completing six cycles of ToriCAPOX. Finally, 29 patients achieved cCR (46.8%, 29/62), 18 of whom decided to adopt a W&W strategy. TME was performed on 32 patients. Pathological examination showed 18 had achieved pCR, four TRG 1, and 10 TRG 2-3. The three patients with MSI-H disease all achieved cCR. One of these patients was found to have pCR after surgery whereas the other two adopted a W&W strategy. Thus, the pCR and CR rates were 56.2% (18/32) and 58.1% (36/62), respectively. The TRG 0-1 rate was 68.8% (22/32). The most common non-hematologic AEs were poor appetite (49/60, 81.7%), numbness (49/60, 81.7%), nausea (47/60, 78.3%) and asthenia (43/60, 71.7%); two patients did not complete this survey. The most common hematologic AEs were thrombocytopenia (48/62, 77.4%), anemia (47/62, 75.8%), leukopenia/neutropenia (44/62, 71.0%) and high transaminase (39/62, 62.9%). The main Grade III-IV AE was thrombocytopenia (22/62, 35.5%), with three patients (3/62, 4.8%) having Grade IV thrombocytopenia. No Grade V AEs were noted. Conclusions: SCRT-based total neoadjuvant therapy combined with toripalimab can achieve a surprisingly good CR rate in patients with LARC and thus has the potential to offer new treatment options for organ preservation in patients with MSS and lower-location rectal cancer. Meanwhile, the preliminary findings of a single center show good tolerability, the main Grade III-IV AE being thrombocytopenia. The significant efficacy and long-term prognostic benefit need to be determined by further follow-up.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pCR，2例采取了等待观察策略。初步疗效显示：pCR率和CR率分别为56.2%（18/32）和58.1%（36/62），肿瘤退缩分级（TRG）0~1分者占比为68.8%（22/32）。最常见的非血液学不良反应是缺乏食欲（49/60，81.7%）、手足麻木（49/60，81.7%）、恶心（47/60，78.3%）和乏力（43/60，71.7%），有2例患者未填写该问卷。血液学不良反应以血小板下降（48/62，77.4%）、血红蛋白下降（47/62，75.8%）、白细胞或中性粒细胞下降（44/62，71.0%）和转氨酶增高（39/62，62.9%）为主。其中Ⅲ~Ⅳ级不良反应主要是血小板下降（22/62，35.5%），3例（3/62，4.8%）患者出现Ⅳ级血小板下降，未观察到Ⅴ级不良反应。 结论： 对于LARC患者，短程放疗联合CAPOX和PD-1单抗的TNT模式可获得令人惊喜的高CR率，有望为MSS和低位直肠癌患者获得器官保留提供新选择。单中心初步结果显示方案耐受性较好，主要Ⅲ~Ⅳ级不良反应为血小板下降。上述显著的肿瘤退缩疗效和长期预后获益仍需进一步随访。.