[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)].
[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)].
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DOI：
10.3760/cma.j.cn441530-20230107-00010
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发表时间：
2023-05-25
影响因子：
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通讯作者：
Xia, F
中科院分区：
文献类型：
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作者：
Wang, Y Q;Shen, L J;Xia, F
目的：全面新辅助治疗已被用于改善局部晚期直肠癌（LARC）患者的肿瘤反应和预防远处转移。有完全临床反应（cCR）的患者可以选择观察和等待（W&W）策略和器官保存。最近有研究表明，与传统的分割放疗相比，低分割放疗与PD-1/PD-L1抑制剂具有更好的协同作用，增加了微卫星稳定型（MSS）结直肠癌对免疫治疗的敏感性。因此，在本试验中，我们旨在确定由短程放疗（SCRT）联合PD-1抑制剂组成的总新辅助治疗是否能改善LARC患者的肿瘤消退程度。方法：TORCH是一项前瞻性、多中心、随机、II期临床试验(TORCH注册号：NCT04518280)。LARC患者（T3-4/N+M0，距离肛门≤10 cm）符合条件，随机分配到巩固组或诱导组。巩固组接受SCRT (25Gy/ 5fx)，随后是6个周期的托帕里单抗加卡培他滨和奥沙利铂（ToriCAPOX）。诱导组接受两个周期的ToriCAPOX，然后接受SCRT，随后接受四个周期的ToriCAPOX。两组患者均行全肠系膜切除术（TME），如果达到cCR，则可选择W&W策略。主要终点是完全缓解率（CR，病理完全缓解[pCR]加上持续1年以上的cCR）。次要终点包括3-4级急性不良反应（ae）率等。结果：截至2022年9月30日，共有62例患者入组（巩固组34例，诱导组28例）。他们的中位年龄为53岁（27-69岁）。MSS/pMMR型癌59例（95.2%），MSI-H/dMMR型癌仅3例。此外，55名患者（88.7%）为III期疾病。以下重要特征分布如下：位置较低（距肛门≤5 cm， 48/62, 77.4%），原发灶浸润较深（cT4 7/62, 11.3%；累及直肠系膜筋膜17/62,27.4%），远处转移风险高（cN2 26/62, 41.9%; EMVI+ 11/62, 17.7%）。所有62例患者均完成了SCRT和至少5个周期的ToriCAPOX， 52/62（83.9%）完成了6个周期的ToriCAPOX。最终，29例患者达到cCR(46.8%, 29/62)，其中18例患者决定采用W&W策略。32例患者行TME手术。病理检查显示pCR阳性18例，TRG 1阳性4例，TRG 2-3阳性10例。3例MSI-H患者均达到cCR。其中一名患者在手术后发现了pCR，而其他两名患者采用了W&W策略。pCR和CR分别为56.2%（18/32）和58.1%（36/62）。TRG 0-1率为68.8%（22/32）。最常见的非血液学ae为食欲不振（49/60,81.7%）、麻木（49/60,81.7%）、恶心（47/60,78.3%）和乏力（43/60,71.7%）；2例患者未完成此项调查。最常见的血液学ae是血小板减少（48/62,77.4%）、贫血（47/62,75.8%）、白细胞减少/中性粒细胞减少（44/62,71.0%）和高转氨酶（39/62,62.9%）。III-IV级AE主要为血小板减少症（22/62,35.5%），其中3例（3/62,4.8%）为IV级血小板减少症。未发现V级ae。结论：基于scrt的全新辅助治疗联合torpalimab可以在LARC患者中获得令人惊讶的良好CR率，因此有可能为MSS和下位直肠癌患者的器官保存提供新的治疗选择。同时，单中心初步结果显示耐受性良好，主要的III-IV级AE为血小板减少症。显著的疗效和长期预后益处需要通过进一步的随访来确定。
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.