Gu Meichen, Guo Yuchen, He Liang, Sun Xuan, Liang Tingting, Wang Zhuo, Li Ying, Liu Zheng, Wang Jingyu, Qiu Xiang, Guo Liang, Chang Pengyu, Wang Quan
Radiation Oncology and Therapy Department, First Hospital of Jilin University, Changchun, China.
Gastric and Colorectal Surgery Department, General Surgery Center, First Hospital of Jilin University, Changchun, China.
Front Oncol. 2025 Aug 8;15:1594927. doi: 10.3389/fonc.2025.1594927. eCollection 2025.
BACKGROUND: Neoadjuvant chemoradiotherapy has become the standard treatment for mid-to-low location LARC. Recently, total neoadjuvant therapy (TNT) has been used in patients with 'high-risk' or 'very high-risk' LARC according to ESMO guideline (2017). TNT not only increases the pathological complete response (pCR) rate, but also provides patients with more opportunities to preserve organ function. However, TNT mode seems to have reached a plateau. Some clinical studies published in recent years have also confirmed that different modes of neoadjuvant chemoradiotherapy combined with ICIs can further improve the pCR rate to varying degrees. It is necessary to explore an appropriate treatment mode for patients with mid-to-low location, who are unresectable or difficult to achieve R0 resection at the initial stage of surgery and have a strong desire to preserve anal cavity. Numerous basic researches have demonstrated that radiotherapy can remodel the tumor immune microenvironment and play a potential synergistic effect on ICIs. Therefore, this study will aim to explore whether TNT combined with ICIs could improve pCR rates in patients with 'high-risk' or 'very high-risk' LARC. METHODS: This prospective, single-center, single-arm phase II trial aims to assess the pCR rate of neoadjuvant long-course concurrent chemoradiotherapy sequential 6 cycles CapeOX regimen combined with sintilimab in 'high-risk/very high-risk' LARC patients with mid-to-low location and with pMMR phenotype. The primary endpoint for this study is the pCR rate. Secondary endpoints include 2-year sustained of clinical complete response (cCR) rate; CR rate (the rate of patients with sustained cCR for 2 years and pCR); major pathological remission; neoadjuvant rectal score; 3-year non-regrowth disease free survival; 3-year disease-free survival; 3-year overall survival; 3-year localized recurrence-free survival; 3-year distant metastasis free survival; 3-year stoma-free survival, anal sphincter preservation rate; surgical R0 resection rate and safety (adverse events during neoadjuvant therapy and 30 days after surgery, as well as tolerance). DISCUSSION: This study will investigate whether neoadjuvant long-course concurrent chemoradiotherapy sequential total neoadjuvant chemotherapy combined with immunotherapy could further enhances tumor pCR rate in 'high-risk/very high-risk' LARC patients with mid-to-low location and with pMMR phenotype and is expected to improve prognosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT05998122.
背景：新辅助放化疗已成为中低位局部晚期直肠癌（LARC）的标准治疗方法。最近，根据欧洲肿瘤内科学会（ESMO）指南（2017年），全新辅助治疗（TNT）已用于“高危”或“极高危”LARC患者。TNT不仅提高了病理完全缓解（pCR）率，还为患者提供了更多保留器官功能的机会。然而，TNT模式似乎已达到平台期。近年来发表的一些临床研究也证实，不同模式的新辅助放化疗联合免疫检查点抑制剂（ICIs）可不同程度地进一步提高pCR率。对于中低位、初始手术时不可切除或难以实现R0切除且有强烈保留肛门腔意愿的患者，有必要探索一种合适的治疗模式。大量基础研究表明，放疗可重塑肿瘤免疫微环境，并对ICIs发挥潜在的协同作用。因此，本研究旨在探讨TNT联合ICIs是否能提高“高危”或“极高危”LARC患者的pCR率。 方法：本前瞻性、单中心、单臂II期试验旨在评估新辅助长程同步放化疗序贯6周期 CapeOX方案联合信迪利单抗在中低位、pMMR表型的“高危/极高危”LARC患者中的pCR率。本研究的主要终点是pCR率。次要终点包括2年临床完全缓解（cCR）持续率；CR率（cCR持续2年且为pCR的患者比例）；主要病理缓解；新辅助直肠评分；3年无瘤生存；3年无病生存；3年总生存；3年局部无复发生存；3年远处无转移生存；3年无造口生存、肛门括约肌保留率；手术R0切除率及安全性（新辅助治疗期间及术后30天的不良事件，以及耐受性）。 讨论：本研究将调查新辅助长程同步放化疗序贯全新辅助化疗联合免疫治疗是否能进一步提高中低位、pMMR表型的“高危/极高危”LARC患者的肿瘤pCR率，并有望改善预后。 试验注册：ClinicalTrials.gov NCT05998122
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