Department of Radiation Oncology, Zhejiang Cancer Hospital, 310022, Hangzhou, Zhejiang, China.
Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), 310022, Hangzhou, Zhejiang, China.
BMC Cancer. 2024 Jan 10;24(1):57. doi: 10.1186/s12885-024-11829-2.
Anus preservation has been a challenge in the treatment of patients with low rectal adenocarcinoma (within 5 cm from the anal verge) because it is difficult to spare the anus with its functioning sphincter complex under the safe margin of tumour resection. Patients with dMMR/MSI-H can achieve a favourable complete response (CR) rate by using a single immune checkpoint inhibitor. For patients with pMMR/MSS/MSI-L, intensified neoadjuvant three-drug chemotherapy may be the preferred option for anal preservation. In addition, the watch and wait (W&W) strategy has been proven safe and feasible for patients with rectal cancer who achieve a clinical complete response (cCR). Therefore, we initiated this clinical trial to explore the optimal neoadjuvant treatment pattern for patients with low locally advanced rectal cancer (LARC) with different MMR/MSI statuses, aiming to achieve a higher cCR rate with the W&W strategy and ultimately provide more patients with a chance of anus preservation.
This is a randomised, controlled, open-label, multicentre phase III trial. Patients with clinical stage T2-4 and/or N + tumours located within 5 cm from the anal verge are considered eligible. Based on the results of pathological biopsy, the patients are divided into two groups: dMMR/MSI-H and pMMR/MSS. Patients in the dMMR/MSI-H group will be randomly allocated in a 1:1 ratio to either arm A (monoimmunotherapy) or arm B (short-course radiotherapy followed by monoimmunotherapy). Patients in the pMMR/MSS group will be initially treated with long-term pelvic radiation with concurrent capecitabine combined with irinotecan. Two weeks after the completion of chemoradiotherapy (CRT), the patients will be randomly allocated in a 1:1 ratio to arm C (XELIRI six cycle regime) or arm D (FOLFIRINOX nine cycle regime). The irinotecan dose will be adjusted according to the UGT1A1-genotype. After treatment, a comprehensive assessment will be performed to determine whether a cCR has been achieved. If achieved, the W&W strategy will be adopted; otherwise, total mesorectal excision (TME) will be performed. The primary endpoint is cCR with the maintenance of 12 months at least, determined using digital rectal examination, endoscopy, and rectal MRI or PET/CT as a supplementary method.
APRAM will explore the best anus preservation model for low LARC, combining the strategies of consolidation chemotherapy, immunotherapy, and short-course radiotherapy, and aims to preserve the anus of more patients using W&W. Our study provides an accurate individual treatment mode based on the MMR/MSI status for patients with low LARC, and more patients will receive the opportunity for anus preservation under our therapeutic strategy, which would transform into long-term benefits.
Clinicaltrials.gov NCT05669092 (Registered 28th Nov 2022).
在治疗低位直肠腺癌（距肛门边缘 5cm 以内）患者时，肛门保留一直是一个挑战，因为在肿瘤切除的安全切缘范围内，很难保留带有功能括约肌复合体的肛门。dMMR/MSI-H 患者可以通过使用单一免疫检查点抑制剂实现有利的完全缓解（CR）率。对于 pMMR/MSS/MSI-L 患者，强化新辅助三联药物化疗可能是保留肛门的首选方案。此外，对于达到临床完全缓解（cCR）的直肠癌患者，观察和等待（W&W）策略已被证明是安全可行的。因此，我们启动了这项临床试验，旨在探索不同 MMR/MSI 状态的低位局部晚期直肠癌（LARC）患者的最佳新辅助治疗模式，以期通过 W&W 策略提高 cCR 率，并最终为更多患者提供保留肛门的机会。
这是一项随机、对照、开放标签、多中心 III 期临床试验。临床 T2-4 期和/或位于距肛门边缘 5cm 以内的 N+肿瘤患者被认为符合条件。根据病理活检结果，患者分为两组：dMMR/MSI-H 和 pMMR/MSS。dMMR/MSI-H 组患者将以 1:1 的比例随机分配至 A 臂（单免疫治疗）或 B 臂（短程放疗后单免疫治疗）。pMMR/MSS 组患者将首先接受长程盆腔放疗联合卡培他滨和顺铂。放化疗（CRT）完成后 2 周，患者将以 1:1 的比例随机分配至 C 臂（XELOXIR 六周期方案）或 D 臂（FOLFIRINOX 九周期方案）。根据 UGT1A1 基因型调整伊立替康剂量。治疗后，将进行全面评估，以确定是否达到 cCR。如果达到，将采用 W&W 策略；否则，将进行全直肠系膜切除术（TME）。主要终点是至少维持 12 个月的 cCR，通过数字直肠检查、内镜和直肠 MRI 或 PET/CT 确定，后两者作为补充方法。
APRAM 将探索联合巩固化疗、免疫治疗和短程放疗的低位 LARC 最佳肛门保留模型，旨在通过 W&W 为更多患者保留肛门。我们的研究为低位 LARC 患者提供了基于 MMR/MSI 状态的精确个体化治疗模式，更多患者将在我们的治疗策略下获得保留肛门的机会，这将转化为长期获益。
Clinicaltrials.gov NCT05669092（2022 年 11 月 28 日注册）。
