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中华结直肠疾病电子杂志 ›› 2021, Vol. 10 ›› Issue (04) : 404 -408. doi: 10.3877/cma.j.issn.2095-3224.2021.04.012

综述

新辅助免疫治疗:dMMR/MSI-H局部进展期结直肠癌患者的“黎明之光”
张旋1, 武涛1, 李进莎1, 李国钰1, 李权2, 董超3, 李婷1, 杨仁芳1, 李云峰1,()   
  1. 1. 650118 云南省肿瘤医院/昆明医科大学第三附属医院结直肠外科
    2. 650118 云南省肿瘤医院/昆明医科大学第三附属医院分子诊断中心
    3. 650118 云南省肿瘤医院/昆明医科大学第三附属医院肿瘤内科
  • 收稿日期:2020-12-29 出版日期:2021-08-30
  • 通信作者: 李云峰
  • 基金资助:
    国家自然科学基金项目(82060542)

Neoadjuvant immunotherapy: the "light of dawn" in patients with dMMR/MSI-H locally advanced colorectal cancer

Xuan Zhang1, Tao Wu1, Jinsha Li1, Guoyu Li1, Quan Li2, Chao Dong3, Ting Li1, Renfang Yang1, Yunfeng Li1,()   

  1. 1. Department of Colorectal Cancer Surgery, Tumor Hospital of Yunnan Province, the Third Affiliated Hospital of Kunming Medical University, Kunming 650118, China
    2. Center of Molecular Diagnosis, Tumor Hospital of Yunnan Province, the Third Affiliated Hospital of Kunming Medical University, Kunming 650118, China
    3. Department of Oncology, Tumor Hospital of Yunnan Province, the Third Affiliated Hospital of Kunming Medical University, Kunming 650118, China
  • Received:2020-12-29 Published:2021-08-30
  • Corresponding author: Yunfeng Li
引用本文:

张旋, 武涛, 李进莎, 李国钰, 李权, 董超, 李婷, 杨仁芳, 李云峰. 新辅助免疫治疗:dMMR/MSI-H局部进展期结直肠癌患者的“黎明之光”[J]. 中华结直肠疾病电子杂志, 2021, 10(04): 404-408.

Xuan Zhang, Tao Wu, Jinsha Li, Guoyu Li, Quan Li, Chao Dong, Ting Li, Renfang Yang, Yunfeng Li. Neoadjuvant immunotherapy: the "light of dawn" in patients with dMMR/MSI-H locally advanced colorectal cancer[J]. Chinese Journal of Colorectal Diseases(Electronic Edition), 2021, 10(04): 404-408.

局部进展期结直肠癌(LACRC)患者术后复发转移风险较高。而新辅助治疗一定程度上有助于改善其预后。但错配修复缺陷(dMMR)/高度微卫星不稳定(MSI-H)LACRC对新辅助(放)化疗敏感性仍然较低,突破这一困境亟待解决。免疫治疗的“横空出世”为该类患者带来了希望的曙光。2013年,免疫治疗被《Science》杂志列为十大科学进展之首。2015年,KEYNOTE-016研究确定了dMMR/MSI-H是免疫治疗疗效的分子标志,从此开创了结直肠癌(CRC)领域免疫治疗的新纪元,更是在精准医学时代开启了精准免疫治疗的新征程。而免疫治疗能否用于LACRC的新辅助治疗成为了临床上关注的热点。2020年发表在《Nature Medicine》上的荷兰单臂NICHE研究,展现出了令人震惊的效果,标志着开启了CRC新辅助免疫治疗的大门,为dMMR/MSI-H LACRC患者开辟了新的治疗道路,并有望引领开拓不同癌种新辅助治疗的全新视角。

Patients with locally advanced colorectal cancer (LACRC) have a higher risk of recurrence and metastasis. Neoadjuvant therapy can improve the prognosis to some extent. However, the sensitivity of mismatch repair defect (dMMR)/microsatellite instability-high (MSI-H) LACRC to neoadjuvant chemotherapy (chemoradiotherapy) is still low. The emergence of immunotherapy brings hope to these patients. Immunotherapy was listed as the top ten scientific progress by Science magazine in 2013. Based on the study of KEYNOTE-016 in 2015, it is confirmed that dMMR/MSI-H is a biomarker for the efficacy of immunotherapy, thus ushering in a novel era of immunotherapy in the field of colorectal cancer(CRC), and opening a new journey of precision immunotherapy in the era of precision medicine. Whether immunotherapy can be used as neoadjuvant treatment of LACRC has become a hot topic in clinic. The Dutch single-arm NICHE study published in Nature Medicine in 2020 has demonstrated shocking results, marking the opening of the door of neoadjuvant immunotherapy for CRC, opening up a new treatment path for patients with dMMR/MSI-H LACRC, and is expected to lead the development of a novel perspective of neoadjuvant therapy for different kinds of cancer.

表1 早中期结直肠癌新辅助免疫治疗临床研究结果
研究 时间 国家 名称 病例数(例) 分期 方案 治疗效果 不良反应
NICHE 2020 荷兰 Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers dMMR 20 pMMR 15 Ⅰ~Ⅲ 1周期ipilimumab(1 mg/kg)d1+2周期nivolumab(3 mg/kg)d1~d5 +根治性手术 dMMR组:病理缓解率100%(20/20),主要病理缓解率95%(19/20),pCR 60%(12/20);pMMR组:病理缓解率27%(4/15),主要病理缓解率20%(3/15) 3~4级免疫相关不良事件的发生率为13%;手术相关不良反应(吻合口漏)10%
VOLTAGE 2020 日本 Short-term results of VOLTAGE-A:Nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer

MSS(A1组)37

MSI-H(A2组)5

先卡培他滨联合放疗(50.4 Gy)→放疗结束后评估肿瘤未进展者则入组→放疗至手术间歇期行5个疗程;Nivolumab治疗(3个疗程后复查无进展者再行2个疗程Nivolumab)→末次免疫治疗后行根治性手术 MSS(A1组):TRG0-1级38%(14/37),TRG-1级8%(3/37),pCR 30%(11/37)。另有1例达到cCR行等待观察;MSI-H(A2组):pCR 60%(3/5) 可出现3级肌无力,间质性肾炎和2级周围运动神经病变,但均能缓解且不影响后续手术
NRG-GI002 2021 美国 NRG-GI002:A phase Ⅱ clinical trial platform using total neoadjuvant therapy(TNT)in locally advanced rectal cancer(LARC)-Pembrolizumab experimental arm(EA)primary results.

对照组 68

Pembrolizumab组 69

Ⅱ/Ⅲ 新辅助FOLFOX*4个月→化放疗(50.4 Gy,卡培他滨+/-Pembrolizumab 200 mg q3w*6周期)→放疗后8~12周行根治性手术 NAR评分:对照组 vs.Pembrolizumab组=14.08 vs.11.53(P=0.26);pCR:对照组vs.Pembrolizumab组=9.4% vs.31.9%(P=0.75);cCR:对照组vs.Pembrolizumab组=13.6% vs.13.9%(P=0.95);保留括约肌手术:对照组 vs.Pembrolizumab组=71.0% vs.59.4%(P=0.15) Pembrolizumab组3~4级不良反应:放化疗期间vs.治疗后=48.2% vs.37.3%
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