Department of General Surgery, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China.
Int J Colorectal Dis. 2024 May 29;39(1):83. doi: 10.1007/s00384-024-04654-3.
Programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are important immune checkpoint molecules that contribute to tumor immune evasion. However, the main treatment modalities for patients with early and intermediate stage colorectal cancer (CRC) are surgery, and the role of PD-1/PD-L1 inhibitors in these patients is not yet clear. Therefore, this study aims to review the treatment progress of PD-1/PD-L1 inhibitors for early- and intermediate-stage microsatellite high-instability (MSI-H) and stable (MSS) colorectal cancer, in order to provide more options for patients with early- and intermediate-stage colorectal cancer.
A scoping review of clinical trial registries ( Clinicaltrials.gov and EU clinical trial registers) and PubMed/Medline database of trials on PD-1/PD-L1 Inhibitors for early and middle-stage MSI-H and MSS CRC was done up to March 2024.
A total of 19 trials related to early to mid-stage MSH-I or MSS CRC were included. Among them, 6 trials are in recruiting status, 3 trials are in active, not recruiting status, 3 trials are completed, 1 trial is terminated, and 1 trial is unknown. Of these, 9 trials involve MSI-H type CRC, and 10 trials involve MSS type CRC. Preclinical phase I/II trials are predominant, with only 3 clinical phase III trials. In trials related to MSI-H type CRC, 4 studies involve PD-1/PD-L1 inhibitors combined with neoadjuvant therapy, and 5 studies involve combination therapy. In trials related to MSS type CRC, 3 studies involve PD-1/PD-L1 inhibitors combined with targeted therapy, 2 studies involve PD-1/PD-L1 inhibitors combined with chemotherapy, 1 study involves PD-1/PD-L1 inhibitor combined immunotherapy, 1 study involves PD-1/PD-L1 inhibitors combined with bacterial therapy, and 3 studies involve PD-1/PD-L1 inhibitors combined with comprehensive therapy. As for primary outcome measures, 4 trials select pathological complete response rates, 3 trials select progression-free survival rate, 3 trials select objective response rate, 3 trials select overall survival rate, 4 trials select disease-free survival rate, 1 trial selects clinical complete response rate, and 1 trial selects percentage of participants with a dose-limiting toxicity.
For early- and middle-stage MSI-H and MSS CRC, PD-1/PD-L1 inhibitors have shown some therapeutic efficacy, as evidenced by phase I/II studies. However, contemporary trial designs exhibit heterogeneity, with relatively few inclusion criteria, the use of various drug combinations and regimens, and significant variations in reported endpoints. Nevertheless, more double-arm, multicenter, randomized controlled trials are still needed to confirm the efficacy of immunotherapy.
程序性细胞死亡受体 1（PD-1）和程序性细胞死亡配体 1（PD-L1）是重要的免疫检查点分子，有助于肿瘤免疫逃逸。然而，早期和中期结直肠癌（CRC）患者的主要治疗方式是手术，PD-1/PD-L1 抑制剂在这些患者中的作用尚不清楚。因此，本研究旨在综述 PD-1/PD-L1 抑制剂治疗早期和中期微卫星高度不稳定（MSI-H）和稳定（MSS）结直肠癌的治疗进展，为早期和中期结直肠癌患者提供更多的治疗选择。
对临床研究注册库（Clinicaltrials.gov 和欧盟临床试验注册库）和 PubMed/Medline 数据库中关于 PD-1/PD-L1 抑制剂治疗早期和中期 MSI-H 和 MSS CRC 的试验进行了范围界定综述，检索时间截至 2024 年 3 月。
共纳入 19 项与早期至中期 MSH-I 或 MSS CRC 相关的试验。其中，6 项试验正在招募中，3 项试验处于活跃但不招募状态，3 项试验已完成，1 项试验已终止，1 项试验状态未知。其中，9 项试验涉及 MSI-H 型 CRC，10 项试验涉及 MSS 型 CRC。以临床前的 I/II 期试验为主，仅有 3 项临床 III 期试验。在与 MSI-H 型 CRC 相关的试验中，4 项研究涉及 PD-1/PD-L1 抑制剂联合新辅助治疗，5 项研究涉及联合治疗。在与 MSS 型 CRC 相关的试验中，3 项研究涉及 PD-1/PD-L1 抑制剂联合靶向治疗，2 项研究涉及 PD-1/PD-L1 抑制剂联合化疗，1 项研究涉及 PD-1/PD-L1 抑制剂联合免疫治疗，1 项研究涉及 PD-1/PD-L1 抑制剂联合细菌治疗，3 项研究涉及 PD-1/PD-L1 抑制剂联合综合治疗。在主要疗效评估指标方面，4 项试验选择了病理完全缓解率，3 项试验选择了无进展生存期，3 项试验选择了客观缓解率，3 项试验选择了总生存期，4 项试验选择了无病生存期，1 项试验选择了临床完全缓解率，1 项试验选择了剂量限制毒性发生率的参与者百分比。
对于早期和中期 MSI-H 和 MSS CRC，PD-1/PD-L1 抑制剂在 I/II 期研究中显示出一定的疗效。然而，目前的试验设计存在异质性，纳入标准相对较少，药物组合和方案使用多种多样，报告的终点差异较大。尽管如此，仍需要更多的双盲、多中心、随机对照试验来证实免疫治疗的疗效。
