PDF(Pubmed)
Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：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，有助于肿瘤免疫逃避。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抑制剂对早期和中期微卫星高不稳定性(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选择。
方法：截至2024年3月，对临床试验注册（Clinicaltrials.gov和EU临床试验注册）和PubMed/Medline数据库中PD-1/PD-L1抑制剂早期和中期MSI-H和MSSCRC的临床试验进行了范围审查。
结果：共纳入19项与早期至中期MSH-I或MSSCRC相关的试验。其中,6项试验处于招募状态，3个试验正在进行中，不是招募状态，3个试验完成,1次审判终止,1个试验未知。其中,9项试验涉及MSI-H型CRC，10项试验涉及MSS类型CRC。临床前I/II期试验占主导地位，只有3个临床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类型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。至于主要结果指标，4项试验选择病理完全缓解率，3项试验选择无进展生存率，3项试验选择客观反应率，3项试验选择总体生存率，4项试验选择无病生存率，1项试验选择临床完全缓解率，1项试验选择了具有剂量限制性毒性的参与者的百分比。
结论：对于早期和中期MSI-H和MSSCRC，PD-1/PD-L1抑制剂已显示出一定的治疗效果，I/II期研究证明了这一点。然而,当代试验设计表现出异质性，纳入标准相对较少，使用各种药物组合和方案，以及报告终点的显著差异。然而，更多的双臂，多中心，仍需要随机对照试验来证实免疫治疗的疗效.
方法：截至2024年3月，对临床试验注册（Clinicaltrials.gov和EU临床试验注册）和PubMed/Medline数据库中PD-1/PD-L1抑制剂早期和中期MSI-H和MSSCRC的临床试验进行了范围审查。
结果：共纳入19项与早期至中期MSH-I或MSSCRC相关的试验。其中,6项试验处于招募状态，3个试验正在进行中，不是招募状态，3个试验完成,1次审判终止,1个试验未知。其中,9项试验涉及MSI-H型CRC，10项试验涉及MSS类型CRC。临床前I/II期试验占主导地位，只有3个临床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类型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。至于主要结果指标，4项试验选择病理完全缓解率，3项试验选择无进展生存率，3项试验选择客观反应率，3项试验选择总体生存率，4项试验选择无病生存率，1项试验选择临床完全缓解率，1项试验选择了具有剂量限制性毒性的参与者的百分比。
结论：对于早期和中期MSI-H和MSSCRC，PD-1/PD-L1抑制剂已显示出一定的治疗效果，I/II期研究证明了这一点。然而,当代试验设计表现出异质性，纳入标准相对较少，使用各种药物组合和方案，以及报告终点的显著差异。然而，更多的双臂，多中心，仍需要随机对照试验来证实免疫治疗的疗效.
