Immune checkpoint inhibitors for patients with microsatellite instability-high colorectal cancer: protocol of a pooled analysis of clinical trials

Xiaojun Tang; Xinshu Xu; Ruobing Chen; Mengmeng Zhang; Zubing Mei; Shuangxi Zhang

doi:10.3389/fonc.2023.1331937

Immune checkpoint inhibitors for patients with microsatellite instability-high colorectal cancer: protocol of a pooled analysis of clinical trials

Front Oncol. 2024 Jan 3:13:1331937. doi: 10.3389/fonc.2023.1331937. eCollection 2023.

Authors

Xiaojun Tang¹, Xinshu Xu^{2

3}, Ruobing Chen^{2

3}, Mengmeng Zhang^{2

3}, Zubing Mei^{4

5}, Shuangxi Zhang²

Affiliations

¹ Department of Spinal Surgery, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
² Department of Anorectal Surgery, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China.
³ First Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, Henan, China.
⁴ Department of Anorectal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁵ Anorectal Disease Institute of Shuguang Hospital, Shanghai, China.

Abstract

Introduction: Colorectal cancer (CRC) is the third most common cause of cancer and the second leading cause of cancer-related deaths worldwide. Microsatellite instability-high (MSI-H) is a distinct molecular subtype of CRC that occurs in approximately 15% of all cases. Recently, immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic approach for patients with MSI-H colorectal cancer, exhibiting higher response rates than standard chemotherapies. To assess the effectiveness and safety of ICIs for the treatment of patients with MSI-H CRC, we propose a comprehensive pooled analysis of clinical trial data.

Methods and analysis: A systematic search of multiple electronic databases, including PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov, will be conducted from their inception until September, 2023 to identify eligible randomized controlled trials (RCTs) and non-randomized studies. Inclusion criteria comprise studies of adult patients with histologically confirmed MSI-H CRC treated with immune checkpoint inhibitors, with a comparison to a control group receiving conventional therapies. Outcomes of interest will be overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and incidence of treatment-related adverse events (AEs). The Cochrane Risk of Bias tool and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool will be employed to evaluate the methodological quality of included studies. A random-effects model using the DerSimonian and Laird method will be applied for pooling the effect estimates, calculating hazard ratios (HRs) or risk ratios (RRs) with their corresponding 95% confidence intervals (CIs). Heterogeneity will be assessed using I² statistics, and subgroup analysis and meta-regression will be performed to explore potential effect modifiers in case of substantial heterogeneity. Publication bias will be evaluated with funnel plots and Egger's test. Sensitivity analysis will be conducted to assess the robustness of the results.

Discussion: This meta-analysis will synthesize available evidence from clinical trials on immune checkpoint inhibitors in treating MSI-H colorectal cancer. The findings will offer valuable information about the effectiveness and safety of ICIs in this patient population, contributing to the refinement of clinical guidelines and enhancing the decision-making process for healthcare providers, policy-makers, and patients. The comprehensive analysis of subgroups and sensitivity allows for an in-depth understanding of potential effect modification, providing essential directions for future research.

Ethics and dissemination: This study will involve the use of published data; hence, ethical approval is not required. The results of the study will be disseminated through publications in peer-reviewed journals and presentations at relevant conferences. The findings will potentially impact clinical decision-making and contribute to the development of evidence-based treatment recommendations for patients with MSI-H colorectal cancer.

Clinical trial registration: Open Science Framework identifier, 10.17605/OSF.IO/ZHJ85.

Keywords: clinical trials; colorectal cancer; immune checkpoint inhibitors; microsatellite instability-high; pooled analysis.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Key Research and Promotion Project of Henan Province (Science and Technology Tackling Project) (grant no. 232102311221), Hunan Provincial Natural Science Foundation of China (grant no. 2022JJ30519), Scientific Research Fund of Hunan Provincial Health Commission (grant no. 20200968) and Scientific Research Fund of Hengyang Science and Technology Bureau (grant no. 2019jh010988). The funder of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the manuscript. The corresponding author had full access to all the data in the study and has final responsibility for the decision to submit for publication.