TITLE: kpoint Inhibitors Combined with Radiotherapy or Chemoradiotherapy for Advanced Non-Small Cell Lung Cancer: A Systematic Review and Single-Arm Meta-Analysis
AUTHORS: ran cui, ran cui

[DESCRIPTION]
Background: The recent usage of immunotherapy combined with chemoradiotherapy has improved survival in advanced non-small cell lung cancer (NSCLC) patients. However, determining the most effective therapy combination remains a topic of debate. Research suggests immune checkpoint inhibitors (ICIs) post-chemoradiotherapy enhance survival, but the impact of concurrent ICIs during chemoradiotherapy on rapid disease progression is unclear. This meta-analysis aims to assess the effectiveness and safety of concurrent ICIs with radiotherapy or chemoradiotherapy in advanced non-small cell lung cancer.
Methods: We searched PubMed, Embase, the Cochrane Library, and Web of Science for relevant studies, extracting data on overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs).
Results: The analysis included ten studies with 490 participants. Stage III NSCLC ORR was 81.8%, while Stage IV ORR was 39.9%. One-year PFS and OS for Stage III were 68.2% and 82.6%, compared to 27.9% and 72.2% for Stage IV. Common adverse events included anemia (46.6%), nausea (47.6%), rash (36.4%), and radiation pneumonitis (36.3%).
Conclusions: Our meta-analysis shows concurrent ICIs with chemoradiotherapy are effective and safe in advanced NSCLC, particularly in stage III patients at risk of progression before starting ICIs after chemoradiotherapy. The findings support further phase III trials. The review protocol was registered on PROSPERO (CRD42023493685) and is detailed on the NIHR HTA programme website.


[BEFORE_START]
Protocol Registration: The study protocol should be registered in a publicly accessible database, such as PROSPERO (International Prospective Register of Systematic Reviews) or the Open Science Framework (OSF), to promote transparency and reduce duplication of efforts.

Search Strategy Development: The search strategy should be developed in consultation with a medical librarian or an information specialist to ensure that it is comprehensive and captures all relevant studies. The search strategy should be peer-reviewed using the Peer Review of Electronic Search Strategies (PRESS) checklist [23] to minimize errors and improve its effectiveness.

Data Management: A data management plan should be established before starting the study to outline how data will be collected, stored, and shared. This plan should include measures to ensure data security, confidentiality, and access control. The use of a secure, cloud-based platform, such as REDCap (Research Electronic Data Capture) [24], can facilitate efficient and secure data management.

Study Protocol: The study protocol should be developed following the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) guidelines to ensure that all essential elements are included. The protocol should be reviewed and approved by all members of the research team before the start of the study.

Authorship and Collaboration: The roles and responsibilities of each member of the research team should be clearly defined, and authorship criteria should be established in accordance with the International Committee of Medical Journal Editors (ICMJE) guidelines . If the meta-analysis involves collaboration with external partners or institutions, data sharing agreements and memoranda of understanding should be established to ensure smooth collaboration and protect intellectual property rights.

Training and Calibration: All members of the research team should receive appropriate training on the study protocol, data extraction, quality assessment, and statistical analysis methods to ensure consistency and minimize errors. Calibration exercises should be conducted to assess inter-rater reliability and resolve any discrepancies in the interpretation of the study criteria.

[GUIDELINES]
Study Design: This meta-analysis will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines  to ensure transparent and comprehensive reporting of the study methods and results.
Literature Search: A comprehensive literature search will be conducted using multiple electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) to identify all relevant studies. The search strategy will be developed in consultation with a medical librarian and will include a combination of MeSH terms and free-text keywords.
Study Selection: Two independent reviewers will screen the titles and abstracts of the retrieved articles for relevance. Full-text articles will be assessed for eligibility based on the predefined inclusion and exclusion criteria. Any discrepancies will be resolved through discussion or consultation with a third reviewer.
Data Extraction: Two independent reviewers will extract data from the included studies using a standardized data extraction form. The extracted data will include study characteristics (e.g., author, year, study design, sample size), patient demographics, treatment details (e.g., type of ICI, radiotherapy dose, chemotherapy regimen), and outcomes (e.g., ORR, PFS, OS, AEs).
Quality Assessment: The quality of the included studies will be assessed using appropriate tools based on the study design. The Cochrane Risk of Bias Tool  will be used for randomized controlled trials, while the Newcastle-Ottawa Scale  will be used for non-randomized studies. Two independent reviewers will perform the quality assessment, and discrepancies will be resolved through discussion.
Statistical Analysis: The meta-analysis will be conducted using a random-effects model to account for heterogeneity among the included studies. Heterogeneity will be assessed using the I² statistic and Cochran's Q test. Subgroup analyses will be performed based on factors such as tumor stage, type of ICI, and type of radiotherapy. Sensitivity analyses will be conducted to evaluate the robustness of the results. Publication bias will be assessed using funnel plots and Egger's test.
Interpretation of Results: The results of the meta-analysis will be interpreted in the context of the available evidence and the limitations of the included studies. The clinical implications of the findings will be discussed, and recommendations for future research will be provided.

[STEPS]
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1. Develop a research question and hypothesis:Clearly define the research question and hypothesis for the meta-analysis, focusing on the efficacy and safety of concurrent immune checkpoint inhibitors combined with radiotherapy or chemoradiotherapy for advanced non-small cell lung cancer.
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2. Register the protocol: Register the study protocol in a publicly accessible database, such as PROSPERO or the Open Science Framework, to promote transparency and reduce duplication of efforts.
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3. Develop a search strategy: In consultation with a medical librarian or information specialist, develop a comprehensive search strategy that captures all relevant studies. Peer-review the search strategy using the PRESS checklist.
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4. Conduct a literature search: Search multiple electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) using the developed search strategy to identify all relevant studies.
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5. Screen and select studies: Two independent reviewers should screen the titles and abstracts of the retrieved articles for relevance. Assess full-text articles for eligibility based on the predefined inclusion and exclusion criteria. Resolve any discrepancies through discussion or consultation with a third reviewer.
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6. Extract data: Two independent reviewers should extract data from the included studies using a standardized data extraction form. Extract study characteristics, patient demographics, treatment details, and outcomes.
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7. Assess study quality: Assess the quality of the included studies using appropriate tools based on the study design (e.g., Cochrane Risk of Bias Tool for randomized controlled trials, Newcastle-Ottawa Scale for non-randomized studies). Two independent reviewers should perform the quality assessment and resolve discrepancies through discussion.
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8. Conduct statistical analysis: Perform meta-analysis using a random-effects model to account for heterogeneity among the included studies. Assess heterogeneity using the I² statistic and Cochran's Q test. Perform subgroup analyses based on factors such as tumor stage, type of ICI, and type of radiotherapy. Conduct sensitivity analyses to evaluate the robustness of the results. Assess publication bias using funnel plots and Egger's test.
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9. Interpret results: Interpret the results of the meta-analysis in the context of the available evidence and the limitations of the included studies. Discuss the clinical implications of the findings and provide recommendations for future research.
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10. Draft the manuscript: Write the manuscript following the PRISMA guidelines, including all essential elements such as the abstract, introduction, methods, results, discussion, and conclusion. Ensure that the manuscript adheres to the journal's formatting and submission requirements.
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11. Review and revise: Circulate the draft manuscript among all authors for review and feedback. Revise the manuscript based on the comments and suggestions received.
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12. Submit for publication: Submit the final manuscript to the target journal and respond to any reviewer comments or editorial requests during the peer-review process.