Abdelhamid Arwa, Tuminello Stephanie, Ivic-Pavlicic Tara, Flores Raja, Taioli Emanuela
Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Population Health, NYU Grossman School of Medicine, New York, NY, USA.
Transl Lung Cancer Res. 2023 Dec 26;12(12):2427-2439. doi: 10.21037/tlcr-23-597. Epub 2023 Dec 22.
In patients with non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) are an effective mode of treatment. Despite their efficacy, responses to ICIs have been shown to differ based on several factors; for example, antibiotic use prior to and/or during immunotherapy has been associated with lower survival in NSCLC patients. The objective of this study is to provide an updated review of the literature and to fill in important knowledge gaps by accounting for potential confounding in the relationship between ICIs and survival.
We performed a systematic review and meta-analysis on peer-reviewed studies that examined the effects of antibiotic use on overall survival (OS) and progression-free survival (PFS) in NSCLC patients treated with ICIs. We searched MEDLINE for studies published up to June 30, 2023 that included NSCLC patients treated with anti-programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) agents, who received antibiotics before and/or during immunotherapy, and included a control group who did not receive antibiotics and had available data on the associations between antibiotics and OS and PFS. We calculated aggregated crude OS and PFS for all studies, and only for studies that reported multivariable hazard ratios (HRs). Risk of bias was assessed using a funnel plot. All results were synthesized and displayed using the metaphor statistical package in R, version 4.2.1.
Nineteen studies, conducted between 2017 and 2022, met the inclusion criteria, and included 2,932 patients with advanced and/or metastatic NSCLC. Compared to those who did not receive antibiotics, immunotherapy patients who did had a significantly reduced PFS (HR: 1.22, 95% CI: 1.03-1.44) and OS (HR: 1.56, 95% CI: 1.23-1.99). Adjusted HRs were even more pronounced (OS HR: 1.67, 95% CI: 1.23-2.27, PFS HR: 1.64, 95% CI: 1.16-2.32).
NSCLC patients treated with antibiotics have significantly lowered survival compared with patients not treated with antibiotics. These results support the hypothesis that antibiotic use in conjunction with ICI among NSCLC patients lowers survival. Limitations of this analysis include the use of studies available only on a single database, limiting the literature search to NSCLC patients, which may impact the generalizability of results to other cancer patient populations, and the inability to account for and adjust the estimates for the same variables (e.g., age, sex) across all studies. Nevertheless, our findings underscore the importance of taking antibiotic use into consideration when using ICIs to treat NSCLC and suggest that confounders should be taken into account when designing future similar studies.
在非小细胞肺癌（NSCLC）患者中，免疫检查点抑制剂（ICI）是一种有效的治疗方式。尽管其疗效显著，但对ICI的反应已显示因多种因素而异；例如，免疫治疗之前和/或期间使用抗生素与NSCLC患者较低的生存率相关。本研究的目的是提供文献的最新综述，并通过考虑ICI与生存率之间关系中的潜在混杂因素来填补重要的知识空白。
我们对同行评审的研究进行了系统综述和荟萃分析，这些研究探讨了抗生素使用对接受ICI治疗的NSCLC患者总生存期（OS）和无进展生存期（PFS）的影响。我们在MEDLINE中搜索截至2023年6月30日发表的研究，这些研究纳入了接受抗程序性细胞死亡蛋白1（PD-1）或程序性死亡配体1（PD-L1）药物治疗的NSCLC患者，他们在免疫治疗之前和/或期间接受了抗生素治疗，并且包括一个未接受抗生素治疗且有关于抗生素与OS和PFS之间关联的可用数据的对照组。我们计算了所有研究的汇总粗OS和PFS，并且仅对报告了多变量风险比（HR）的研究进行计算。使用漏斗图评估偏倚风险。所有结果均使用R版本4.2.1中的隐喻统计软件包进行合成和展示。
2017年至2022年期间进行的19项研究符合纳入标准，共纳入2932例晚期和/或转移性NSCLC患者。与未接受抗生素治疗的患者相比，接受抗生素治疗的免疫治疗患者的PFS（HR：1.22，95%CI：1.03 - 1.44）和OS（HR：1.56，95%CI：1.23 - 1.99）显著降低。调整后的HR更为明显（OS HR：1.67，95%CI：1.23 - 2.27，PFS HR：1.64，95%CI：1.16 - 2.32）。
与未使用抗生素治疗的患者相比，接受抗生素治疗的NSCLC患者生存率显著降低。这些结果支持了NSCLC患者中抗生素与ICI联合使用会降低生存率的假设。本分析的局限性包括仅使用单个数据库中的可用研究，将文献搜索限制在NSCLC患者中，这可能会影响结果对其他癌症患者群体的普遍性，以及无法对所有研究中的相同变量（例如年龄、性别）的估计进行考虑和调整。尽管如此，我们的研究结果强调了在使用ICI治疗NSCLC时考虑抗生素使用的重要性，并建议在设计未来类似研究时应考虑混杂因素。
