Wan Guihong, Nguyen Nga, Lu Charles, Khattab Sara, Yan Boshen, Amadife Munachimso, Leung Bonnie W, Chen Wenxin, Rajeh Ahmad, Tang Kimberly, Thang Christopher, Boland Genevieve, Reynolds Kerry L, Yu Kun-Hsing, Gusev Alexander, LeBoeuf Nicole R, Kwatra Shawn G, Semenov Yevgeniy R
medRxiv. 2025 Jun 23:2025.06.23.25330022. doi: 10.1101/2025.06.23.25330022.
Systemic immunosuppression (sISP), particularly with glucocorticoids, is commonly used among patients receiving immune checkpoint inhibitor (ICI) therapy. Although recent studies have demonstrated that sISP is associated with poor outcomes in ICI recipients, there is limited information on how the timing, dose, and duration of sISP affect overall survival (OS). This multi-cohort retrospective study aims to address these gaps.
This study included 13,086 ICI recipients from Massachusetts General Hospital, Brigham and Women's Hospital, and Dana-Farber Cancer Institute (MGBD) between May 31, 2015, and October 11, 2021. For independent validation, 26,172 ICI recipients were identified from the TriNetX database between April 30, 2010, and October 11, 2021, using 2:1 propensity score matching. Multivariable survival analyses were conducted with Accelerated Failure Time (AFT) models, reporting Time Ratios (TRs) and 95% Confidence Intervals (CIs), where TR<1 indicates shorter OS.
In the MGBD cohort, sISP within one year of ICI initiation was associated with worse OS compared to patients without sISP via landmark analysis. This association was accentuated among patients receiving sISP closer to ICI initiation, with those receiving sISP within one month of ICI initiation having the worst outcomes (TR: 0.49; 95% CI: 0.44-0.54; p<0.0001). Increased dose and duration of sISP were associated with a greater survival time loss, such that doses beyond 60 mg/day had a 40% survival time loss and durations longer than 7 days were associated with a 35% survival time loss. These findings were independently validated in the TriNetX cohort.
Three key factors are associated with significantly worse OS: sISP near ICI initiation, higher sISP dose, and longer sISP duration, regardless of indication. These findings provide clinicians with valuable information to guide sISP management among ICI recipients.
NIH, USA.
We reviewed PubMed and existing literature for studies on systemic immunosuppression (sISP), particularly glucocorticoids, and outcomes among immune checkpoint inhibitor (ICI) recipients. Previous research, including clinical trial studies, indicated that sISP, especially at higher doses or for managing immune-related adverse events (irAEs), was associated with poorer survival. However, studies were limited by small sample sizes, focused on single cancer types, or did not comprehensively assess the nuanced impacts of sISP timing relative to ICI initiation, dose, and duration across diverse cancer types and ICI indications. Thus, a clear understanding of these specific parameters in large, real-world cohorts was lacking. This multi-cohort study analyzed approximately 40,000 ICI recipients, leveraging data from a large academic medical center system (MGBD) and validating findings in a national, population-level database (TriNetX) with access to granular patient-level data. We comprehensively investigated how the timing, dose, and duration of systemic glucocorticoid immunosuppression influence overall survival across a pan-cancer population. Our large scale and detailed approach provide robust, generalizable insights into these critical factors, addressing limitations of prior, smaller, or more narrowly focused investigations. Our findings offer clinicians critical, actionable insights for managing systemic glucocorticoid immunosuppression in patients receiving ICI therapy. Knowing that sISP administered near ICI initiation, at higher doses, or for longer durations is associated with significantly worse overall survival can guide clinical decision-making. This allows for more informed risk-benefit discussions, strategies to minimize steroid exposure when feasible (e.g., lowest effective dose, shortest duration), and consideration of steroid-sparing alternatives, ultimately aiming to optimize survival outcomes for cancer patients on ICI therapy.
全身免疫抑制（sISP），尤其是使用糖皮质激素，在接受免疫检查点抑制剂（ICI）治疗的患者中普遍使用。尽管最近的研究表明，sISP与ICI接受者的不良预后相关，但关于sISP的时机、剂量和持续时间如何影响总生存期（OS）的信息有限。这项多队列回顾性研究旨在填补这些空白。
本研究纳入了2015年5月31日至2021年10月11日期间来自麻省总医院、布莱根妇女医院和丹娜法伯癌症研究所（MGBD）的13086名ICI接受者。为了进行独立验证，通过2:1倾向评分匹配，从TriNetX数据库中识别出2010年4月30日至2021年10月11日期间的26172名ICI接受者。使用加速失效时间（AFT）模型进行多变量生存分析，报告时间比（TRs）和95%置信区间（CIs），其中TR<1表示OS较短。
在MGBD队列中，通过标志性分析，与未接受sISP的患者相比，ICI开始后一年内接受sISP与较差的OS相关。这种关联在更接近ICI开始时接受sISP的患者中更为明显，在ICI开始后一个月内接受sISP的患者预后最差（TR：0.49；95%CI：0.44 - 0.54；p<0.0001）。sISP剂量和持续时间的增加与更大的生存时间损失相关，即超过60毫克/天的剂量有40%的生存时间损失，持续时间超过7天与35%的生存时间损失相关。这些发现在TriNetX队列中得到了独立验证。
三个关键因素与显著更差的OS相关：ICI开始附近的sISP、更高的sISP剂量和更长的sISP持续时间，无论其适应症如何。这些发现为临床医生提供了有价值的信息，以指导ICI接受者的sISP管理。
美国国立卫生研究院。
我们检索了PubMed和现有文献，以查找关于全身免疫抑制（sISP），特别是糖皮质激素以及免疫检查点抑制剂（ICI）接受者结局的研究。先前的研究，包括临床试验研究，表明sISP，特别是高剂量或用于管理免疫相关不良事件（irAEs）时，与较差的生存率相关。然而，这些研究受到样本量小、专注于单一癌症类型或未全面评估sISP相对于ICI开始的时机、剂量和持续时间在不同癌症类型和ICI适应症中的细微影响的限制。因此，缺乏对这些特定参数在大型真实世界队列中的清晰理解。这项多队列研究分析了约40000名ICI接受者，利用了大型学术医疗中心系统（MGBD）的数据，并在可获取详细患者层面数据的国家人口水平数据库（TriNetX）中验证了研究结果。我们全面研究了全身糖皮质激素免疫抑制的时机、剂量和持续时间如何影响泛癌人群的总生存期。我们大规模且详细的方法为这些关键因素提供了有力的、可推广的见解，解决了先前较小规模或更狭义研究的局限性。我们的发现为临床医生在管理接受ICI治疗患者的全身糖皮质激素免疫抑制方面提供了关键的、可操作的见解。知道在ICI开始附近、高剂量或更长持续时间使用sISP与显著更差的总生存期相关，可以指导临床决策。这允许进行更明智的风险 - 收益讨论，在可行时尽量减少类固醇暴露的策略（例如，最低有效剂量、最短持续时间），以及考虑使用类固醇替代药物，最终目标是优化接受ICI治疗的癌症患者的生存结局。
