Strouse Jennifer, Chan Karmela Kimi, Baccile Rachel, He Gong, Louden Diana K N, Giurcanu Mihai, Singh Arohi, Rieth John, Abdel-Wahab Noha, Katsumoto Tamiko R, Singh Namrata, Rouhani Sherin, Reid Pankti
Division of Immunology, University of Iowa, Iowa City, IA, United States.
Division of Rheumatology, Department of Medicine, Hospital for Special Surgery, New York, NY, United States.
Front Immunol. 2024 Dec 16;15:1499478. doi: 10.3389/fimmu.2024.1499478. eCollection 2024.
The impact of steroid-sparing immunosuppressive agents (SSIAs) for immune-related adverse events (irAEs) on tumor outcome is not well-known. This systematic review evaluates tumor outcomes for corticosteroid (CS) monotherapy versus CS with SSIA (CS-SSIA) for irAE treatment with a focus on melanoma.
Search was conducted through 1/5/23 using PubMed, Embase, Cochrane CENTRAL, and Web of Science. We included case series, retrospective/prospective observational studies and interventional clinical trials. Individual-level data was analyzed using KM curves and Cox regression for overall survival (OS) and progression free survival (PFS). Time to SSIA was treated as a time-varying exposure using landmark analysis (landmark timepoint=3 months after irAE) to account for immortal time bias. For group-level data, meta-analysis compared the use of SSIA to No SSIA for irAEs.
Of twenty-two publications with individual-level data, 147 patients with any cancer (57 CS, 90 CS-SSIA) and 65 with melanoma (18 CS, 47 CS-SSIA) underwent landmark analysis. Twenty-two publications underwent group-level evaluation and four were included in the meta-analysis. CS-SSIA versus CS showed higher risk of all-cause mortality and progression (HR 2.75, 95%CI: 1.44-5.27, p<0.01 and HR 1.75, 95%CI: 1.07-2.85, p=0.03, respectively). Melanoma showed worse OS and PFS for CS-SSIA versus CS (HR 5.68, 95%CI: 1.31-24.67, p=0.02 and HR 2.68, 95%CI: 1.12-6.40, p=0.03, respectively). In the meta-analysis of group-level data (n=2558), we found worse OS and PFS for CS-SSIA versus No SSIA (HR 1.58, 95%CI: 1.25; 2.01, p<0.01 and 1.70, 95%CI: 1.25-2.33, p<0.01). Tumor necrosis factor-alpha inhibitors (TNFi) were the most common SSIA. In the melanoma cohort, TNFi had worse OS and PFS versus CS (HR 6.46, 95%CI: 1.43-29.19, p = 0.02 and HR 7.49, 95%CI: 2.29-24.48, p<0.01, respectively). TNFi versus Other SSIAs showed a trend toward worse OS and worse PFS (HR 6.96, 95%CI: 0.90-53.65, p=0.06 and HR 21.5, 95%CI: 2.63-175.8, p<0.01, respectively). Meta-analysis showed a concern for TNFi compared to Other SSIA (HR 1.56, 95%CI: 1.17-2.09, p<0.01 respectively).
While our results raise concern about the effects of CS-SSIA and TNFi for irAE therapy on tumor outcomes, prospective randomized controlled trials are needed to definitively assess the effect of SSIAs on tumor outcomes.
甾体类药物节省免疫抑制剂（SSIA）用于免疫相关不良事件（irAE）对肿瘤结局的影响尚不明确。本系统评价评估了皮质类固醇（CS）单药治疗与CS联合SSIA（CS - SSIA）治疗irAE的肿瘤结局，重点关注黑色素瘤。
于2023年1月5日通过PubMed、Embase、Cochrane CENTRAL和Web of Science进行检索。我们纳入了病例系列、回顾性/前瞻性观察性研究和干预性临床试验。使用Kaplan - Meier曲线和Cox回归分析个体水平数据的总生存期（OS）和无进展生存期（PFS）。将开始使用SSIA的时间作为随时间变化的暴露因素，采用标志性分析（标志性时间点 = irAE发生后3个月）以解决不朽时间偏倚问题。对于组水平数据，荟萃分析比较了使用SSIA与不使用SSIA治疗irAE的情况。
在22篇包含个体水平数据的出版物中，对147例患有任何癌症的患者（57例CS治疗，90例CS - SSIA治疗）和65例黑色素瘤患者（18例CS治疗，47例CS - SSIA治疗）进行了标志性分析。22篇出版物进行了组水平评估，其中4篇纳入了荟萃分析。与CS相比，CS - SSIA的全因死亡率和疾病进展风险更高（风险比[HR] 2.75，95%置信区间[CI]：1.44 - 5.27，p < 0.01；HR 1.75，95%CI：1.07 - 2.85，p = 0.03）。黑色素瘤患者中，与CS治疗相比，CS - SSIA治疗的OS和PFS更差（HR 5.68，95%CI：1.31 - 24.67，p = 0.02；HR 2.68，95%CI：1.12 - 6.40，p = 0.03）。在组水平数据的荟萃分析中（n = 2558），我们发现与不使用SSIA相比，CS - SSIA治疗的OS和PFS更差（HR 1.58，95%CI：1.25 - 2.01，p < 0.01；HR 1.70，95%CI：1.25 - 2.33，p < 0.01）。肿瘤坏死因子α抑制剂（TNFi）是最常见的SSIA。在黑色素瘤队列中，与CS治疗相比，TNFi治疗的OS和PFS更差（HR 6.46，95%CI：1.43 - 29.19，p = 0.02；HR 7.49，95%CI：2.29 - 24.48，p < 0.01）。与其他SSIA相比，TNFi治疗的OS和PFS有更差的趋势（HR 6.96，95%CI：0.90 - 53.65，p = 0.06；HR 21.5，95%CI：2.63 - 175.8，p < 0.01）。荟萃分析显示，与其他SSIA相比，TNFi治疗存在问题（HR 1.56，95%CI：1.17 - 2.09，p < 0.01）。
虽然我们的结果引发了对CS - SSIA和TNFi治疗irAE对肿瘤结局影响的担忧，但需要前瞻性随机对照试验来明确评估SSIA对肿瘤结局的影响。
