免疫检查点抑制剂相关性腹泻和结肠炎治疗中皮质类固醇使用时间及其并发症的 5 年回顾：晚期黑色素瘤研究
Five-year review of corticosteroid duration and complications in the management of immune checkpoint inhibitor-related diarrhoea and colitis in advanced melanoma.
机构信息
Melanoma and Renal Unit, Royal Marsden NHS Foundation Trust, London, UK.
Department of Oncology and Haematology, Kantonsspital St Gallen, Sankt Gallen, Switzerland.
出版信息
ESMO Open. 2020 Jul;5(4). doi: 10.1136/esmoopen-2019-000585.
BACKGROUND
Immune-related diarrhoea/colitis (ir-D/C) is a common adverse event of immune checkpoint inhibitor (ICI) therapy. Guidelines recommend corticosteroid (CS) treatment; however, the average treatment duration for ir-D/C remains poorly defined.
METHODS
All advanced melanoma patients treated with ICI therapy at the Royal Marsden Hospital between 2011 and 2016 were reviewed to identify ir-D/C cases alongside clinical variables.
RESULTS
117 any-grade ir-D/C episodes occurred in 109 (21%) patients out of a total of 519 patients treated (ipilimumab=77 episodes, anti-PD1=17 (nivolumab or pembrolizumab), ipilimumab and nivolumab=23 (ipi+nivo)) (seven patients had ir-D/C more than once on different lines of treatment) and >/=grade 3 ir-D/C occurred most frequently (63/519 patients (12%) vs 29/519 (5%) grade 1, and 25/519 (5%) grade 2). Median onset (days) of all-grade ir-D/C after starting ICI therapy was 41 for ipilimumab (IQR 24 to 59, n=77), 91 for anti-PD1 (IQR 46 to 355, n=17) and 45 for ipi+nivo (IQR 24 to 67, n=23). In 71/117 (61%) patients, ir-D/C episodes were treated with CS (17% grade 2; 79% grade 3/4): 54 being steroid-responsive; 17 being steroid-refractory and received additional anti-tumor necrosis factor (TNF) treatment. Median grade 3 ir-D/C CS duration was similar across treatments, averaging 58 days. Median overall CS duration (days) was longer in the grade 3/4 D/C steroid-refractory group (94 vs 45 days). Infection developed in 11/71 (15%) CS recipients and in 6/17 (35%) anti-TNF recipients. In 65/117 (55%) patients, ir-D/C episodes were investigated with flexible sigmoidoscopy. Of these patients, 38/65 (58%) had macroscopic colitis and 12/65 (18%) had microscopic colitis. The steroid-refractory group had more macroscopic changes, 13/17 (76%), than the steroid-responsive group, 22/41 (54%).
CONCLUSION
Rates of grade 3 ir-D/C were higher than reported in clinical trials. The 58-day median duration of CS therapy for grade 3 ir-D/C places a significant number of patients at risk of complications. We demonstrate that microscopic colitis is an important subgroup, advocating biopsies in ir-D/C even with macroscopically normal bowel.
背景
免疫相关腹泻/结肠炎（ir-D/C）是免疫检查点抑制剂（ICI）治疗的常见不良反应。指南推荐使用皮质类固醇（CS）治疗；然而，ir-D/C 的平均治疗持续时间仍未得到明确界定。
方法
回顾了 2011 年至 2016 年间在皇家马斯登医院接受 ICI 治疗的所有晚期黑色素瘤患者，以确定 ir-D/C 病例以及临床变量。
结果
在总共 519 名接受治疗的患者中（伊匹单抗=77 例，抗 PD1=17 例（nivolumab 或 pembrolizumab），伊匹单抗和 nivolumab=23 例（ipi+nivo）），有 109 名（21%）患者出现了 117 例任何级别的 ir-D/C 发作（7 名患者在不同的治疗线上出现了不止一次的 ir-D/C），最常发生的是> / = 3 级 ir-D/C（519 名患者中有 63 名（12%），519 名中有 29 名（5%）为 1 级，25 名（5%）为 2 级）。开始 ICI 治疗后，所有级别的 ir-D/C 出现的中位时间（天）为伊匹单抗 41（IQR 24 至 59，n=77），抗 PD1 91（IQR 46 至 355，n=17）和 ipi+nivo 45（IQR 24 至 67，n=23）。在 71/117（61%）名患者中，ir-D/C 发作用 CS 治疗（2 级 17%；3/4 级 79%）：54 名患者对 CS 有反应；17 名患者对 CS 耐药，接受了额外的抗肿瘤坏死因子（TNF）治疗。治疗之间，3 级 ir-D/C CS 治疗的中位持续时间相似，平均为 58 天。3/4 级 D/C 类固醇耐药组的总体 CS 中位持续时间（天）较长（94 天 vs 45 天）。在 71/71（100%）名 CS 接受者和 17/17（100%）名抗 TNF 接受者中，发生了感染。在 65/117（55%）名患者中，对 ir-D/C 发作进行了软性乙状结肠镜检查。在这些患者中，38/65（58%）有宏观结肠炎，12/65（18%）有微观结肠炎。类固醇耐药组有更多的宏观变化，13/17（76%），而类固醇反应组，22/41（54%）。
结论
3 级 ir-D/C 的发生率高于临床试验报道。3 级 ir-D/C 皮质类固醇治疗的 58 天中位持续时间使大量患者面临并发症风险。我们证明微观结肠炎是一个重要的亚组，即使在肠道宏观正常的情况下，也提倡对 ir-D/C 进行活检。
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