2017年11月21日，癌症免疫治疗学会（SITC）旗下杂志《癌症免疫疗法》在线刊登了有关免疫检查点抑制剂在癌症治疗中的毒性管理建议，即《免疫检查点抑制剂相关毒性管理共识建议》。

中山大学肿瘤防治中心蔡修宇博士等对文章内容进行了翻译。我们在此分部分，将共识建议的中文内容与全国医生分享，以期在未来工作中参考应用。

免疫检查点抑制剂相关毒性管理共识建议

中文版

《免疫检查点抑制剂相关毒性管理：来自美国癌症免疫治疗学会（SITC）毒性管理工作组的共识建议》

作者：

I. Puzanov1†, A. Diab2†, K. Abdallah3, C. O. Bingham III4, C. Brogdon5, R. Dadu2, L. Hamad1, S. Kim2, M. E. Lacouture6, N. R. LeBoeuf7, D. Lenihan8, C. Onofrei9, V. Shannon2, R. Sharma1, A. W. Silk12, D. Skondra10, M. E. Suarez-Almazor2,Y. Wang2, K. Wiley11, H. L. Kaufman12†, M. S. Ernstoff1*†，代表美国癌症免疫治疗协会（SITC）毒性管理工作组编写

摘要及背景：

免疫检查点抑制剂相关毒性管理共识建议（1）

  肾不良事件

总体而言，肾irAE被认为是罕见的，接受ICI治疗患者的发生率在2％（ICI单药治疗）至5％（联合伊匹单抗/纳武单抗联合治疗），基于病理学的特征和报告才刚开始[89,90]。大多数报道记录了特定药物和方案相关的单独的间质性肾炎病例，其中包括用于黑色素瘤患者的抗PD-1单药治疗和抗CTLA-4/PD-1联合治疗[91,92]。到目前为止，尚未发现肾炎与抗PD-L1单药治疗相关。在一项纳武单抗联合双药含铂方案化疗用于治疗NSCLC的研究中，报告了3例患者出现急性肾功能衰竭[93]。在伊匹单抗治疗后也有狼疮性肾炎[94]和肉芽肿性肾炎[95,96]的病例报道，以及用avelumab治疗后发生肾炎的一例报告[97]。然而，最近的数据表明肾脏irAEs的发病率可能存在漏报，接受某些ICI治疗的患者中高达25%-29%出现了低级别肾损伤[90]。 PD-1抑制剂所致的肾脏损伤发病通常在治疗开始后3-10个月出现，而继发于抗CTLA-4药物的irAEs往往在2-3个月后或在更早的时间发病[90]。因ICI导致的肾毒性通常是无症状的，尽管偶有报道少尿、血尿、外周性水肿和厌食症。不良事件的管理需要相当的临床判断。

在免疫治疗前或者在免疫治疗过程中施用的伴随药物可能会使肾损伤的诊断变得复杂。毫无疑问，存在血清肌酐逐渐升高的证据应引起临床怀疑。因此，应在开始免疫治疗时以及在整个治疗过程中每间隔一段时间监测血清肌酐。如果肌酐持续升高> 2-3天，则每周监测一次（1级）或每2-3天监测一次（2级）。通过积极询问使用的新药物、脱水的纠正情况以及可能的话行额外的检查如膀胱和/或肾脏超声、尿液分析、血清电解质评估或基于病史的其它检查，以便排除引起肾功能不全的其它原因，这是很重要的。对于疑似存在免疫相关肾脏疾病的患者，应考虑行肾活检明确病因和指导管理。由于肾毒性通常可以得到解决，如果2-3级不良事件迅速得到解决，治疗可以恢复，但对于持续性或复发的2-3级不良事件或出现4级毒性时应停止治疗。任何持续性≥3级肾损伤或皮质类固醇激素试验后肾毒性复发，应考虑请肾内科会诊。

对于持续性的2-3级肌酐水平升高、基线以上肌酐升高3倍以上、或有与肾功能衰竭相一致的代谢改变证据的患者，应考虑进行请肾内科会诊。

神经不良事件

神经irAE并不常见，接受抗CTLA-4抗体治疗后的患者总体发生率<4％，抗PD-1抗体总发生率为6％，抗CTLA-4抗体和抗PD-1抗体联合治疗组的发生率为12％[98]。大多数的不良事件是轻微的，表现为非特异性症状，如头痛；3级或3级以上irAEs的患者发生率<1％[98]。神经irAE的例子包括自身免疫性脑炎、肌无力综合征/重症肌无力、格林-巴利综合征、外周感觉运动神经病、可逆性后部脑病综合征（PRES）、无菌性脑膜炎和横贯性脊髓炎[99]。有关的CTCAE术语包括脑病、白质脑病、外周运动神经病、外周感觉神经病、可逆性后部白质脑病综合征，和“非特指的神经系统”。自身免疫性脑炎、脑膜炎和脑病的常见表现包括精神状态改变、头痛、癫痫发作、局灶性神经异常和PRES。

对于所有患者，诊断性检查应包括病史和体格检查以及全面的神经检查。可能存在自身免疫性脑炎、脑膜炎和脑病的评估应该包括腰椎穿刺和脑MRI联合或不联合增强扫描；排除感染、筛查非疑似的中枢神经系统（CNS）转移和/或软脑膜转移是重要的。 还应考虑副肿瘤综合征。 对可疑的外周感觉运动神经病的诊断评估应包括疾病的鉴别诊断，包括但不限于糖尿病性神经病和维生素B12缺乏症。酌情考虑行影像检查以及神经活检；这是一个排除性诊断，但在大多数情况下，这是一个临床诊断。

所有存在2级或2级以上神经irAEs的患者都建议请神经内科会诊。

 眼科不良事件

在接受ICI治疗的患者中，眼科irAE（主要是葡萄膜炎[前部比后部或全部更常见]）的发生率<1% [13,15]。 也有眼眶炎症、巩膜外层炎、睑缘炎、视神经肿胀、周边溃疡性角膜炎和伴局部浆液性视网膜脱离的Vogt-Koyanagi-Harada综合征的报道[100-102]。 对于接受ICIs治疗的患者，应提醒临床医生出现新发的视力模糊、飞蚊症、闪光感、色觉变化、眼睛发红、畏光或光敏感、视觉畸变和视野改变、暗点、眼球运动时疼痛、眼睑肿胀或眼球突出或复视。 患者咨询对于及时确认早期体征和症状至关重要。

虽然对于所有主诉视觉不适的患者，迅速转诊眼科都很重要，但某些检查可在办公室由肿瘤医生完成。这些检查包括视力检查，可以通过使用智能手机上的视力表来完成，患者根据需要佩戴近视眼镜或远视眼镜；色觉；红光反射；瞳孔（是否瞪大、圆形、反应），包括瞳孔传入障碍的检查，可指示视神经或广泛的视网膜病变；和眼睛前部的手电筒检查。直接检眼镜检查视神经和视网膜，当由非接受过眼科训练的医师进行时，不太可能用于诊断视神经或视神经的问题。眼irAE可能是不对称的，因此分开检查每只眼睛是很重要的。眼irAE经常伴随有其它系统的irAE，尤其是结肠炎，所以更广泛的系统检查是有帮助的。

接受ICI治疗的患者，如果诉有眼发红、疼痛、干燥或眼发炎、或视觉障碍，应提醒临床医生需要立即进行眼科检查以进行诊断、分类和处理，这对于肿瘤科医师来说可能是困难的，因为不同的眼科病理和分级可能会出现类似的症状，需要由眼科医生进行详细的眼科评估，包括裂隙灯检查和扩瞳眼底检查 。有时2级或3级严重的眼irAEs可能只表现为无症状或轻微的视力改变，并且眼科检查的时间可能因环境而异（学院型医院Vs社区医院）。因此，临床怀疑和及时转诊是至关重要的。应该避免在进行眼科检查之前开始全身或局部使用皮质类固醇治疗，除非全身性类固醇给药是同时发生的非眼科毒性的指征，因为它可能会恶化由于感染引起的眼部疾病（例如，疱疹性角膜炎/葡萄膜炎），或者可能在患者接受眼科医生检查时掩盖了准确的诊断和严重程度分级。对于所有3级或4级irAEs，紧急转诊是必要的，但即使是1级或2级毒性的患者也应该在几天内接受眼科专家的全面眼科评估、适当的分级、检查和治疗评估。眼睑浮肿可能指示早期蜂窝组织炎，需要全身抗生素治疗。出现警示标志（眼睑肿胀伴疼痛和红斑、眼球突出、眼球运动疼痛、运动受限/复视、视力改变）应紧急转诊至眼科。

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