Chinese Journal of Lung Cancer
中国肺癌杂志编辑部
image
免疫检查点抑制剂相关消化系统不良反应的临床诊治建议
Volume: 22, Issue: 10
DOI 10.3779/j.issn.1009-3419.2019.10.10
  • PDF   
  • XML   
  •       
Abstract

恶性肿瘤的免疫治疗是当前肿瘤研究和治疗领域的热点,免疫检查点分子程序性死亡受体-1(programmed cell death receptor-1, PD-1)和细胞毒性T淋巴细胞相关抗原4(cytotoxic T lymphocyte-associated antigen 4, CTLA-4)相关信号通路的激活可以抑制T淋巴细胞活化,肿瘤细胞通过激活该信号通路实现免疫逃逸。免疫检查点抑制剂(immuno-checkpoint inhibitors, ICIs)通过抑制该信号通路,活化T淋巴细胞发挥机体对肿瘤细胞的清除。因此,ICIs的相关毒性包括免疫相关的不良事件(immune-related adverse effects, irAEs)。消化系统如胃肠道、肝脏作为人体重要的消化吸收器官、代谢解毒器官,同时也是重要的免疫相关器官,是irAEs的常见受累系统。本文将分别对ICIs的肝脏、胃肠道不良反应的发生率、临床表现、诊断和处理分别进行阐述。

Keywords
免疫检查点抑制剂相关消化系统不良反应的临床诊治建议

1. 免疫检查点抑制剂(immuno-checkpoint inhibitors, ICIs)的肝脏不良反应

1.1. 发生率

免疫相关肝毒性的发生率单药治疗(ipilimumab, nivolumab, pembrolizumab)约5%-10%,其中3级约1%-2%。联合治疗(如ipilimumab联合nivolumab)的发生率为25%-30%,其中3级约15% [1, 3]。单药治疗(nivolumab)3级-4级肝毒性的发生时间是14.1周(1.9周-25.1周),联合治疗(如ipilimumab联合nivolumab)3级-4级肝毒性的发生时间提前,平均为7.4周(2.1周-48周),并且持续时间延长[3]

1.2. 诊断

irAEs肝毒性的发生通常隐匿,可不伴随明显的临床表现,用药后定期监测肝功能有助于早期发现。一旦出现肝功能异常,或较用药前水平上升,需尽早完善包括血生化、肝炎病毒检测、肝脏影像检查,必要时肝活检等一系列检查。通常在肿瘤患者药物治疗前,需完善慢性肝病病史的询问,如饮酒史、长期用药史、慢性肝炎病史、自身免疫性肝病病史等。用药前应筛查自身免疫性肝病相关抗体、病毒性肝炎如乙型、丙型肝炎病毒等。当治疗后出现肝功能异常,需重复上述肝炎病毒血清学检查,以及甲肝、戊肝血清学检查,必要时检测病毒载量(如HBV-DNA、HCV-RNA)。还需常规完善机会性感染病原体,包括巨细胞病毒(Cytomegalovirus, CMV)、人类疱疹病毒第四型(Epstein-Barr virus, EBV)的相关检查。除上述病毒性肝炎、感染、酒精、其他合并药物等因素后,还需考虑肿瘤本身肝脏受累,治疗前的肝脏影像学评估对判断病因有一定帮助。以胆汁淤积(即胆红素升高,以直接胆红素为主,伴随GGT、ALP升高)为主要表现的患者,还需要行腹部影像学(如超声、MRCP)等除外胆道结石、肿瘤等梗阻性因素。

上述病因的鉴别应尽可能及早完善,强调用药治疗前的全面评估,以保证治疗过程中以最短的时间明确诊断,以免延误治疗时机。

对于不良反应严重程度分级为4级(表 1)的患者,需考虑行肝活检,以判断预后。肝穿刺活检病理最常见的表现是小叶性肝炎,与自身免疫性肝炎无法鉴别。大多数病例为广泛小叶病变,如有窦组织细胞增生和中央静脉内皮炎的表现有助于ipilimumab相关炎症的诊断。罕见病例表现为门静脉炎症和胆管炎[4]

1
irAEs肝毒性的评估和处理Evaluation and management of liver toxicity of irAEs
SeverityALT/ASTManagementEvaluation
ALT: alanine aminotransferase; AST: aspartate aminotransferase; ICIs: immune-checkpoint inhibitors; LFTs: liver function tests; ULN: upper limit of normal; Ⅳ: intravenous; irAEs: immune-related adverse events.
G1< 3 × upper limit of normal (ULN)Continue ICIsMonitor liver function tests (LFTs) in 1 week
G23-5 × ULNHold ICIs
Consider prednisone 0.5 mg/kg/d-1 mg/kg/d
Monitor LFTs every 3 days
Discontinue concurrent medicine
Limits/discontinue hepatotoxic medications (eg. antibiotics, statins, alcohol use, etc)
Rule out viral etiology, disease-related hepatic dysfunction
Consider abdominal ultrasound
G35-20 × ULNDiscontinue ICIs
If ALT/AST < 400 and normal TBIL/INR/albumin, consider prednisonlone 1 mg/kg/d
If ALT/AST > 400 or abnormal TBIL/INR/albumin, initiate Ⅳ methylpredinisolone 2 mg/kg/d
Evaluation as above
Monitor LFTs everyday
Consider abdominal ultrasound
Hospitalization
G4> 20 × ULNPermanently discontinue ICIs
Initiate Ⅳ methylpredinisolone 2 mg/kg/d
Evaluation as above
Consider hepatologist consultation and liver biopsy

1.3. 处理

肝毒性的处理原则见表 1,按照肝功能ALT/AST的升高水平和是否存在胆红素/INR/白蛋白的异常进行分级。通常G1无需停药;G2根据肝功能好转情况,可考虑择期恢复ICIs治疗;G3/G4需考虑永久性停药。激素是治疗肝毒性的主要药物。如分级为G3/G4,激素治疗有效,肝功能降至G2水平,可由静脉甲强龙转换为口服泼尼松龙,之后约4周逐渐减停。如G2,口服泼尼松龙治疗有效,可在2周内减停。在激素治疗的过程中,肝功能仍进行性加重,需考虑升级强化治疗。如:口服泼尼松龙转换为静脉甲强龙,静脉激素治疗2 d-3 d无效,加用口服麦考酚酸脂(mycophenolic acid, MMF)500 mg-1, 000 mg bid;如MMF无效,可考虑加用他克莫司。也有采用抗胸腺细胞球蛋白(anti-thymocyte globulin, ATG)治疗MMF无效的爆发性肝炎的病例报道。ICIs相关肝毒性通常在4-6周恢复,对于持续不缓解的患者,需警惕其他因素导致的肝功能异常,再次排查其他病因,特别需要警惕其他药物、机会性感染(如CMV)等病因。

2. ICIs的消化道不良反应

2.1. 发生率

消化道是irAEs最常见的受累部位。不同作用靶点的消化道irAEs发生率不同,CTLA-4单克隆抗体消化道不良反应发生率高于PD-1单克隆抗体[6]。比较PD-1抗体治疗黑色素瘤、非小细胞肺癌、肾细胞癌的irAEs发生率,显示黑色素瘤患者的消化道不良反应发生率更高,肺炎的发生率较低。提示同一药物在不同的免疫微环境中可能驱动组织学特异性的irAEs模式[6]

CTLA-4单克隆抗体治疗肿瘤患者腹泻的发生率为27%-54%。腹泻的发生率约占1/3,结肠炎的发生率为8%-22% [7]。消化道不良反应是CTLA-4单克隆抗体治疗最常见的irAEs,也是最重且最早出现的,常导致药物停用。有研究报道,1%-1.5%黑色素瘤接受ipilimumab治疗的患者发生结肠穿孔,肾细胞癌患者发生穿孔的比例高达6.6% [8]。PD-1单克隆抗体发生3级/4级消化道irAEs的比例为1%-2% [1]

CTLA-4抗体消化道irAEs可出现在第1-10次用药的任何时间,甚至可在末次用药后数月出现[8]。消化道irAEs发生中位时间是7.4周(1.0周-48.9周)[3]。CTLA-4抗体与PD-1抗体联合应用消化道irAEs的发生率更高,程度更重,且发生时间更早[1]

消化道irAEs的高危因素包括服用NSAIDs药物,有炎症性肠病病史等[9, 10]

2.2. 诊断

消化道irAEs最常见的表现是腹泻,其他包括腹痛、便血、恶心、呕吐、体重下降、发热等。可同时伴随多种肠道外受累表现,如关节痛、内分泌异常、皮肤损害、肝炎、肾炎、心包炎、胰腺炎等irAEs。实验室检查可出现C反应蛋白升高、贫血、低白蛋白血症,少部分患者可出现自身免疫性抗体如抗中性粒细胞胞浆抗体(antineutrophil cytoplasmic antibody, ANCA)等阳性[9]。内镜下表现多为左半结肠受累,黏膜充血、血管纹理消失、糜烂和溃疡,病变可弥漫分布,也可呈不连续性分布。组织学特点常表现为急性损伤(如中性粒细胞、嗜酸性粒细胞浸润),局灶或弥漫,可有隐窝脓肿。一部分患者可呈现组织学上慢性炎症如隐窝结构紊乱(分支、萎缩、出芽、扭曲等)、基底部浆细胞增多甚至肉芽肿表现[9]。消化道irAEs和消化道一类慢性非特异性疾病即炎症性肠病(inflammatory bowel disease, IBD)的临床表现、内镜表现、甚至病理特点均有相似、重叠之处,表 2总结了消化道irAEs的临床、内镜、病理和发病机制等特点,以及与IBD的可鉴别之处[11]

2
消化道irAEs的临床、内镜、病理特点总结Summary of clinical, endoscopic and pathological features of gastrointestinal irAEs
Gastrointestinal irAEs
IBD: inflammatory bowel disease; GVHD: graft versus host disease.
Clinical featuresAcute onset
Mild to life-threatening diarrhea, bowel perforation in severe patients
Severity of gastrointestinal differs in different ICIs
Higher risk in patients with a medical history of inflammatory bowel disease
Endoscopic featuresDiverse endoscopic manifestations; Rectum often spared; left colon often involved; diffuse lesion or segmental lesions
Pathological featuresIBD-like (increased basal plasma cells, crypts and apoptotic bodies are more common)
Lymphocytic colitis-like
Celiac disease-like (mostly seen in upper gastrointestinal tract)
GVHD like
Immune changesClear immune pathogenesis
CD4+ based T lymphocyte proliferation
Th1/Th17 up-regulation interaction with intestinal microbiota

消化道irAEs的诊断有赖于出现上述临床症状与ICIs用药的时间关系,具有上述实验室检查、内镜、组织病理学特点。同时,需除外其他病因,包括:感染性肠炎,如艰难梭菌感染、CMV结肠炎等机会性感染;缺血性结肠炎;其他药物导致的结肠炎,如非甾体抗炎药(nonsteroidal anti-inflammatory drugs, NSAIDs)等;放射性肠炎等。因此,建议完善粪便病原学检查(便常规、便培养、便艰难梭菌毒素检测、粪便寄生虫检测等)、血CMV-DNA等病毒相关病原学检测;同时建议完善腹盆部增强CT;经消化科医生会诊后完善消化内镜并内镜下组织活检。

2.3. 处理

消化道irAEs的处理原则是尽早识别、及时足量治疗、快速升级、改善预后。根据腹泻的次数进行严重程度分级,给予分层治疗。表 3详细列举不同严重程度消化道irAEs的处理方案。糖皮质激素是中重度消化道irAEs的主要治疗,如中度患者治疗有效,激素可在2周-4周减停;重度患者可在4周-8周减停。如激素治疗效果不佳,需及时调整激素剂量/剂型,必要时快速升级至英夫利昔单抗(infliximab, IFX)或维多株单抗。研究显示,与长期激素治疗比较,短期激素联合IFX治疗消化道irAEs合并各种感染的风险降低[12]。对于激素、IFX、维多株单抗均无效的难治性消化道irAEs,有病例报道显示肠道菌群移植治疗有效[13]

3
消化道irAEs的评估和处理Evaluation and management of gastrointestinal irAEs
SeverityManagementEvaluation
CMV: cytomegalovirus; Ⅳ: intravenous; IFX: infliximab; NPO: nothing by mouth.
Mild(G1): fewer than 4 bowel movements per day above baselineContinue ICIs
Symptom control: hydration, loperamide
Avoid high fiber/lactose diet
Stool evaluation to rule out infectious etiology: Clostridium difficile, CMV, etc
Moderate (G2): 4-6 bowel movements above baseline per day, colitis symptom (bloody diarrhea, abdominal pain)Hold ICIs
Prednisone 0.5 mg/kg/d-1 mg/kg/d
No response in 48-72 hours, increase dose to 2 mg/kg/d
Evaluation as above
GI consultation
Schedule colonoscopy/sigmoidoscopy
Recheck above tests every 3 days
Severe (G3/4): more than 6 bowel movements above baseline per day, other serious complications (eg. Ischemic bowel, perforation, toxic mega-colon)Discontinue ICIs
Hospitalization
Consider NPO, supportive care
Ⅳ methylprednisolone 1 mg/kg/d-2 mg/kg/d
No response in 48 hours, continue steroids, consider adding IFX
If IFX refractory, consider vedolizumab
Evaluation as above Consider abdominal/pelvic CT with contrast Monitor complete blood count, liver and kidney function tests, electrolytes, and C-reactive protein every day

3. 肠道菌群与消化道irAEs及肿瘤预后

目前尚未发现可预测消化道irAEs的生物标志物。最新的研究探索,ICIs治疗前基线的粪便微生物群组成可预测ipilimumab诱导的结肠炎。研究显示,基线时富含梭菌属和其他厚壁菌门的肠道微生物群与ipilimumab的治疗效果好相关,同时免疫相关结肠炎发生率高[14]。2018年初发表于Science上的多项研究提示治疗前特定的粪便微生物群组成与肿瘤对于ICIs的治疗反应相关[15, 16]。这将为进一步提高ICIs治疗肿瘤的疗效、改善预后带来前景。

4. 总结

伴随ICIs在肿瘤治疗中的广泛应用,irAEs也越来越被肿瘤科医生以及所涉及的各个专科医生所重视。消化系统以消化道受累(腹泻/结肠炎)最为突出,其次是肝脏受累。irAEs的基线筛查、早期识别、及时诊断和快速足量的治疗是解决该类临床问题的关键。肠道微生物群组成是否能预测消化道irAEs以及预测ICIs治疗肿瘤的预后值得进一步的研究探索。

References

1 

    Larkin J, Chiarion Sileni V, Gonzalez R, . Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015. 373: 13, pp.1270-1271, doi: 10.1056/NEJMoa1504030

2 

    Robert C, Schachter J, Long GV, . Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015. 372: 26, pp.2521-2532, doi: 10.1056/NEJMoa1503093

3 

    Larkin J. Efficacy and safety in key patient subgroups of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naive patients with advanced melanoma (MEL) (CheckMate067). Eur J Cancer 2015. 51: Suppl 3, pp.S664-S665, doi: 10.1016/S0959-8049(16)31822-6

4 

    Johncilla M, Misdraji J, Pratt DS, . Ipilimumab-associated hepatitis:clinicopathologic characterization in a series of 11 cases. Am J Surg Pathol 2015. 39: 8, pp.1075-1084, doi: 10.1097/PAS.0000000000000453

5 

    Mellati M, Eaton KD, Brooks-Worrell BM, . Anti-PD-1 and anti-PDL-1 monoclonal antibodies causing type 1 diabetes. Diabetes Care 2015. 38: 9, pp.e137-e138, doi: 10.2337/dc15-0889

6 

    Khoja L, Day D, WeiWu Chen T, . Tumor- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review. Ann Oncol 2017. 28: 10, pp.2377-2385, doi: 10.1093/annonc/mdx286

7 

    Gupta A, De Felice KM, Loftus EV, J r, . Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment Pharmacol Ther 2015. 42: 4, pp.406-417, doi: 10.1111/apt.13281

8 

    Beck KE, Blansfield JA, Tran KQ, . Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen. J Clin Oncol 2006. 24: 15, pp.2283-2289, doi: 10.1200/JCO.2005.04.5716

9 

    Marthey L, Mateus C, Mussini C, . Cancer immunotherapy with anti-CTLA-4 monoclonal antibodies induces an inflammatory bowel disease. J Crohns Colitis 2016. 10: 4, pp.395-401, doi: 10.1093/ecco-jcc/jjv227

10 

    Johnson DB, Sullivan RJ, Ott PA, . Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol 2016. 2: 2, pp.234-240, doi: 10.1001/jamaoncol.2015.4368

11 

    Bamias G, Delladetsima I, Perdiki M, . immunological characteristics of colitis associated with anti-CTLA-4 antibody therapy. Cancer Invest 2017. 35: 7, pp.443-455, doi: 10.1080/07357907.2017.1324032

12 

    Wang Y, Abu-Sbeih H, Mao E, . Immune-checkpoint inhibitor-induced diarrhea and colits in patients with advanced malignancies: retrospective review at MD Anderson. J immunother Cancer 2018. 6: 1, pp.37

13 

    Wang Y, Wiesnoski DH, Helmink BA, . Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med 2018. 24: 12, pp.1804-1808, doi: 10.1038/s41591-018-0238-9

14 

    Chaput N, Lepage P, Coutzac C, . Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol 2017. 28: 6, pp.1368-1379, doi: 10.1093/annonc/mdx108

15 

    Matson V, Fessler J, Bao R, . The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018. 359: 6371, pp.104-108, doi: 10.1126/science.aao3290

16 

    Gopalakrishnan V, Spencer CN, Nezi L, . Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018. 359: 6371, pp.97-103, doi: 10.1126/science.aan4236
https://www.researchpad.co/tools/openurl?pubtype=article&doi=10.3779/j.issn.1009-3419.2019.10.10&title=免疫检查点抑制剂相关消化系统不良反应的临床诊治建议&author=&keyword=免疫检查点抑制剂,免疫相关不良反应,肝脏毒性,消化道不良反应,Immune-checkpoint inhibitors,Immune-related adverse events,Liver toxicity,Gastrointestinal adverse events,&subject=免疫检查点抑制剂专题,