抗PD-1单抗SHR-1210治疗原发性肝癌引发皮肤毛细血管增生症的临床病理报告  

Clinicopathological report of cutaneous capillary endothelial proliferation related with anti-PD-1 monoclonal antibody SHR-1210 in the treatment of primary hepatic carcinoma

作　　者：王锋[1] 秦叔逵[1] 方维佳[2] 刘秀峰 华海清[1] 李桂梅[3] 杨柳青[1] 龚新雷[1] 

机构地区：[1]南京中医药大学附属八一医院全军肿瘤中心,南京210002 [2]浙江大学医学院附属第一医院肿瘤细胞生物治疗中心,310006 [3]南京中医药大学附属八一医院病理科,210002

出　　处：《临床肿瘤学杂志》2017年第12期1066-1072,共7页Chinese Clinical Oncology

摘　　要：目的观察和分析国产抗PD-1单抗新药SHR-1210在治疗原发性肝癌临床研究中出现皮肤毛细血管增生症(CCEP)的情况。方法我院2016年11月1日至2017年9月30日参加了SHR-1210治疗原发性肝癌的两项临床研究,其中单药组:SHR-1210 3 mg/kg静滴q2W或3 mg/kg静滴q3W,42天为1个治疗周期。联合A组:SHR-1210 3 mg/kg静滴q2W,甲磺酸阿帕替尼起始剂量125 mg口服qd。联合B组:SHR-1210 3 mg/kg静滴q2W,FOLFOX 4方案(奥沙利铂85 mg/m^2静滴d_1,亚叶酸钙200 mg/m^2静滴d_1、d_2,氟尿嘧啶400 mg/m^2静推d_1、d_2,600 mg/m^2持续静滴d_1、d_2,q2W)。严密观察随访两项临床研究用药后引发CCEP的发生率,根据形态学进行分型和分析临床特征,并且分享典型病例。结果 38例接受SHR-1210单药治疗者,包括2周治疗组16例,3周治疗组22例,均为肝细胞癌。联合A组6例,包括肝细胞癌2例和胆管细胞癌4例;联合B组18例,包括肝细胞癌8例和胆管细胞癌10例。至少用药2次者共59例可以观察CCEP的发生情况,按照形态学表现大致可分为"红痣型"、"珍珠型"、"桑椹型"、"斑片型"和"瘤样型"5种类型。SHR-1210单药组发生CCEP的总体发生率为77.1%(27/35),联合A组和联合B组CCEP发生率分别为33.3%(2/6)和61.1%(11/18)。在所有可评价疗效的45例患者中,35例发生CCEP;发生CCEP者获部分缓解(PR)31.4%(11/35),疾病稳定(SD)14.3%(5/35),疾病进展(PD)54.3%(19/35),而未发生CCEP者无完全缓解(CR)或PR,SD 40.0%(4/10),PD 60.0%(6/10);发生CCEP者的有效率(CR+PR)明显高于未发生CCEP者,但差异尚未达显著性(P=0.105),可能与本中心统计的样本量较小有关。结论 CCEP是SHR-1210治疗原发性肝癌临床研究中常见的药物相关性不良事件,其发生机制尚不清楚,可能与其引起的应激性血管内皮细胞免疫反应有关;初步观察CCEP多见于颜面部和体表皮肤,未见发生于呼吸道和消化道黏膜的病例。同时SHR-1210单药引发CCEP者的客观有效率较高,而SHObjective To observe and analyze the appearance of cutaneous capillary endothelial proliferation（CCEP）in clinical trials of primary hepatic carcinoma treated with domestic anti-PD-1 monoclonal antibody SHR-1210.Methods From Nov 1,2016to Sep 30,2017,SHR-1210 was used to treat primary hepatic carcinoma in our hospital.Among them,single drug group：SHR-1210 3mg/kg iv q2W or 3 mg/kg iv q3W.The combined group A：SHR-1210 3 mg/kg iv q2W;apatinib starting dose 125 mg po qd.The combined group B：SHR-1210 3 mg/kg iv q2W;FOLFOX 4 regimen（oxaliplatin 85 mg/m^2iv d_1;leucovorin 200 mg/m^2iv d_1,d_2;fluorouracil 400 mg/m^2iv d_1,d_2;fluorouracil 600 mg/m^2CIV d_1,d_2,q2W）.The incidence of CCEP was observed during SHR-1210treatment and classified according to the shape.Pathological examinations were performed in some patients and 2 typical cases were shared.Results Thirty-eight patients received SHR-1210 monotherapy,including 2 weeks group（n=16）and 3 weeks group（n=22）,all of which were hepatocellular carcinoma.There were 6 cases in SHR-1210 combined with apatinib group,including 2 cases of hepatocellular carcinoma,and 4 cases of cholangiocarcinoma.There were 18 cases in SHR-1210 combined with FOLFOX 4 regimen group,including 8 cases of hepatocellular carcinoma and 10 cases of cholangiocarcinoma.CCEP can be observed in 59 patients treated with SHR-1210 at least 2 times.CCEP were divided into＂red-nevus＂,＂pearl＂,＂mulberry＂,＂patch＂and＂tumor type＂according to morphological features.The total incidence rate of CCEP of SHR-1210 monotherapy was 77.1%（27/35）.The incidence of CCEP in the combined A group and the combined B group was 33.3%（2/6）and 61.1%（11/18）,respectively.Among the 45 patients could be evaluated,CCEP was found in 35 cases.Patients with CCEP achieved PR 31.4%（11/35）,SD 14.3%（5/35）and PD 54.3%（19/35）,while those without CCEP got SD 40%and PD 60%.The response rate of patients with CCEP was significantly higher than those without CCEP,but there was no statistica

关 键 词：原发性肝癌 抗PD-1单抗/SHR-1210 皮肤毛细血管增生症(CCEP) 临床试验 免疫相关不良反应 

分 类 号：R735.7[医药卫生—肿瘤]