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

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SHR-1210与阿帕替尼或FOLFOX 4方案联合使用能够降低CCEP发生率,其具体机制有待于进一步研究。

Objective 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 statistical difference（P=0.105）,which may be related to the small sample size.Conclusion CCEP is the most common and drug-related adverse event in clinical trials of SHR-1210 for primary hepatic carcinoma.Its pathogenesis is still unclear and maybe related to the immune response caused by SHR-1210.CCEP often take place on the skin of face and body surface,never on the mucosa of respiratory tract and digestive tract.It is preliminarily observed that patients with CCEP tend to have higher response rate during SHR-1210 monotherapy.SHR-1210 combined with apatinib or FOLFOX 4 regimen can reduce the incidence of CCEP,and the specific mechanism of it needs further study.