口服西罗莫司治疗难治性脉管性疾病的有效性与安全性

Efficacy and safety of oral sirolimus in the treatment of refractory vascular anomalies

目的探讨口服西罗莫司在治疗难治性脉管性疾病中的有效性和安全性。方法2017年2月至2018年2月,南京医科大学附属儿童医院烧伤整形外科收治20例经过传统手术、药物治疗等无显著效果的脉管性疾病患儿,男11例,女9例,年龄1个月至8岁。其中卡波西样血管内皮瘤(KHE)伴卡梅现象(KMP)5例,淋巴管畸形10例,静脉畸形3例,淋巴管-静脉畸形2例。西罗莫司单疗程为3个月,具体治疗方案为:每次0.8 mg/m2,分2次口服,监测血药浓度维持在10~15 ng/ml。观察服药前后患儿瘤体变化、病情转归、肝肾功能、血常规以及其他可能的药物不良反应等。疗程结束后进行疗效评价,有效为瘤体体积缩小超过50%和(或)血小板稳定在正常范围;部分有效为瘤体体积缩小25%~50%;无效为瘤体体积缩小不足25%或无明显变化。结果所有患儿口服西罗莫司治疗1~3个疗程,有效11例,部分有效6例,无效3例。全疗程结束后随访3个月以上,患儿瘤体无再次增大。5例KHE伴KMP患儿口服西罗莫司治疗后瘤体均明显缩小,血小板稳定在正常范围,但其中2例1个月龄患儿出现了重症肺炎,其中1例最终死亡,另外2例分别出现肝酶升高及高热不良反应。10例淋巴管畸形患儿病灶减小,药物使用过程中,4例出现轻度肝功能异常。2例淋巴管-静脉畸形患儿出现瘤体不同程度缩小,3例静脉畸形患儿无效,但疼痛症状明显缓解,疼痛评分由治疗前的(8.7±1.2)分下降至(1.3±1.2)分,差异具有统计学意义(t=7.778,P=0.001),1例静脉畸形患儿出现口腔溃疡。其余11例患儿均未出现明显不良反应。结论口服西罗莫司治疗难治性脉管性疾病可获得较好的效果,安全性尚可,但小婴儿患者使用时需要谨慎。

Objective To investigate the efficacy and safety of oral sirolimus in the treatment of refractory vascular anomalies.Methods From February 2017 to February 2018,20 cases of vascular deformity with no obvious improvements after multiple therapies in our hospital were included.Among them,5 have Kaposiform hemangioendothelioma(KHE)with Kasabach-Merritt phenomenon(KMP),10 have lymphatic malformation,3 have venous malformation and 2 have lymphatic venous malformation.A single course of oral sirolimus lasted for 3 months.Initial dose was 0.8 mg/m2 once,oral administration twice per day,and subsequent dose was adjusted to maintain the concentration of blood drug at 10-15 ng/ml.Before and after taking sirolimus,the general information,tumor changes and the adverse reactions were gathered.Efficacy was evaluated at the end of the treatment course.Effective:tumor volume reduced by more than 50%and or platelets stabilized in the normal range.Partly effective:tumor volume reduced by 25%-50%.No effect:tumor volume reduced by less than 25%or no significant change.Results All the patients were treated with sirolimus orally for 1-3 courses,among which 11 were effective,6 were partially effective,and 3 were ineffective.They were followed up for more than 3 months after the end of the whole course and no tumor enlargement was observed.All the 5 cases with KHE and KMP had significantly reduced tumor size and the platelets were stable in the normal range,but 2 of them suffered from severe pneumonia,one of them eventually perished.Two of the remaining children had elevated liver enzymes and high fever.The lesions of 10 patients with lymphatic malformations were reduced,and 4 of them had mild liver dysfunction.Two with lymphatic venous malformations had shrunk in different degree,and 3 with venous malformations had no effect.Three of them showed significant relief of pain symptoms,and their pain score was significantly lower than that before oral administration(8.7±1.2 vs 1.3±1.2,P=0.001).Except for 1 case with venous malformation had oral ulcer.No obvious adverse reaction were observed in the remaining 11 patients.Conclusions Oral sirolimus may be effective and safe in the treatment of refractory vascular anomalies,but it should be treated with caution in little infants.