小剂量白细胞介素2联合肝动脉化疗栓塞术和CT引导下射频消融术治疗大于5 cm原发性肝癌的疗效和安全性

Safety and efficacy of low-dose interleukin-2 plus transcatheter arterial chemoembolization followed by immediate radiofrequency ablation for the treatment of large primary liver cancer： a single-center experience

目的 探讨小剂量白细胞介素2（IL-2）联合肝动脉化疗栓塞术（TACE）在CT引导下行射频消融术（RFA）对大于5 cm的原发性肝癌的疗效和安全性.方法 将2011年1月至2013年12月初治的50例原发性肝癌患者,按照随机数字表法分入小剂量IL-2联合RFA ＋TACE组（A组）或单纯RFA＋ TACE组（B组）,各25例.患者至少有1个肿瘤最大直径≥5 cm.第1天行TACE.第（5±2）天行RFA.A组患者白第10天连续皮下注射重组人IL-2 250万单位,隔日皮下注射,共8周.主要观察终点为随机化开始至疾病进展时间（TTP）;次要观察终点为客观有效率（ORR）、总生存期和安全性.结果 患者中位年龄为55岁.中位随访期为518 d（91 ～1 227 d）.IL-2相关的不良事件主要为注射部位硬结[64.0％ （16/25）]、低热[48.0％ （12/25）]和乏力[36.0％ （9/25）].TACE联合RFA治疗相关的不良事件包括发热[88.0％（44/50）]、丙氨酸转氨酶（ALT）及天冬氨酸转氨酶（AST）升高[均为80.0％ （40/50）]、疼痛[76.0％（38/50）]和胆红素升高[66.0％ （33/50）].其中Ⅲ度疼痛10例,Ⅲ度ALT和AST升高各5例.2组之间在微创治疗的安全性方面差异无统计学意义（P=0.062）.总ORR均为74.0％ （37/50）,其中完全缓解11例,部分缓解26例.A组TTP较B组明显延长,差异有统计学意义.1年和2年生存率分别为67.8％（34例）和52.9％（26例）.结论 小剂量IL-2可能会进一步提高RFA＋ TACE治疗大于5 cm的原发性肝癌的临床效果,且耐受性良好.

Objective To explore the safety and efficacy of low-dose recombinant human interleukin-2 for injection （IL-2） plus transcatheter arterial chemoembolization （TACE） followed by immediate CT-guided radiofrequency ablation （RFA） treating primary liver cancer （PLC） with tumors ≥5 cm.Methods From January 2009 to September 2013,PLC patients with at least one tumor ≥5 cm in diameter were randomly assigned into either low-dose IL-2 plus RFA combined with TACE （group A） or RFA plus TACE alone （group B）.Lipiodol-based TACE was done on D1.The patients received CT-guided RFA on D5 ± 2.After that,IL-2 was administered for patients in Group A.The primary end point was time to progression （TTP）.The secondary end points included objective response rate （ORR）,overall survival （OS） and safety.Results In total,50 patients were recruited.25 were in group A and 25 were in group B.The median age of the cohort was 55 years （range：39-80 years）.Mean follow-up time was 518 days （range：91 to 1227 days）.IL-2 treatment-related adverse events （AEs） included injection site reaction64.0％ （16/25）,mild fever 48.0％ （12/25） andhypodynamia 36.0％ （9/25）.TACE plus RFA related AEs were mainly mild to moderate; 44 cases had fever （88.0％,44/50） ; 40 cases had ALTelevation （80.0％,40/50） ; 40 cases had AST elevation （80.0％,40/50） ; 38 cases had abdominal pain （76.0％,38/50） and 33 cases hadTBIL elevation （66.0％,33/50）.Grade 3 adverse events had 10 cases and 5 cases had ALT or AST elevation.Moreover,all AEs disappeared within 2 weeks without sequelae.Overall,the two groups had similar invasive treatment-emergent safety profiles.The total ORR was 74.0％ （37/50）,with 11 CR and 26 PR.The 1-year and 2-year overall survival rates were 67.8％ and 52.9％.No difference was found between groups regardingORR and OS（P =0.069）.However,the results demonstrated that IL-2 could significantly prolong TTP,301 d vs 153 d,P =0.047.In multivariate Cox-regression model showed that IL-2 could not change OR,TTP or OS.Conclusion Low-dose IL-2 may further improve the efficacy of RFA plus TACE in ≥5 cm hepatocellular carcinomas.