低剂量白介素-2联合肝动脉化疗栓塞术序贯CT引导下射频消融术在≥5cm的原发性肝癌的疗效和安全性

Safety and Efficacy of Low-dose IL-2 Combined with Transcatheter Arterial Chemoembolization Followed by Immediate Radiofrequency Ablation in Patients with Large Primary Liver Cancer: a Single Center Experience

目的：探讨低剂量白介素-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）（RFA）在≥5cm 的原发性肝癌的疗效和安全性。方法：2010年10月至2013年9月入组初治的原发性肝癌患者，随机分入低剂量 IL-2联合 RFA＋TACE 组（A 组）或单纯RFA＋TACE 组（B 组）；患者至少有1个肿瘤最大径≥5cm。D1行 TACE 术。D5＆#177;2行 RFA 术。A 组患者自 D10连续皮下注射重组人白介素-250万单位 QOD，共8周。主要观察终点为至疾病进展时间（TTP）；次要观察终点为客观有效率（ORR）、总生存期（OS）和安全性。结果：共50例患者入组，A、B 组均25例。患者中位年龄为55岁。中位随访期为518d（91-1227d）。IL-2相关的不良事件主要为注射部位硬结（64%）、低热（48%）和乏力（36%）。TACE 联合 RFA 治疗相关的不良事件多为轻至中度或一过性，最常见的包括发热（88.0%）、ALT 及 AST 升高（均为80.0%），疼痛（76.0%）和胆红素升高（66.0%）。其中 III 度疼痛10例，III 度 ALT 和 AST 升高各5例。两组之间在微创治疗的安全性方面无显著差异。总 ORR 均为74.0%，其中 CR 11例，PR 26例。1年和2年生存率分别为67.8%和52.9%。两组之间在 ORR 和 OS 方面无差异。但是，A组较 B 组 TTP 显著延长（301d 比153d，P =0.047）。在多因素分析中，IL-2并未改变患者预后或疗效。结论：低剂量 IL-2可能会进一步提高 RFA＋TACE 在≥5cm 的原发性肝癌的疗效，且耐受性良好。需要进一步扩大样本量、探讨更高剂量或更长疗程 IL-2在此类患者的作用。

Objective： To explore the safety and efficacy of low-dose interleukin 2 （IL-2） combined with transcatheter arterial chemoembolization （TACE） fol owed by immediate CT-guided radiofrequency ablation （RFA） for large primary liver cancer （PLC） （maximum diameter ≥ 5 cm）. Methods： From January 2009 to September 2013, treatment-naive patients with PLC ≥ 5 cm were randomly assigned to receive either low-dose IL-2 plus RFA combined with TACE （Group A） or RFA combined with TACE （Group B）. All patients underwent lipiodol-based TACE on D1, and then received CT-guided RFA on D5±2. After that, for the patients in Group A, IL-2 was administered subcutaneously QOD at a dose of 500,000 u, for 8 consecutive weeks since D10. The primary endpoint was time to progression （TTP）. The secondary endpoints included objective response rate （ORR）, overal survival （OS） and safety. Results：A total of 50 patients （25 in each group） were recruited in this study. The median age of the cohort was 55 （range： 39-80）. The median fol ow-up time was 518 days （range： 91-1227 days）. IL-2 treatment-related adverse events （AEs） included reaction at injection site （64%, 16 cases）, mild fever （48%, 12 cases） and hypodynamia （36%, 9cases）. TACE combined with RFA treatment-emergent AEs were mainly mild or moderate, including 44 cases of fever （88.0%）, 40 cases of ALT elevation （80.0%）, 40 cases of AST elevation （80.0%）, 38 cases of abdominal pain （76.0%） and 33 cases of TBIL elevation （66.0%）. Grade 3 AEs comprised pain （10 cases）, ALT elevation （5 cases） and AST elevation （5 cases）. Moreover, al patients recovered from these AEs within 2 weeks without sequelae. Overal , the invasive treatment was associated with similar safety profiles in both two groups. The total ORR was 74.0% （ 11/50 CR and 26/50 PR）. The 1-year and 2-year OS rates were 67.8% and 52.9%, respectively. No difference was found between the two groups in either ORR or OS. However, the results demonstrated that IL-2 significantly prolonged TTP （301d vs 153d, P=0.047）. Multivariate Cox-regression model shown IL-2 administration was not significantly associated with outcome endpoints （OR, TTP or OS）. Conclusion： Low-dose IL-2 may improve the efficacy of RFA combined with TACE for large hepatocellular carcinomas with well tolerability. The effect of IL-2 for the treatment of PLC would be identified by further investigations with higher doses or longer regimen period of IL-2.