射频消融术后序贯非特异性免疫治疗早期肝细胞癌的前瞻性研究

Radiofrequency ablation combined with non-specific sequential immunotherapy for early hepatocellular carcinoma： a prospective study

目的：探讨射频消融术（RFA）后序贯非特异性免疫治疗早期肝细胞癌的临床疗效，分析影响早期肝细胞癌患者行RFA后预后的因素。方法：采用前瞻性研究方法。选取2009年1月至2015年10月广西壮族自治区人民医院收治的72例早期肝细胞癌患者的临床病理资料。采用随机数字表法将患者分为3组：A组患者单纯行RFA治疗；B组患者行RFA序贯非特异性免疫治疗（1-3次）；C组患者行RFA序贯非特异性免疫治疗（≥4次）。由同一手术团队医师施行RFA，非特异性免疫方案为胸腺法新联合白细胞介素-2（IL-2）。观察指标：（1）治疗情况。（2）随访和生存情况。（3）早期肝细胞癌患者行RFA后预后因素分析。采用门诊方式进行随访，了解患者肿瘤复发及总体生存情况。随访时间截至2015年12月。正态分布的计量资料采用x±s 表示，多组间比较采用方差分析。计数资料比较采用χ^2检验。采用Kaplan-Meier法绘制治疗后肿瘤复发曲线和总体生存曲线，并计算肿瘤复发率、肿瘤复发时间和总体生存时间，采用Log-rank检验进行生存分析。单因素和多因素分析采用COX比例风险回归模型。结果：筛选出符合研究条件的患者72例，其中A组31例，B组22例，C组19例。（1）治疗情况：3组患者均完成RFA，术后5 d超声造影检查示肿瘤均完全消融。B组和C组患者行RFA后免疫治疗过程中均未见明显不良反应。（2）随访和生存情况：72例患者均获得治疗后随访，随访时间为2-66个月，中位随访时间为34个月。A、B、C组患者治疗后1年肿瘤复发率分别为19.4%、13.6%、10.5%，3组比较，差异无统计学意义（χ^2=0.714，P〉0.05）。A、B、C组患者中位肿瘤复发时间分别为24.0个月、30.0个月、33.0个月，3组比较，差异无统计学意义（χ^2=3.283，P〉0.05）。A、B、C组患者中位总体生存时间分别为46.0个月、56.0个月、57.0个月，3组比较，差异有统计学意义（χ^2=7.709，P〈0.05）。其中A组分别与B组、C组比较，差异均有统计学意义（χ^2=4.566，4.243，P〈0.05）；B组与C组比较，差异无统计学意义（x2=0.078，P〉0.05）。（3）早期肝细胞癌患者行RFA后预后因素分析。单因素分析结果显示：肿瘤初发、肿瘤数目、巴塞罗那临床肝癌（BCLC）分期、RFA后序贯免疫治疗是影响早期肝细胞癌患者行RFA后预后的相关因素［风险比（HR）=2.636，2.530，0.145，0.582，95%可信区间（CI）：1.218-5.703，1.110-5.767，0.041-0.517，0.321-0.867，P〈0.05］。多因素分析结果显示：肿瘤数目〉1个、BCLC分期为B期、RFA后未序贯免疫治疗是影响早期肝细胞癌患者行RFA后预后不良的独立危险因素（HR=2.376，2.683，0.567，95%CI：1.080-5.229，1.530-21.112，0.335-0.962，P〈0.05）。结论：RFA后序贯胸腺法新联合IL-2非特异性免疫治疗方案可有效延长早期肝细胞癌患者总体生存时间。肿瘤数目〉1个、BCLC分期为B期、RFA后未序贯免疫治疗是影响早期肝细胞癌患者RFA后预后不良的独立危险因素。

Objective：To investigate the clinical effect of radiofrequency ablation （RFA） combined with non-specific sequential immunotherapy （IM） for early hepatocellular carcinoma （HCC）,and analyze the factors affecting prognosis of patients after RFA. Methods：The prosepctive study was conducted. The clinicopathological data of 72 early HCC patients who were admitted to the People′s Hospital of Guangxi Zhuang Autonomous Region from January 2009 to October 2015 were collected. Patients were divided into 3 groups by random number table： patients in group A underwent single RFA therapy; patients in group B underwent RFA ＋ non-specific sequential IM （1-3 times）; patients in group C underwent RFA ＋ non-specific sequential IM （≥4 times）. RFA was performed by the same doctors team, and non-specific sequential IM planning included thymalfasin ＋ interleukin-2 （IL-2）. Observation indicators： （1） treatment situations; （2） follow-up and survival; （3） analysis of prognostic factors after RFA. Follow-up using outpatient examination was performed to detect tumor recurrence and overall survival up to December 2015. Measurement data with normal distribution were represented as ±s, and comparison among groups were evaluated with the ANOVA. Comparison of count data were analyzed using the chi-square test. The curve, rate and time of tumor recurrence after treatment,overall survival curve and time were respectively drawn and calculated by the Kaplan-Meier method, and the Log-rank test was used for survival analysis. The univariate analysis and multivariate analysis were respectively done using the COX proportional hazard regression model. Results：Seventy-two patients were screened for eligibility, including 31 in group A, 22 in group B and 19 in group C. （1） Treatment situations： patients in 3 groups underwent RFA, and contrast-enhanced ultrasound showed complete tumors ablation at 5 days postoperatively. Patients in group B and C didn′t have significant adverse reactions after RFA during IM therapy. （2） Follow-up and survival： 72 patients were followed up for 2-66 months after treatment, with a median time of 34 months. The 1-year tumor recurrence rates after treatment in group A, B and C were respectively 19.4%, 13.6% and 10.5%, with no statistically significant difference （χ^2=0.714, P〉0.05）. The median tumor recurrence times in group A, B and C were respectively 24.0 months, 30.0 months and 33.0 months, with no statistically significant difference （χ^2=3.283, P〉0.05）. The median overall survival times in group A, B and C were respectively 46.0 months, 56.0 months and 57.0 months, with a statistically significant difference （χ^2=7.079, P〈0.05）. There were statistically significant differences between group A and group B and C （χ^2=4.566, 4.243, P〈0.05）, and no statistically significant difference between group B and group C （χ^2=0.078, P〉0.05）. （3） Analysis of prognostic factors after RFA： results of univariate analysis showed that initial tumor, tumor number, Barcelona clinic liver cancer （BCLC） staging and sequential IM after RFA were related factors affecting prognosis of early HCC patients [hazard ratio （HR）=2.636, 2.530, 0.145, 0.582, 95% confidence interval （CI）： 1.218-5.703, 1.110-5.767, 0.041-0.517, 0.321-0.867, P〈0.05]. Results of multivariate analysis showed that tumor number 〉 1, staging B of BCLC and without sequential IM after RFA were independent risk factors affecting prognosis of early HCC patients （HR=2.376, 2.683, 0.567, 95%CI： 1.080-5.229, 1.530-21.112, 0.335-0.962, P〈0.05）. Conclusions： The non-specific sequential IM of thymalfasin ＋ IL-2 can prolong survival time of early HCC patients after RFA. Tumor number 〉 1, staging B of BCLC and without sequential IM after RFA are independent risk factors affecting prognosis of early HCC patients.