摘要
目的肝内复发是乙型肝炎病毒(hepatitis B virus,HBV)相关性肝癌经导管动脉化疗栓塞(transcatheter arterial chemoembolitation,TACE)术后死亡的主要原因,目前已报道了几种方法可以降低TACE术后复发率,TACE术后辅以干扰素(interferon,IFN)治疗报道较少。本研究旨在探讨IFN对HBV相关性肝癌TACE术后临床转归的影响。方法选取2014-05-01-2015-10-31山东省千佛山医院收治HBV相关性原发性肝癌(hepatocenular carcinoma,HCC)患者138例,随机数字表法分为对照组(仅行TACE术)68例和观察组(TACE+IFN)70例。监测治疗前后免疫功能、肝功能、肝纤维化指标、HBV DNA载量、HBeAg阴转率及转换率等临床指标,疗效判定采用实体瘤治疗疗效评分标准(modified response evaluation criteria in solid tumors,mRECIST),比较两组患者近期、中远期疗效及复发情况。结果与治疗前比较,对照组TACE术后CD3+、CD4+、NK细胞百分数及CD4+/CD8+比值下降(P<0.001),观察组则升高(P<0.001);治疗后4周,观察组CD3+、CD4+、NK细胞百分数及CD4+/CD8+比值高于对照组,差异有统计学意义,P<0.001。观察组与对照组ALT水平随治疗时间的延长均有改善,差异有统计学意义,均P<0.001;24、48周观察组ALT水平低于对照组,差异有统计学意义,P<0.001。治疗48周,观察组HBV DNA载量随治疗时间的延长逐渐降低,差异有统计学意义(F=122.283,P<0.001),HBV DNA转阴率达59.8%;而对照组HBV DNA载量随治疗时间的延长逐渐升高,差异有统计学意义(F=2.468,P=0.045),有14例患者HBV DNA升高较基线水平>10倍,HBV激活率达20.6%(14/68);两组HBV DNA载量比较差异有统计学意义,P<0.001。观察组HBeAg阴转率45.0%,HBeAg转换率35.0%,对照组未出现HBeAg阴转或转换,两组比较差异有统计学意义,χ~2=9.258,P=0.001。观察组透明质酸(hyaluronidase,HA)、层黏蛋白(laminin,LN)、Ⅲ型前胶原(procollagenⅢ,PCⅢ)和Ⅳ型胶原(collagenⅣ,CⅣ)较治疗前降低(P<0.05),而对照组较治疗前升高,两组比较差异有统计学意义,P<0.05。观察组客观缓解率(objective response rate,ORR)为57.1%,较对照组的39.7%升高,χ~2=4.199,P=0.040;观察组疾病控制率(disease control rate,DCR)为88.6%,明显高于对照组的66.2%,χ~2=9.932,P=0.001。随访24个月,观察组复发率为55.7%,低于对照组的69.1.%,χ~2=4.503,P=0.034;观察组死亡率为38.6%,低于对照组的64.7%,χ~2=9.431,P=0.002;中位无进展生存期(progression-free survival,PFS)观察组23.6个月(95%CI:21.4~25.8),对照组20.3个月(95%CI:15.8~24.8),两者比较差异有统计学意义,χ~2=4.58,P=0.026;中位总生存期(overall survival,OS)观察组29个月(95%CI:27.5~32.1),对照组26个月(95%CI:20.1~31.9),两组比较差异有统计学意义,χ~2=8.96,P=0.003。多因素分析结果显示,肿瘤结节数目(P=0.012)和TACE-IFN治疗(P=0.008)是降低OS的独立影响因素。结论 HBV相关性肝癌TACE术后给予IFN治疗能增强患者的免疫功能,抑制HBV复制,减轻肝脏炎性改变及肝纤维化,降低肝内复发,提高近期疗效和OS。IFN治疗安全有效。
OBJECTIVE Intrahepatic recurrence is the major cause of death among patients with hepatitis B virus（HBV）-related hepatocellular carcinoma（HCC）after TACE.Several approaches have been reported to decrease the recurrence rate.There were few reports of adjuvant interferon（IFN）therapy on HBV-related HCC after TACE.The study is to evaluate the efficacy of interferon therapy on clinical outcome in patients with hepatitis B virus（HBV）-related primary hepatic carcinoma after transcatheter arterial chemoembolization（TACE）.METHODS 138 patients with HBV-related unresectable hepatocellular carcinoma（HCC）were recruited from May 2014 to October 2015.All the patients were randomly assigned into control group（n=68,TACE alone）or experimental group（n=70,TACE＋IFN）and were followed up for more than 24 months.Clinical indexes（cellular immune function,hepatic function,HBV DNA capacity,HBeAg seroconversion and conversion rate and hepatic fibrosis）before and after treatment,as well as the short-term curative effect and recurrence were compared between the two groups.To further assess the effect of treatment based on mRECIST,the time for progressive-free survival（PFS）,overall survival（OS）time and adverse events were recorded and compared between the two groups.RESULTS After treatment,the levels of CD3^＋,CD4^＋,CD4^＋/CD8^＋and NK were significantly increased in experimental group（TACE＋IFN group）（P〈0.001）while significantly decreased in control group（TACE group）（P〈0.001）.After 4 weeks,the levels of CD3^＋,CD4^＋,CD4^＋/CD8^＋and NK in experimental group were significantly higher than those in control group（P〈0.001）.The ALT level was improved significantly during the follow-up in both control and experimental group（P〈0.001）,but was significantly decreased in experimental group than that in control group at the end of 24 and 48 weeks（P〈0.001）.The HBV DNA undetectable rate after treatment was 59.8% at the end of 48 weeks in experimental group,while the HBV DNA levels increased after treatment in the control group.In the control group,there were 14 cases whose HBV DNA level increased more than 10 times,compared to that at baseline,and the activation rate of HBV was 20.6%.There was significant difference in HBV DNA levels after treatment between the two groups（P〈0.001）.The HBeAg seroconversion rate in the experimental group was 45.0%,and the HBeAg conversion rate was 35.0%;while there was no HBeAg seroconversion or conversion in control group（χ^2=9.258,P=0.001）.The hyaluronidase（HA）,the layer of mucin（LN）,type Ⅲ collagen（PCⅢ）and type Ⅳ peptide（CⅣ）were decreased in experimental group（P〈0.05）and increased in control group,the difference was statistically significant between the two groups（P〈0.05）.There were statistically significant difference in both disease control rate（DCR）and objective response rate（ORR）between the two groups（χ^2=4.199,χ^2=9.932,P=0.040,P=0.001）.At the 24-month follow up,the intrahepatic tumor recurrence rate（55.7%vs 69.1%,χ^2=4.503,P=0.034）and death rate（38.6% vs 64.7%,χ^2=9.431,P=0.002）in experimental group were significantly lower than those in the control group.Both the median PFS [23.6（95%CI：21.4-25.8）months vs 20.3（95%CI：15.8-24.8）months,χ^2=4.58,P=0.026]and median OS time[29.0（95%CI：27.5-32.1）months vs 26.0（95%CI：20.1-31.9）months,χ^2=8.96,P=0.003]were significantly longer in experiment group,compared to control group.Multivariate analysis showed that number of tumor nodules（P=0.012）and TACE-IFN treatment（P=0.008）were independent factors for overall survival.CONCLUSIONS Interferon therapy can effectively enhance cellular immune function,inhibit HBV replication,improve hepatic function,reduce recurrence and improve the survival in patients with HBV-related HCC after TACE treatment.The side effects of interferon are controllable and the treatment is safe and effective.
作者
辛梦
冯东峰
殷蓓蓓
李岩
XIN Meng;FENG Dong- feng;YIN Bei-bei;LI Yan(School of Medicine, Shandong University , Jinan 250012 , P. R. China;Department of Oncology , Shandong Provincial Qian f oshan Hospital, Jinan 250014,P. R. China)
出处
《中华肿瘤防治杂志》
CAS
北大核心
2018年第9期652-658,共7页
Chinese Journal of Cancer Prevention and Treatment
关键词
原发性肝癌
乙型肝炎病毒
动脉化疗栓塞
干扰素
复发率
总体生存率
hepatocellular carcinoma
interferon
hepatitis B virus
transcatheter arterial chemoembolization
recur-rence rate loverall survival rate
