经导管动脉内化疗栓塞术联合索拉非尼序贯微波消融和经导管动脉内化疗栓塞术联合索拉非尼治疗肿瘤直径>5cm肝细胞癌的前瞻性研究

目的比较经导管动脉内化疗栓塞术(TACE)联合索拉非尼序贯微波消融(MWA)和TACE联合索拉非尼治疗肿瘤直径>5 cm肝细胞癌的疗效和安全性,分析预后影响因素。方法采用前瞻性队列研究方法。选取2012年7月至2013年11月两家医疗中心收治的61例(潍坊医学院附属烟台市莱阳中心医院30例、青岛大学附属青岛市中心医院31例)肿瘤直径>5 cm肝细胞癌患者的临床病理资料。患者采用TACE联合索拉非尼序贯MWA治疗设为观察组;采用TACE联合索拉非尼治疗设为对照组。观察指标:(1)治疗和并发症及药物不良反应情况。(2)近期疗效。(3)随访和生存情况。(4)预后影响因素分析。采用住院、门诊或电话方式进行随访。随访时间为治疗后6个月内每个月随访1次,之后每3个月随访1次,随访内容包括实验室指标、肿瘤标志物、腹部增强X线计算机体层摄影术或磁共振成像检查。了解患者生存与疾病进展情况。随访时间截至2018年11月。正态分布的计量资料以±s表示,组间比较采用t检验;偏态分布的计量资料以M(范围)表示,组间比较采用Wilcoxon秩和检验。计数资料以绝对数和(或)百分比表示,组间比较采用χ2检验或Pearson校正χ2检验。等级资料采用Wilcoxon秩和检验。采用Kaplan-Meier法计算生存率并绘制生存曲线,采用Log-rank检验进行生存分析。多个时间点生存率比较采用Bonferroni法调整检验水准。采用多元COX比例风险模型进行单因素和多因素分析。结果筛选出符合研究条件的肝细胞癌患者61例;男36例,女25例;年龄为(58±8)岁,年龄范围为43~73岁。61例患者中,观察组31例,对照组30例。(1)治疗和并发症及药物不良反应情况:①治疗情况,观察组患者TACE治疗次数、MWA治疗次数、首次TACE治疗至首次索拉非尼服药时间、索拉非尼服药时间分别为1次(1~5次)、2次(1~4次)、5 d(5~9 d)、24个月(6~72个月),对照组患者上述指标分别为3次(1~5次)、0、6 d(5~9 d)、16个月(6~60个月),两组患者TACE治疗次数、MWA治疗次数、索拉非尼服药时间比较,差异均有统计学意义(Z=4.701,-7.213,-2.614,P<0.05)。两组患者首次TACE治疗至首次索拉非尼服药时间比较,差异无统计学意义(Z=0.573,P>0.05)。②并发症情况:观察组和对照组患者均无TACE并发症发生;观察组3例患者发生MWA并发症,其中肝包膜下少量出血2例,胸腔积液1例,经保守治疗后均缓解。③索拉非尼不良反应情况:观察组和对照组患者口服索拉非尼2个月后均出现≥1种与索拉非尼相关的Ⅰ~Ⅲ级不良反应,无Ⅳ级不良反应。观察组患者发生手足皮肤反应、皮疹、瘙痒、皮肤色素脱失、腹泻、食欲下降、恶心呕吐、肝区疼痛、发热、疲劳、肝功能障碍、骨髓抑制分别为8、3、4、3、10、18、20、20、20、15、3、2例,对照组患者上述指标分别为9、3、3、2、13、19、23、12、21、12、6、2例,两组患者上述指标比较,差异均无统计学意义(χ2=0.133,0.000,0.000,0.000,0.796,0.177,1.082,3.674,0.208,0.435,0.601,0.000,P>0.05)。发生索拉非尼不良反应患者经对症治疗、减少索拉非尼剂量或间断停药后均缓解。(2)近期疗效:观察组患者治疗1个月后甲胎蛋白(AFP)为16μg/L(3~538μg/L),对照组患者治疗1个月后AFP为292μg/L(9~642μg/L),两组患者AFP比较,差异有统计学意义(Z=3.744,P<0.05)。观察组患者治疗3个月后肿瘤完全缓解、部分缓解、疾病稳定、疾病进展,肿瘤客观缓解率,疾病控制率分别为14、11、6例、0,80.6%(25/31),100.0%(31/31),对照组患者上述指标分别为2、13、12、3例,50.0%(15/30),90.0%(27/30),两组患者肿瘤客观缓解率比较,差异有统计学意义(χ2=6.343,P<0.05);两组患者疾病控制率比较,差异无统计学意义(χ2=1.473,P>0.05)。(3)随访和生存情况:61例肝细胞癌患者均获得随访,随访时间为9.0~75.0个月,中位随访时间为22.0个月。随访期间,观察组28例患者出现疾病进展,其中8例为肿瘤局部进展,4例为门静脉主干癌栓,11例为肝内转移,5例为肺转移;对照组30例患者出现疾病进展,其中13例为肿瘤局部进展,6例为门静脉主干癌栓,6例为肝内转移,5例为肺转移。61例患者中,观察组28例死亡,对照组29例死亡。观察组患者中位总体生存时间、中位无进展生存时间分别为28.0个月、18.0个月,对照组患者上述指标分别为19.5个月、11.5个月,两组患者上述指标比较,差异均有统计学意义(χ2=8.021,10.506,P<0.05)。观察组患者1、3、5年总体生存率分别为97%、37%、20%,对照组患者上述指标分别为83%、13%、7%,两组患者上述指标比较,差异均有统计学意义(Z=23.635,4.623,3.139,P<0.0167)。观察组患者1、2、3年无进展生存率分别为77%、40%、27%,对照组患者上述指标分别为43%、13%、7%,两组患者上述指标比较,差异均有统计学意义(Z=9.965,4.900,3.684,P<0.0167)。(4)预后影响因素分析:单因素分析结果显示治疗方案、肿瘤最大直径、巴塞罗那临床肝癌(BCLC)分期、肝硬化、乙型肝炎病毒(HBV)感染、肝功能Child-Pugh分级是影响肝细胞癌患者总体生存时间和无进展生存时间的相关因素[(风险比=0.483,6.196,12.646,5.049,2.950,4.791,95%可信区间为0.284~0.823,3.198~12.003,5.031~31.785,2.586~9.858,1.366~6.369,2.507~9.155,P<0.05)和(风险比=0.427,5.804,7.032,5.405,2.925,4.410,95%可信区间为0.248~0.735,3.043~11.070,3.071~16.101,2.685~10.881,1.364~6.270,2.331~8.342,P<0.05)]。多因素分析结果显示:治疗方案、肿瘤最大直径、BCLC分期、肝硬化、HBV感染是肝细胞癌患者总体生存时间和无进展生存时间的独立影响因素[(风险比=0.183,5.886,17.544,4.702,3.801,95%可信区间为0.090~0.370,2.648~13.083,5.740~53.622,1.928~11.470,1.368~10.562,P<0.05)和(风险比=0.201,3.850,3.843,3.598,3.726,95%可信区间为0.098~0.411,1.761~8.414,1.526~9.682,1.444~8.963,1.396~9.947,P<0.05)]。结论与TACE联合索拉非尼比较,TACE联合索拉非尼序贯MWA治疗肿瘤直径>5 cm肝细胞癌安全、有效。治疗方案、肿瘤最大直径、BCLC分期、肝硬化、HBV感染是肝细胞癌患者总体生存时间和无进展生存时间的独立影响因素。

A prospective study on transcatheter arterial chemoembolization combined with sorafenib and sequential microwave ablation versus transcatheter arterial chemoembolization combined with sorafenib in the treatment of hepatocellular carcinoma with tumor diameter over 5 cm

Objective To investigate the efficacy and safety of transcatheter arterial chemoembolization(TACE)combined with sorafenib and sequential microwave ablation(MWA)versus TACE combined with sorafenib in the treatment of hepatocellular carcinoma(HCC)with tumor diameter over 5 cm,and to analyze risk factors affecting the prognosis of patients.Methods The prospective cohort study was conducted.The clinicopathological data of 61 HCC patients with tumor diameter over 5 cm who were admitted to two medical centers(30 in the Laiyang Central Hospital of Yantai City Affiliated to Weifang Medical College and 31 in the Qingdao Central Hospital Affiliated to Qingdao University)between July 2012 and November 2013 were collected.Patients who were treated with TACE combined with sorafenib and sequential MWA were allocated into observation group,and patients who were treated with TACE combined with sorafenib were allocated into control group.Observation indicators:(1)treatment,complications and adverse drug reactions;(2)short-term efficacies;(3)follow-up and survival situations;(4)analysis of prognostic factors.Follow-up was performed by inpatient,outpatient examinations or telephone interview once a month within the first 6 months after treatment and once every 3 months thereafter up to November 2018.The follow-up included laboratory indicators,tumor markers,abdominal enhanced computed tomography or magnetic resonance imaging examinations.The survival of patients and disease progression were fully documented.Measurement data with normal distribution were expressed as Mean±SD,and comparison between groups was performed by the t test.Measurement data with skewed distribution were described as M(range),and comparison between groups was performed using the Wilcoxon rank sum test.Count data were expressed as absolute numbers or percentages,and comparison between groups was performed using the chi-square test or pearson-corrected chi-square test.Ranked data were analyzed using the Wilcoxon rank sum test.The Kaplan-Meier method was used to calculate survival rates and draw survival curves.The Log-rank test was used for survival analysis.Comparison of survival rates between time points was performed using the Bonferroni method to adjust the test level.Univariate and multivariate analyses were performed using the multiple COX proportional hazard model.Results A total of 61 HCC patients were selected for eligibility,including 36 males and 25 females,aged(58±8)years,with a range from 43 to 73 years.Of the 61 patients,31 were in the observation group and 30 in the control group.(1)Treatment,complications and adverse drug reactions:①treatment information.The treatment times of TACE,treatment times of MWA,time from the first TACE to the first sorafenib medication,and duration of sorafenib medication in the observation group were 1 time(range,1-5 times),2 times(range,1-4 times),5 days(range,5-9 days),24 months(range,6-72 months),respectively.The above indicators of patients in the control group were 3 times(range,1-5 times),0,6 days(range,5-9 days),and 16 months(range,6-60 months).There were significant differences in the treatment times of TACE,treatment times of MWA,and duration of sorafenib medication between the two groups(Z=4.701,-7.213,-2.614,P<0.05).There was no significant difference in the time from the first TACE to the first sorafenib medication between the two groups(Z=0.573,P>0.05).②Complications:there was no TACE related complications in the two groups.There were 3 patients with MWA related complications in the observation group,including 2 cases of minor hemorrhage under the liver capsule and 1 case of pleural effusion,and they were relieved after conservative treatment.③Adverse reactions to sorafenib:after 2 months of sorafenib medication,patients in the observation group and control group had at least one kind of sorafenib related stageⅠ-Ⅲadverse reaction,without stageⅣadverse reaction.The numbers of cases with hand-foot skin reaction,rash,pruritus,loss of skin pigmentation,diarrhea,decreased appetite,nausea and vomiting,pain in the liver area,fever,fatigue,liver dysfunction,bone marrow suppression were 8,3,4,3,10,18,20,20,20,15,3,2 in the observation group,and 9,3,3,2,13,19,23,12,21,12,6,2 in the control group,respectively,showing no significant difference in the above indices between the two groups(χ2=0.133,0.000,0.000,0.000,0.796,0.177,1.082,3.674,0.208,0.435,0.601,0.000,P>0.05).Patients with adverse reactions to sorafenib were relieved by symptomatic treatment,reducing the dose of sorafenib or intermittent drug withdrawal.(2)Short-term efficacies:the level of alpha fetoprotein was 16μg/L(range,3-538μg/L)in the observation group and 292μg/L(range,9-642μg/L)in the control group after one month of treatment,showing a significant difference between the two groups(Z=3.744,P<0.05).After 3 months of treatment,cases with tumor complete remission,cases with tumor partial remission,cases with stable disease,cases with progressive disease,objective response rate,and disease control rate in the observation group were 14,11,6,0,80.6%(25/31),100.0%(31/31),respectively.The above indicators in the control group were 2,13,12,3,50.0%(15/30),90.0%(27/30).There was a significant difference in the objective response rate between the two groups(χ2=6.343,P<0.05),but no significant difference in the disease control rate between the two groups(χ2=1.473,P>0.05).(3)Follow-up and survival situations:61 HCC patients were followed up for 9.0-75.0 months,with a median follow-up time of 22.0 months.During the follow-up,28 patients in the observation group had progressive disease,including 8 cases of local tumor progression,4 of portal vein tumor thrombi,11 of intrahepatic metastasis,and 5 of pulmonary metastasis.Thirty patients in the control group had progressive disease,including 13 cases of local tumor progression,6 of portal vein tumor thrombi,6 of intrahepatic metastasis,and 5 of pulmonary metastasis.Among the 61 patients,28 patients in the observation group and 29 patients in the control group died.The median overall survival time and median progression-free survival time of the observation group was 28.0 months and 18.0 months,versus 19.5 months and 11.5 months of the control group,showing significant differences between the two groups(χ2=8.021,10.506,P<0.05).The 1-,3-,5-year overall survival rates of the observation group were 97%,37%and 20%,respectively,versus 83%,13%and 7%of the control group,showing significant differences in the above indicators between the two groups(Z=23.635,4.623,3.139,P<0.0167).The 1-,2-,3-year progression-free survival rates of the observation group were 77%,40%,and 27%,respectively,versus 43%,13%,and 7%of the control group,showing significant differences in the above indicators between the two groups(Z=9.965,4.900,3.684,P<0.0167).(4)Analysis of prognostic factors:results of univariate analysis showed that treatment method,maximum tumor diameter,Barcelona clinical liver cancer(BCLC)stage,liver cirrhosis,hepatitis B virus(HBV)infection,and Child-Pugh classification were related factors for overall survival time[hazard ratio(HR)=0.483,6.196,12.646,5.049,2.950,4.791,95%confidence interval(CI):0.284-0.823,3.198-12.003,5.031-31.785,2.586-9.858,1.366-6.369,2.507-9.155,P<0.05]and progression-free survival time(HR=0.427,5.804,7.032,5.405,2.925,4.410,95%CI:0.248-0.735,3.043-11.070,3.071-16.101,2.685-10.881,1.364-6.270,2.331-8.342,P<0.05).Results of multivariate analysis showed that treatment method,maximum tumor diameter,BCLC stage,liver cirrhosis,and HBV infection were independent influencing factors for overall survival time(HR=0.183,5.886,17.544,4.702,3.801,95%CI:0.090-0.370,2.648-13.083,5.740-53.622,1.928-11.470,1.368-10.562,P<0.05)and progression-free survival time(HR=0.201,3.850,3.843,3.598,3.726,95%CI:0.098-0.411,1.761-8.414,1.526-9.682,1.444-8.963,1.396-9.947,P<0.05).Conclusions Compared with TACE combined with sorafenib,TACE combined with sorafenib and sequential MWA is safe and effective in the treatment of HCC with tumor diameter over 5 cm.The treatment method,maximum tumor diameter,BCLC stage,liver cirrhosis,and HBV infection are independent influencing factors for overall survival time and progression-free survival time of patients.