索拉非尼联合三氧化二砷治疗晚期原发性肝癌的临床研究
|
摘要
目的:观察索拉非尼联合三氧化二砷治疗原发性肝癌的临床疗效、生活质量和不良反应。方法:对2014年1月至2017年1月期间于我院确诊的57例晚期原发性肝癌患者的相关临床资料进行回顾性分析。索拉非尼(0. 4 g,口服,2次/日)联合三氧化砷(10 mg,静滴,1次/日,连用2周停1周为1周期,共2周期)的30例患者视为观察组;口服索拉非尼(0. 4 g,口服,2次/日)单药的27例患者为对照组。观察临床获益率、疾病进展时间和不良反应发生率。结果:观察组和对照组的临床获益率、生活质量改善率、甲胎蛋白(AFP)下降率分别为73. 33%、63. 33%、66. 67%,48. 15%、37. 04%、40. 74%,观察组的近期疗效显著优于对照组(P<0. 05)。观察组与对照组中位TTP分别为5. 6个月、3. 7个月,差异有统计学意义。两组主要不良反应为手足皮肤反应、疲乏、腹泻、高血压、肝功异常、恶心、骨髓抑制,两组差异无统计学意义(P> 0. 05)。观察组出现心电图异常1例、轻度末梢神经毒性(四肢轻度麻木) 1例,均自行缓解,未影响治疗,且发生率均为3. 33%,无统计学意义(P> 0. 05)。结论:索拉非尼联合三氧化二砷一线治疗晚期原发性肝癌患者可能是一种有效且耐受良好的治疗策略,可能延迟索拉非尼的耐药时间,还需大规模多中心的临床随机对照实验证实。
Objective: To observe the efficacy,quality of life and adverse reactions of sorafenib combined with arsenic trioxide in the treatment of advanced primary liver cancer. Methods: This was a retrospective analysis of 57 cases of advanced primary liver cancer in our hospital from January 2014 to January 2017. 30 patients who received Sorafenib( 0. 4 g,oral,2 times/day) combined with arsenic trioxide( 10 mg,intravenous drip,1 time/day,continuous 2 weeks,3 week for 1 cycle,2 cycles) were considered as observation group,while 27 patients who were administered at Sorafenib( 0. 4 g,oral,2 times/day) were considered as control group. The time to progression,objective response rate and incidence of adverse reactions were estimated. Results: The clinical benefit rate,quality of life improvement rate and AFP decline rate of the observation group and the control group were 73. 33%,63. 33%,66. 67% and 48. 15%,37. 04%,40. 74%,respectively. The short-term efficacy of the observation group was significantly better than that of the control group( P < 0. 05). The median TTP of the observation group and the control group were 5. 6 months and3. 7 months,respectively,and the difference was statistically significant. The main adverse reactions in the two groups were hand-foot skin reaction,fatigue,diarrhea,hypertension,abnormal liver function,nausea,and bone marrow suppression. There was no significant difference between the two groups( P > 0. 05). In the observation group,1 case of abnormal electrocardiogram and 1 case of mild peripheral neurotoxicity were happened,which were all resolved spontaneously,and the incidence was 3. 33%,which was not statistically significant. Conclusion: Sorafenib combined with arsenic trioxide in the treatment of patients with advanced primary liver cancer appears to be an effective and well-tolerated treatment strategy,and may prolong the resistance time of sorafenib. Large-scale,multicenter randomized controlled clinical trials are needed to confirm this conclusion.
Objective: To observe the efficacy,quality of life and adverse reactions of sorafenib combined with arsenic trioxide in the treatment of advanced primary liver cancer. Methods: This was a retrospective analysis of 57 cases of advanced primary liver cancer in our hospital from January 2014 to January 2017. 30 patients who received Sorafenib( 0. 4 g,oral,2 times/day) combined with arsenic trioxide( 10 mg,intravenous drip,1 time/day,continuous 2 weeks,3 week for 1 cycle,2 cycles) were considered as observation group,while 27 patients who were administered at Sorafenib( 0. 4 g,oral,2 times/day) were considered as control group. The time to progression,objective response rate and incidence of adverse reactions were estimated. Results: The clinical benefit rate,quality of life improvement rate and AFP decline rate of the observation group and the control group were 73. 33%,63. 33%,66. 67% and 48. 15%,37. 04%,40. 74%,respectively. The short-term efficacy of the observation group was significantly better than that of the control group( P < 0. 05). The median TTP of the observation group and the control group were 5. 6 months and3. 7 months,respectively,and the difference was statistically significant. The main adverse reactions in the two groups were hand-foot skin reaction,fatigue,diarrhea,hypertension,abnormal liver function,nausea,and bone marrow suppression. There was no significant difference between the two groups( P > 0. 05). In the observation group,1 case of abnormal electrocardiogram and 1 case of mild peripheral neurotoxicity were happened,which were all resolved spontaneously,and the incidence was 3. 33%,which was not statistically significant. Conclusion: Sorafenib combined with arsenic trioxide in the treatment of patients with advanced primary liver cancer appears to be an effective and well-tolerated treatment strategy,and may prolong the resistance time of sorafenib. Large-scale,multicenter randomized controlled clinical trials are needed to confirm this conclusion.
引文
[1]LI GH,LE Y,YU P,et al.Advances in research on sensitivity-related factors of sorafenib in the treatment of liver cancer[J].Journal of Hepatobiliary Surgery,2018,26(1):74-77.[李高桦,乐羿,俞鹏,等.索拉菲尼治疗肝癌的敏感性相关因素研究进展[J].肝胆外科杂志,2018,26(1):74-77.]
[2]Wanqing Chen,Rongshou Zheng,Peter D Baade,et al.Cancer statistics in China,2015[J].CA cancer J Clin,2016(66):115-132.
[3]Llovet JM,Ricci S,Mazzaferro V,et al.Sorafenib in advanced hepatocellular carcinoma[J].N Engl J Med,2008(359):378-390.
[4]Cheng AL,Kang YK,Chen Z,et al.Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma:A phaseⅢrandomized.Double-blind.Placebo-controlledtria1[J].Lancet Oncol,2009(10):25-34.
[5]Novi M,Lauritano EC,Piscaglia AC,et al.Portal vein tumor thrombosis revascularization during sorafenib treatment for hepatocellular carcinoma[J].Am J Gastroenterol,2009(104):1852-1854.
[6]Yanjing Zhu,Bo Zheng,Hong-yang Wang,et al.New knowledge of the mechanisms of sorafenib resistance in liver cancer[J].Acta Pharmacol Sin,2017,38(5):614-622.
[7]Jiayan Ni,Shanshan Liu,Hongliang Sun,et al.Transcatheter hepatic arterial infusion chemotherapy vs sorafenib in the treatment of patients with hepatocellular carcinoma of barcelona clinic liver cancer stage C:A Meta-analysis of asian population[J].Onco Targets Ther,2018(11):7883-7894.
[8]Shinichi Ikuta,Tsukasa Aihara,Naoki Yamanaka.Efficacy of sequential sorafenib plus hepatic arterial infusion chemotherapy in patients with Barcelona Clinic Liver Cancer stage B and C hepatocellular carcinoma:A retrospective single-institution study[J].Contemp Oncol(Pozn),2018,22(3):165-171.
[9]FENG LH,CHEN YD,ZHENG ZG,et al.Clinical observation of patients with primary liver cancer treated by sorafenib combined cinobufagin[J].China Oncology,2012,22(11):856-859.[冯丽华,陈毅德,郑志高,等索拉非尼联合华蟾素治疗中晚期原发性肝癌的临床疗效观察[J].中国癌症杂志,2012,22(11):856-859.]
[10]HU X,ZHOU YJ.Clinical observation of 3 cases of advanced liver cancer treated with sorafenib combined with thymosinα1[J].JClini Hepatol,2011,27(6):658-659.[胡侠,周岳进.索拉非尼联合胸腺肽α1治疗晚期肝癌3例的临床观察[J].J Clini Hepatol,2011,27(6):658-659.]
[11]JISO YH,ZHANG Q,PAN LL,et al.Rat liver mitochondrial dysfunction induced by an organic arsenical compound 4-(2-Nitrobenzaliminyl)phenyl arsenoxide[J].J Membr Biol,2015,248(6):1071-1078.
[12]Nadra,Sadaf,Nitish Kumar,Mehboob Ali,et al.Arsenic trioxide induces apoptosis and inhibits the growth of human liver cancer cells[J].Life Sciences,2018,205(7):9-17.
[13]ZHAO CW.Clinical application analysis of arsenic trioxide in the treatment of liver cancer patients[J].The World's Latest Medical Information Abstracts,2016,71(16):145-146.[赵存武.三氧化二砷治疗肝癌患者的临床应用效果分析[J].世界最新医学信息文摘,2016,71(16):145-146.]
[14]HOU YB,LIU Q,DUAN GF,et al.The role of arsenic trioxide in the interventional treatment of advanced primary liver cancer[J].Journal of North Pharmacy,2015,18(03):24-25.[侯毅斌,刘琦,段光峰,等.三氧化二砷在中晚期原发性肝癌介入治疗的作用[J].北方药学,2015,18(03):24-25.]
[15]HU Qin,WEI Yongming,GUAN Rui,et al.Clinical effect of transcatheter arterial chemoembolization combined with arsenic trioxide in the treatment of primary liver cancer[J].Modern Oncology,2014,22(11):2679-2681.[胡琴,韦永明,管睿,等.TACE联合三氧化二砷治疗原发性肝癌的临床研究[J].现代肿瘤医学,2014,22(11):2679-2681.]
[16]YIN WH,HU XX,FAN HZ,et al.Different doses of arsenic trioxide intravenous infusion and appropriate radiotherapy for advanced primary liver cancer[J].Shandong Medical Journal,2014,54(3):32-34.[尹卫华,胡小雄,范惠珍,等.不同剂量三氧化二砷静滴联合适形放疗治疗中晚期原发性肝癌[J].山东医药,2014,54(3):32-34.]
[17]Yan Xia,Xianhao Liu,Beibei Liu,et al.Enhanced antitumor activity of combined megestrol acetate and arsenic trioxide treatment in liver cancer cells[J].Exp Ther Med,2018,15(4):4047-4055.
[18]WANG LY,MIN ZH,WANG XD,et al.Arsenic trioxide and sorafenib combination therapy for human hepatocellular carcinoma functions via up regulation of TNF related apoptosis inducing ligand[J].Oncology Letters,2018(16):3341-3350.
[19]MIAO Z,WU L,LU M,et al.Analysis of the transcriptional regulation of cancer-related genes by aberrant DNA methylation of the cis-regulation sites in the promoter region during hepatocyte carcinogenesis caused by arsenic[J].Oncotarget,2015,6(25):21493-21506.
[20]HUANG Q,ZHOU JY.The study of Sorafenib combined with As2O3in treatment of hepatoma[J].Chin J Gastroenterol Hepatol,2014,23(7):807-809.[黄强,周建英.索拉非尼联合三氧化二砷治疗肝癌的研究[J].胃肠病学和肝病学杂志,2014,23(7):807-809.
[2]Wanqing Chen,Rongshou Zheng,Peter D Baade,et al.Cancer statistics in China,2015[J].CA cancer J Clin,2016(66):115-132.
[3]Llovet JM,Ricci S,Mazzaferro V,et al.Sorafenib in advanced hepatocellular carcinoma[J].N Engl J Med,2008(359):378-390.
[4]Cheng AL,Kang YK,Chen Z,et al.Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma:A phaseⅢrandomized.Double-blind.Placebo-controlledtria1[J].Lancet Oncol,2009(10):25-34.
[5]Novi M,Lauritano EC,Piscaglia AC,et al.Portal vein tumor thrombosis revascularization during sorafenib treatment for hepatocellular carcinoma[J].Am J Gastroenterol,2009(104):1852-1854.
[6]Yanjing Zhu,Bo Zheng,Hong-yang Wang,et al.New knowledge of the mechanisms of sorafenib resistance in liver cancer[J].Acta Pharmacol Sin,2017,38(5):614-622.
[7]Jiayan Ni,Shanshan Liu,Hongliang Sun,et al.Transcatheter hepatic arterial infusion chemotherapy vs sorafenib in the treatment of patients with hepatocellular carcinoma of barcelona clinic liver cancer stage C:A Meta-analysis of asian population[J].Onco Targets Ther,2018(11):7883-7894.
[8]Shinichi Ikuta,Tsukasa Aihara,Naoki Yamanaka.Efficacy of sequential sorafenib plus hepatic arterial infusion chemotherapy in patients with Barcelona Clinic Liver Cancer stage B and C hepatocellular carcinoma:A retrospective single-institution study[J].Contemp Oncol(Pozn),2018,22(3):165-171.
[9]FENG LH,CHEN YD,ZHENG ZG,et al.Clinical observation of patients with primary liver cancer treated by sorafenib combined cinobufagin[J].China Oncology,2012,22(11):856-859.[冯丽华,陈毅德,郑志高,等索拉非尼联合华蟾素治疗中晚期原发性肝癌的临床疗效观察[J].中国癌症杂志,2012,22(11):856-859.]
[10]HU X,ZHOU YJ.Clinical observation of 3 cases of advanced liver cancer treated with sorafenib combined with thymosinα1[J].JClini Hepatol,2011,27(6):658-659.[胡侠,周岳进.索拉非尼联合胸腺肽α1治疗晚期肝癌3例的临床观察[J].J Clini Hepatol,2011,27(6):658-659.]
[11]JISO YH,ZHANG Q,PAN LL,et al.Rat liver mitochondrial dysfunction induced by an organic arsenical compound 4-(2-Nitrobenzaliminyl)phenyl arsenoxide[J].J Membr Biol,2015,248(6):1071-1078.
[12]Nadra,Sadaf,Nitish Kumar,Mehboob Ali,et al.Arsenic trioxide induces apoptosis and inhibits the growth of human liver cancer cells[J].Life Sciences,2018,205(7):9-17.
[13]ZHAO CW.Clinical application analysis of arsenic trioxide in the treatment of liver cancer patients[J].The World's Latest Medical Information Abstracts,2016,71(16):145-146.[赵存武.三氧化二砷治疗肝癌患者的临床应用效果分析[J].世界最新医学信息文摘,2016,71(16):145-146.]
[14]HOU YB,LIU Q,DUAN GF,et al.The role of arsenic trioxide in the interventional treatment of advanced primary liver cancer[J].Journal of North Pharmacy,2015,18(03):24-25.[侯毅斌,刘琦,段光峰,等.三氧化二砷在中晚期原发性肝癌介入治疗的作用[J].北方药学,2015,18(03):24-25.]
[15]HU Qin,WEI Yongming,GUAN Rui,et al.Clinical effect of transcatheter arterial chemoembolization combined with arsenic trioxide in the treatment of primary liver cancer[J].Modern Oncology,2014,22(11):2679-2681.[胡琴,韦永明,管睿,等.TACE联合三氧化二砷治疗原发性肝癌的临床研究[J].现代肿瘤医学,2014,22(11):2679-2681.]
[16]YIN WH,HU XX,FAN HZ,et al.Different doses of arsenic trioxide intravenous infusion and appropriate radiotherapy for advanced primary liver cancer[J].Shandong Medical Journal,2014,54(3):32-34.[尹卫华,胡小雄,范惠珍,等.不同剂量三氧化二砷静滴联合适形放疗治疗中晚期原发性肝癌[J].山东医药,2014,54(3):32-34.]
[17]Yan Xia,Xianhao Liu,Beibei Liu,et al.Enhanced antitumor activity of combined megestrol acetate and arsenic trioxide treatment in liver cancer cells[J].Exp Ther Med,2018,15(4):4047-4055.
[18]WANG LY,MIN ZH,WANG XD,et al.Arsenic trioxide and sorafenib combination therapy for human hepatocellular carcinoma functions via up regulation of TNF related apoptosis inducing ligand[J].Oncology Letters,2018(16):3341-3350.
[19]MIAO Z,WU L,LU M,et al.Analysis of the transcriptional regulation of cancer-related genes by aberrant DNA methylation of the cis-regulation sites in the promoter region during hepatocyte carcinogenesis caused by arsenic[J].Oncotarget,2015,6(25):21493-21506.
[20]HUANG Q,ZHOU JY.The study of Sorafenib combined with As2O3in treatment of hepatoma[J].Chin J Gastroenterol Hepatol,2014,23(7):807-809.[黄强,周建英.索拉非尼联合三氧化二砷治疗肝癌的研究[J].胃肠病学和肝病学杂志,2014,23(7):807-809.