癌痛消颗粒联合肝动脉化疗栓塞术治疗原发性肝癌的疗效及其对白介素12、白介素10、γ干扰素的影响研究
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摘要
背景肝动脉化疗栓塞术(TACE)为中晚期原发性肝癌(PLC)患者的重要治疗手段,但仍有部分患者在TACE治疗后发生近期疾病进展,生存质量、生活能力较低。癌痛消颗粒是广西中医药大学第一附属医院韦艾凌教授自拟药方,经临床证实治疗PLC有效,而癌痛消颗粒与TACE联合应用的临床疗效及其对自然杀伤细胞(NK细胞)相关免疫因子[白介素(IL)-12、IL-10、γ干扰素(IFN-γ)]的影响尚不明确。目的探究癌痛消颗粒联合TACE治疗PLC的疗效,并观察其对IL-12、IL-10、IFN-γ的影响。方法本研究为随机对照的单盲、单中心试验。选取2014年6月—2016年2月于广西中医药大学第一附属医院就诊的符合研究标准的PLC癌患者86例,采用随机数字表法将其分为对照组和试验组,各43例。另选取同期本院健康体检者20例为健康组。患者均给予低脂优质蛋白饮食和保肝治疗,对照组采用TACE治疗,试验组在对照组的基础上给予癌痛消颗粒,1剂/d。患者均治疗1个疗程(8周)。随访截至2018-03-05。比较对照组和试验组患者临床疗效,治疗前及治疗后7 d、4周、8周的中医证候积分,治疗前及治疗后8周血清IL-12水平、血清IL-10水平、血清IFN-γ水平、欧洲癌症治疗研究组织的生存质量测定量表(EORTC QLQ-C30)评分,预后情况[总生存时间(OS)和疾病进展时间(TTP)]和毒副作用。结果试验组患者治疗后总有效率(ORR)为83.72%(36/43),高于对照组的65.12%(28/43)(χ~2=3.909,P=0.048)。试验组患者治疗后4、8周中医证候积分均低于对照组(P<0.05);治疗后7 d、4周、8周对照组和试验组患者中医证候积分均低于本组治疗前(P<0.05)。对照组与试验组治疗前、治疗后8周血清IL-10水平均高于健康组,血清IL-12、IFN-γ水平低于健康组(P<0.05);试验组治疗后8周血清IL-10水平低于对照组,血清IL-12、IFN-γ水平高于对照组(P<0.05);治疗后8周对照组与试验组血清IL-10水平低于本组治疗前,血清IL-12、IFN-γ水平高于本组治疗前(P<0.05)。试验组治疗后8周EORTC QLQ-C30中功能领域评分高于对照组,症状领域评分低于对照组(P<0.05);治疗后8周对照组与试验组患者EORTC QLQ-C30中功能领域评分高于治疗前,症状领域评分低于治疗前(P<0.05)。对照组患者中位OS、TTP分别为17(10,30)、11(6,15)个月,试验组患者中位OS、TTP分别为26(14,30)、15(11,22)个月;试验组患者死亡风险、疾病进展风险低于对照组[HR=0.529,95%CI(0.309,0.919),P=0.019;HR=0.568,95%CI(0.361,0.893),P=0.006]。结论癌痛消颗粒联合TACE治疗PLC具有较好的临床疗效,能够显著减轻患者临床症状,有效调节免疫因子水平,并改善患者的远期预后。
Background Hepatic arterial chemoembolization(TACE) is an important treatment for advanced primary liver cancer(PLC).But some patients still have recent disease progression,low quality of life and functional ability for independent living after TACE treatment.Aitongxiao granules,a prescription developed by Professor WEI Ailing,the First Affiliated Hospital of Guangxi University of Chinese Medicine,has been clinically proved to be effective for PLC.But the efficacy of Aitongxiao granules combined with TACE for PLC and natural killer cell immune functions[including interleukin(IL)-12,IL-10 and gamma interferon(IFN-γ)] is still unclear.Objective To explore the clinical response and responses of IL-12,IL-10 and IFN-γ to Aitongxiao granules combined with TACE in PLC.Methods This study was a randomized controlled singleblind,single-center test.According to the inclusion criteria,we enrolled 86 cases of PLC and 20 physical examinees(healthy group) from the First Affiliated Hospital of Guangxi University of Chinese Medicine,from June 2014 to February 2016.The PLC patients were equally divided into the experimental group and control group by a random number table.All PCL cases ate low-fat high-quality protein diet and were treated with TACE,the cases in the experimental group additionally took Aitongxiao granules,one dose per day.The treatment for PCL cases lasted for one course of treatment(8 weeks),and the follow-up for them ended on March 5,2018.Comparisons were made between the experimental and control groups in terms of clinical response,TCM syndrome score at baseline,by the end of the 7 th day,4 th and 8 th weeks of treatment,and serum IL-12,IL-10 and IFN-γ levels,quality of life(assessed by EORTC QLQ-C30),before and after treatment,and long-term prognosis [total survival(OS) and time-to-progression(TTP)] and treatment-related side effects.Results The overall response rate of the experimental group was much higher than that of the control group [83.72%(36/43) vs 65.12%(28/43)](χ~2=3.909,P=0.048).The TCM syndrome score decreased significantly in both the experimental and the control groups by the end of the 7 th day,4 th and 8 th weeks of treatment(P<0.05).The experimental group showed lower TCM syndrome score than the control group by the end of 4 th,and 8 th weeks of treatment(P<0.05).At baseline and at the end of treatment,both the experimental and control groups had higher IL-10 levels and lower serum IL-12 and IFN-γ levels compared with the healthy group(P<0.05).When the treatment ended, serum IL-10 was lower and serum IL-12 and IFN-γ were higher in the experimental group compared with the control group(P<0.05).When the treatment ended,serum IL-10 decreased significantly but serum IL-12 and IFN-γ increased obviously in both the experimental and control groups(P<0.05).At the end of treatment,both experimental and control groups had increased mean function score and decreased mean symptom score of EORTC QLQ-C30 compared with baseline(P<0.05).Moreover,the experimental group showed higher mean function score and lower mean symptom score than the control group(P<0.05).The median OS and TTP were 17(10,30),11(6,15) months for the control group,and 26(14,30),15(11,22) months for the experimental group.Both the risk of death and risk of disease progression of the experimental group were lower than those of the control group[HR=0.529,95%CI(0.309,0.919),P=0.019;HR=0.568,95%CI(0.361,0.893),P=0.006].Conclusion Aitongxiao granules combined with TACE has good clinical efficacy for PLC,which can significantly reduce the symptoms,effectively regulate the immune factor levels and improve the long-term prognosis.
Background Hepatic arterial chemoembolization(TACE) is an important treatment for advanced primary liver cancer(PLC).But some patients still have recent disease progression,low quality of life and functional ability for independent living after TACE treatment.Aitongxiao granules,a prescription developed by Professor WEI Ailing,the First Affiliated Hospital of Guangxi University of Chinese Medicine,has been clinically proved to be effective for PLC.But the efficacy of Aitongxiao granules combined with TACE for PLC and natural killer cell immune functions[including interleukin(IL)-12,IL-10 and gamma interferon(IFN-γ)] is still unclear.Objective To explore the clinical response and responses of IL-12,IL-10 and IFN-γ to Aitongxiao granules combined with TACE in PLC.Methods This study was a randomized controlled singleblind,single-center test.According to the inclusion criteria,we enrolled 86 cases of PLC and 20 physical examinees(healthy group) from the First Affiliated Hospital of Guangxi University of Chinese Medicine,from June 2014 to February 2016.The PLC patients were equally divided into the experimental group and control group by a random number table.All PCL cases ate low-fat high-quality protein diet and were treated with TACE,the cases in the experimental group additionally took Aitongxiao granules,one dose per day.The treatment for PCL cases lasted for one course of treatment(8 weeks),and the follow-up for them ended on March 5,2018.Comparisons were made between the experimental and control groups in terms of clinical response,TCM syndrome score at baseline,by the end of the 7 th day,4 th and 8 th weeks of treatment,and serum IL-12,IL-10 and IFN-γ levels,quality of life(assessed by EORTC QLQ-C30),before and after treatment,and long-term prognosis [total survival(OS) and time-to-progression(TTP)] and treatment-related side effects.Results The overall response rate of the experimental group was much higher than that of the control group [83.72%(36/43) vs 65.12%(28/43)](χ~2=3.909,P=0.048).The TCM syndrome score decreased significantly in both the experimental and the control groups by the end of the 7 th day,4 th and 8 th weeks of treatment(P<0.05).The experimental group showed lower TCM syndrome score than the control group by the end of 4 th,and 8 th weeks of treatment(P<0.05).At baseline and at the end of treatment,both the experimental and control groups had higher IL-10 levels and lower serum IL-12 and IFN-γ levels compared with the healthy group(P<0.05).When the treatment ended, serum IL-10 was lower and serum IL-12 and IFN-γ were higher in the experimental group compared with the control group(P<0.05).When the treatment ended,serum IL-10 decreased significantly but serum IL-12 and IFN-γ increased obviously in both the experimental and control groups(P<0.05).At the end of treatment,both experimental and control groups had increased mean function score and decreased mean symptom score of EORTC QLQ-C30 compared with baseline(P<0.05).Moreover,the experimental group showed higher mean function score and lower mean symptom score than the control group(P<0.05).The median OS and TTP were 17(10,30),11(6,15) months for the control group,and 26(14,30),15(11,22) months for the experimental group.Both the risk of death and risk of disease progression of the experimental group were lower than those of the control group[HR=0.529,95%CI(0.309,0.919),P=0.019;HR=0.568,95%CI(0.361,0.893),P=0.006].Conclusion Aitongxiao granules combined with TACE has good clinical efficacy for PLC,which can significantly reduce the symptoms,effectively regulate the immune factor levels and improve the long-term prognosis.
引文
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[7]韦艾凌,唐健,陈逸恒,等.癌痛消颗粒治疗原发性肝癌血瘀毒结兼正虚证疗效分析[J].辽宁中医杂志,2007,34(5):570-572.DOI:10.3969/j.issn.1000-1719.2007.05.014.
[8]ZHANG L,WANG N,ZHANG J J,et al.Cross-cultural verification of the EORTC QLQ-C15-PAL questionnaire in mainland China[J].Palliat Med,2016,30(4):401-408.DOI:10.1177/0269216315593671.
[9]CHEN A P,SETSER A,ANADKAT M J,et al.Grading dermatologic adverse events of cancer treatments:the Common Terminology Criteria for Adverse Events Version 4.0[J].J Am Acad Dermatol,2012,67(5):1025-1039.DOI:10.1016/j.jaad.2012.02.010.
[10]BEI C,TAN C,ZHU X,et al.Association between polymorphisms in CMTM family genes and hepatocellular carcinoma in Guangxi of China[J].DNA Cell Biol,2018,37(8):691-696.DOI:10.1089/dna.2018.4274.
[11]LI X,YANG G,LI X,et al.Traditional Chinese medicine in cancer care:a review of controlled clinical studies published in Chinese[J].PLoS One,2013,8(4):e60338.DOI:10.1371/journal.pone.0060338.
[12]施贝德,唐婷婷.中晚期原发性肝癌中医姑息治疗临床观察[J].辽宁中医杂志,2013,40(9):1855-1856.
[13]张永琴,刘潇,韦艾凌.癌痛消颗粒对SMMC-7721和Bel-7404肝癌细胞体外抑瘤作用和细胞周期影响的实验研究[J].广西中医药大学学报,2014,17(1):1-3.
[14]李文婷,周红光,刘颖,等.消癌解毒方对移植性肝癌大鼠免疫功能影响研究[J].中华中医药学刊,2015,33(8):1880-1883.DOI:10.13193/j.issn.1673-7717.2015.08.026.
[15]SUN C,SUN H Y,XIAO W H,et al.Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy[J].Acta Pharmacol Sin,2015,36(10):1191-1199.DOI:10.1038/aps.2015.41.
[16]SADEGH L,CHEN P W,BROWN J R,et al.NKT cells act through third party bone marrow-derived cells to suppress NK cell activity in the liver and exacerbate hepatic melanoma metastases[J].Int J Cancer,2015,137(5):1085-1094.DOI:10.1002/ijc.29480.
[17]KUO Y J,LIN J P,HSIAO Y T,et al.Ethanol extract of hedyotis diffusa willd affects immune responses in normal balb/c mice in vivo[J].In Vivo,2015,29(4):453-460.
[18]LI Y L,ZHANG J,MIN D,et al.Anticancer effects of 1,3-Dihydroxy-2-Methylanthraquinone and the ethyl acetate fraction of hedyotis diffusa willd against HepG2 carcinoma cells mediated via apoptosis[J].PLoS One,2016,11(4):e0151502.DOI:10.1371/journal.pone.0151502.
[19]LIAO Y H,LIN C C,LAI H C,et al.Adjunctive traditional Chinese medicine therapy improves survival of liver cancer patients[J].Liver Int,2015,35(12):2595-2602.DOI:10.1111/liv.12847.
[20]DAI Z J,WANG B F,LU W F,et al.Total flavonoids of Scutellaria barbata inhibit invasion of hepatocarcinoma via MMP/TIMP in vitro[J].Molecules,2013,18(1):934-950.DOI:10.3390/molecules18010934.
[21]KUEHNL S,SCHROECKSNADEL S,TEMML V,et al.Lignans from Carthamus tinctorius suppress tryptophan breakdown via indoleamine 2,3-dioxygenase[J].Phytomedicine,2013,20(13):1190-1195.DOI:10.1016/j.phymed.2013.06.006.
[22]SHARULA,WU Z.Regulation of apoptosis by SYB in HepG2liver cancer cells is mediated by the P53/Caspase 9 axis[J].Anticancer Agents Med Chem,2017,17(7):941-947.DOI:10.2174/1871520617666170327161433.
[23]DAI Z J,WU W Y,KANG H F,et al.Protective effects of Scutellaria barbata against rat liver tumorigenesis[J].Asian Pac J Cancer Prev,2013,14(1):261-265.DOI:10.7314/APJCP.2013.14.1.261.
[2]FEI B,DAI W,ZHAO S.Efficacy,safety,and cost of therapy of the traditional chinese medicine,catalpol,in patients following surgical resection for locally advanced colon cancer[J].Med Sci Monit,2018,24:3184-3192.DOI:10.12659/MSM.907569.
[3]唐秋媛,韦艾凌,潘哲,等.癌痛消颗粒方联合肝动脉栓塞化疗治疗中晚期肝癌患者的临床疗效观察[J].时珍国医国药,2015,26(4):906-908.DOI:10.3969/j.issn.1008-0805.2015.04.056.TANG Q Y,WEI A L,PAN Z,et al.Clinical observation of patients with advanced liver cancer in the treatment of Aitongxiao combined with Hepatic artery embolization chemotherapy[J].Lishizhen Medicine and Materia Medica Research,2015,26(4):906-908.DOI:10.3969/j.issn.1008-0805.2015.04.056.
[4]中华人民共和国卫生部.原发性肝癌诊疗规范(2011年版)[J].临床肝胆病杂志,2011,27(11):1141-1159.
[5]郑筱萸.中药新药临床研究指导原则(试行)[M].北京:中国医药科学技术出版社,2002:208.
[6]王永炎.中医内科学[M].上海:上海科学技术出版社,1997:233.WANG Y Y.Internal medicine of traditional Chinese medicine[M].Shanghai:Shanghai Science and Technology Press,1997:233.
[7]韦艾凌,唐健,陈逸恒,等.癌痛消颗粒治疗原发性肝癌血瘀毒结兼正虚证疗效分析[J].辽宁中医杂志,2007,34(5):570-572.DOI:10.3969/j.issn.1000-1719.2007.05.014.
[8]ZHANG L,WANG N,ZHANG J J,et al.Cross-cultural verification of the EORTC QLQ-C15-PAL questionnaire in mainland China[J].Palliat Med,2016,30(4):401-408.DOI:10.1177/0269216315593671.
[9]CHEN A P,SETSER A,ANADKAT M J,et al.Grading dermatologic adverse events of cancer treatments:the Common Terminology Criteria for Adverse Events Version 4.0[J].J Am Acad Dermatol,2012,67(5):1025-1039.DOI:10.1016/j.jaad.2012.02.010.
[10]BEI C,TAN C,ZHU X,et al.Association between polymorphisms in CMTM family genes and hepatocellular carcinoma in Guangxi of China[J].DNA Cell Biol,2018,37(8):691-696.DOI:10.1089/dna.2018.4274.
[11]LI X,YANG G,LI X,et al.Traditional Chinese medicine in cancer care:a review of controlled clinical studies published in Chinese[J].PLoS One,2013,8(4):e60338.DOI:10.1371/journal.pone.0060338.
[12]施贝德,唐婷婷.中晚期原发性肝癌中医姑息治疗临床观察[J].辽宁中医杂志,2013,40(9):1855-1856.
[13]张永琴,刘潇,韦艾凌.癌痛消颗粒对SMMC-7721和Bel-7404肝癌细胞体外抑瘤作用和细胞周期影响的实验研究[J].广西中医药大学学报,2014,17(1):1-3.
[14]李文婷,周红光,刘颖,等.消癌解毒方对移植性肝癌大鼠免疫功能影响研究[J].中华中医药学刊,2015,33(8):1880-1883.DOI:10.13193/j.issn.1673-7717.2015.08.026.
[15]SUN C,SUN H Y,XIAO W H,et al.Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy[J].Acta Pharmacol Sin,2015,36(10):1191-1199.DOI:10.1038/aps.2015.41.
[16]SADEGH L,CHEN P W,BROWN J R,et al.NKT cells act through third party bone marrow-derived cells to suppress NK cell activity in the liver and exacerbate hepatic melanoma metastases[J].Int J Cancer,2015,137(5):1085-1094.DOI:10.1002/ijc.29480.
[17]KUO Y J,LIN J P,HSIAO Y T,et al.Ethanol extract of hedyotis diffusa willd affects immune responses in normal balb/c mice in vivo[J].In Vivo,2015,29(4):453-460.
[18]LI Y L,ZHANG J,MIN D,et al.Anticancer effects of 1,3-Dihydroxy-2-Methylanthraquinone and the ethyl acetate fraction of hedyotis diffusa willd against HepG2 carcinoma cells mediated via apoptosis[J].PLoS One,2016,11(4):e0151502.DOI:10.1371/journal.pone.0151502.
[19]LIAO Y H,LIN C C,LAI H C,et al.Adjunctive traditional Chinese medicine therapy improves survival of liver cancer patients[J].Liver Int,2015,35(12):2595-2602.DOI:10.1111/liv.12847.
[20]DAI Z J,WANG B F,LU W F,et al.Total flavonoids of Scutellaria barbata inhibit invasion of hepatocarcinoma via MMP/TIMP in vitro[J].Molecules,2013,18(1):934-950.DOI:10.3390/molecules18010934.
[21]KUEHNL S,SCHROECKSNADEL S,TEMML V,et al.Lignans from Carthamus tinctorius suppress tryptophan breakdown via indoleamine 2,3-dioxygenase[J].Phytomedicine,2013,20(13):1190-1195.DOI:10.1016/j.phymed.2013.06.006.
[22]SHARULA,WU Z.Regulation of apoptosis by SYB in HepG2liver cancer cells is mediated by the P53/Caspase 9 axis[J].Anticancer Agents Med Chem,2017,17(7):941-947.DOI:10.2174/1871520617666170327161433.
[23]DAI Z J,WU W Y,KANG H F,et al.Protective effects of Scutellaria barbata against rat liver tumorigenesis[J].Asian Pac J Cancer Prev,2013,14(1):261-265.DOI:10.7314/APJCP.2013.14.1.261.