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肝外胆管癌(extrahepatic cholangiocarcinoma,EHCC)早期诊断率较低,手术可切除率仅为20%~35%[1-2]。近年来,胆道引流及胆道支架植入术因可显著解除胆管癌病人胆道梗阻症状、改善病人生存状况,已被国内外部分学者应用于晚期EHCC的治疗[3-4]。化疗是晚期EHCC的重要治疗方法,然而整体疗效较差[5-6]。与静脉内途径相比,增加肿瘤组织中化学治疗药物的浓度可具有抗肿瘤作用。腔内给药途径将药物直接递送至肿瘤组织,从而起到抗肿瘤的作用。多项临床研究已经证实,腔内灌注化疗在卵巢癌伴胸膜转移、尿道上皮癌、结直肠癌腹膜转移、胶质母细胞瘤、恶性胸腹水等多种肿瘤的治疗应用中安全、有效[7-12]。部分学者曾对EHCC病人行经皮经肝腔内灌注化疗的治疗尝试,发现可取得较好的临床效果,且对肝脏和胆道的损伤程度较低[13],但其疗效仍需要更多的临床研究加以验证。本中心自2012年1月起对晚期EHCC病人行经皮经肝胆道支架置入(PTBS)治疗,并根据病人意愿联合或不联合125I腔内照射,取得了令人满意的疗效[14-16]。然而,有些病人并不愿接受125I粒子置入。我们根据病人及家属意愿,对部分病人采用了PTBS联合5-氟脲嘧啶(5-Fu)和丝裂霉素腔内灌注化疗,并与单纯行PTBS治疗的晚期EHCC病人的临床资料作一对比分析。
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PTBS组共71例,其中男43例,女38例;HCCA 44例,DCCA 27例。PTBS+腔内灌注化疗组共15例,其中男10例,女5例;HCCA 11例,DCCA 4例。2组之间性别、年龄、肿瘤部位、CA19-9、CEA、ALB及TBIL水平差异均无统计学意义(P>0.05);与PTBS组相比,PTBS+腔内灌注化疗组病人有较高的术前ALT、AST、ALP及GGT(P<0.05)(见表 1)。
基线资料 PTBS组(n=71) PTBS+腔内灌注化疗组(n=15) uc P 男/女 43/28 10/5 0.20▲ >0.05 年龄 68.8±14.1 66.8±9.5 0.52△ >0.05 HCCA/DCCA 44/27 11/4 0.69▲ >0.05 CA19-9/(ng/mL) 886(1.1~1967) 636.6(6.68~1200) 0.22 >0.05 CEA/(ng/mL) 4.35(0.96~490.51) 5.69(1.40~40.32) 0.27 >0.05 ALT/(U/L) 106(18~542) 149(67~273) 2.16 <0.05 AST/(U/L) 98(19~793) 158(56~347) 2.69 <0.01 ALP/(U/L) 404(102~1990) 685(176~1734) 2.41 <0.05 GGT/(U/L) 406(47~1837) 683(102~2528) 2.22 <0.05 TBIL/(μmol/L) 158(5.8~551.5) 212.4(108.3~706.2) 1.83 <0.05 ALB/(g/L) 34.6(25.1~43.6) 34.3(31.1~40.5) 0.62 >0.05 △示t值;▲示χ2值 表 1 病人基线资料比较
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2组病人的临床症状(如皮肤瘙痒、发热等)均有不同程度的改善。与术前相比,PTBS组病人术后1月、3月及6月血清中ALT、AST及TBIL水平均有不同程度的降低(P<0.05),病人术后ALB水平的变化不明显(P>0.05);与术前相比,PTBS+腔内灌注化疗组病人术后1月、3月及6月血清中ALT、AST及TBIL水平均有不同程度的降低(P<0.05),且下降趋势比PTBS组更为显著;与术前相比,PTBS+腔内灌注化疗组病人术后1个月、3个月及6个月血清中ALB水平明显增加(P<0.05)(见表 2)。
分组 n 术前 术后1月 术后3月 术后6月 F P MS组内 TBIL/(μmol/L) PTBS组 71 198.9±16.8 55.7±13.6* 118.2±32.7* 57.2±37.2*# 443.50 <0.01 730.083 PTBS+腔内灌注化疗组 15 275.4±41.3 45.1±8.9* 20.4±5.9* 28.2±5.5*# 412.40 <0.01 462.491 t — 11.81 2.88 11.49 2.30 — — — P — <0.01 <0.01 <0.01 <0.01 — — — ALB/(g/L) PTBS组 71 34.2±0.5 34.3±0.8 33.2±1.4*■ 31.8±4.0*■# 20.33 0.01 4.713 PTBS+腔内灌注化疗组 15 35.1±0.8 39.6±1.0* 41.1±0.6* 38.5±0.9*# 138.80 <0.01 0.703 t — 5.64 22.29 21.36 6.42 — — — P — <0.01 <0.01 <0.01 <0.01 — — — ALT/(U/L) PTBS组 71 133.4±12.5 43.8±5.4* 90.2±25.6* 52.5±22.1*# 357.71 <0.01 332.295 PTBS+腔内灌注化疗组 15 160.6±16.0 60.8±7.7* 49.8±11.4* 64.3±18.8*# 199.42 <0.01 199.673 t — 7.30 10.23 1.92 0.41 — — — P — <0.01 <0.01 <0.01 >0.05 — — — AST/(U/L) PTBS组 71 130.4±15.2 56.3±9.5* 135.3±49.6 32.1±7.8*# 271.90 0.01 710.573 PTBS+腔内灌注化疗组 15 171.5±19.9 69.1±9.4* 64.2±15.0* 70.6±22.0*■# 135.11 <0.01 298.343 t — 9.00 4.75 5.48 11.82 — — — P — <0.01 <0.01 <0.01 <0.01 — — — 与术前比较*P<0.05;与术后1月比较■P<0.05;与术后3月比较#P<0.05 表 2 2组病人术后主要生化指标的变化情况
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PTBS组病人术后总体并发症发生率为12.7%(9/71),其中6例出现高淀粉酶血症;有3例出现胆道感染,无其他严重并发症及围手术期死亡。PTBS+腔内灌注化疗组病人术后总体并发症发生率为13.3%(2/15),均为高淀粉酶血症,没有其他严重并发症,未发现由灌注化疗引起的相关并发症如肠黏膜损伤、肠功能紊乱等,无围手术期死亡。2组术后并发症的发生率差异无统计学意义(P>0.05)。
PTBS组术后共有25例(35.2%)病人发生胆道再次梗阻;PTBS+腔内灌注化疗组术后3例(20.0%)病人发生胆道再次梗阻。联合腔内灌注化疗降低了胆道再梗阻发生的风险,但2组间的差异无统计学意义(χ2=1.30,P>0.05)。
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随访病人至2017年9月或至病人死亡。结果显示,PTBS组病人生存时间中位数为7(四分位数间距:4~10)个月,半年生存率为54.5%,1年生存率为11.3%;PTBS+腔内灌注化疗组病人生存时间中位数为10(四分位数间距:7~14)个月,半年生存率为86.7%,1年生存率为37.5%;log-rank检验提示2组之间总生存时间(OS)差异有统计学意义(χ2=6.27,P<0.05)。
单因素分析表明,术前CA19-9及治疗方式是病人术后OS的主要影响因素(见表 3)。随后,上述两个因素进入Cox多因素回归模型,结果表明接受PTBS+腔内灌注化疗和CA19-9(P<0.05<P<0.01)是独立的保护性预后因素。
变量 单因素分析 多因素分析 HR(95%CI) P HR(95%CI) P 性别 1.125(0.699~1.811) >0.05 2.285(1.308~3.993) <0.01 年龄 1.197(0.752~1.906) >0.05 DCCA/HCCA 1.040(0.638~1.694) >0.05 CA19-9 2.176(1.426~3.319) <0.01 ALT 1.058(0.688~1.626) >0.05 AST 1.100(0.703~1.724) >0.05 TBIL 1.003(0.954~1.055) >0.05 ALB 1.028(0.834~1.267) >0.05 PTBS+腔内灌注化疗/PTBS 0.454(0.229~0.902) <0.05 0.459(0.230~0.918) <0.05 表 3 影响病人术后OS的单因素和多因素分析
胆道支架植入联合胆管腔内灌注化疗在晚期肝外胆管癌中的应用
Effect of biliary stent implantation combined with intrabile duct perfusion chemotherapy in the treatment of advanced extrahepatic cholangiocarcinoma
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摘要:
目的探讨胆道支架植入联合胆管腔内灌注化疗在晚期胆管癌中的治疗效果。 方法回顾性分析经皮经肝胆道支架置入(PTBS,PTBS组)或PTBS联合腔内灌注化疗(PTBS+腔内灌注化疗组)的86例晚期EHCC病人的临床资料,分析病人肝功能的改善情况、并发症发生情况及术后生存情况等。Kaplan-Meier曲线及Cox比例风险回归模型分析影响病人术后总体生存时间(OS)的相关因素。 结果与术前相比,2组病人术后1月、3月及6月血清中ALT、AST及TBIL水平均有不同程度的降低(P < 0.05),且PTBS+腔内灌注化疗组病人下降趋势比PTBS组更为显著;PTBS+腔内灌注化疗组病人术后血清ALB水平增加更为明显。2组病人术后并发症的发生差异无统计学意义(P>0.05)。PTBS组病人生存时间中位数为7个月,1年生存率为11.3%;PTBS+腔内灌注化疗组病人生存时间中位数为10个月,1年生存率为37.5%。log-rank检验提示PTBS联合腔内灌注化疗可改善EHCC病人的预后,延长其生存期。Cox多因素回归模型结果表明接受PTBS+腔内灌注化疗是预后独立的保护性因素(HR=0.46,95%CI:0.23~0.92,P < 0.05)。 结论与单纯PTBS相比,PTBS联合腔内灌注化疗可改善EHCC病人的预后,延长其生存期。PTBS联合腔内灌注化疗可获得更佳治疗效果,值得临床进一步探索与研究。 Abstract:ObjectiveTo explore the effects of biliary stent implantation combined with intrabile duct perfusion chemotherapy in the treatment of advanced extrahepatic cholangiocarcinoma(EHCC). MethodsThe clinical data of 86 advanced EHCC patients treated with percutaneous extrahepatic biliary stenting(PTBS group) or PTBS combined with intraductal perfusion chemotherapy(PTBS combined with intraductal perfusion chemotherapy group) were retrospectively analyzed.The improvement of liver function, complications and postoperative survival were analyzed.The influencing factors of overall survival(OS) were analyzed using Kaplan-Meier curve and Cox regression model. ResultsCompared with before operation, the serum levels of ALT, AST and TBIL significantly reduced after 1, 3 and 6 months of operation(P < 0.05), the decreasing degree of which in PTBS combined with intraductal perfusion chemotherapy group was more obviously than that in PTBS group, and the increasing degree of ALB level in PTBS combined with intraductal perfusion chemotherapy group was more obviously than that in PTBS group.The difference of the incidence rate of postoperative complication between two groups was not statistically significant(P>0.05).The median survival time and 1-year survival rate in PTBS group were 7 months and 11.3%, respectively.The median survival time and 1-year survival rate in PTBS combined with intraductal perfusion chemotherapy group were 10 months and 37.5%, respectively.Log-rank test suggested that the PTBS combined with intraductal perfusion chemotherapy could improve the prognosis, and prolong the survival of EHCC patients.Cox regression analysis showed that the PTBS combined with intraductal perfusion chemotherapy was an independent protective factor for prognosis(HR=0.46, 95%CI:0.23-0.92, P < 0.05). ConclusionsCompared with the simple PTBS, the PTBS combined with intraductal perfusion chemotherapy can improve the prognosis, and prolong the survival of EHCC patients.The PTBS combined with intraductal perfusion chemotherapy has good treatment effect, which is worthy of further clinical exploration and research. -
表 1 病人基线资料比较
基线资料 PTBS组(n=71) PTBS+腔内灌注化疗组(n=15) uc P 男/女 43/28 10/5 0.20▲ >0.05 年龄 68.8±14.1 66.8±9.5 0.52△ >0.05 HCCA/DCCA 44/27 11/4 0.69▲ >0.05 CA19-9/(ng/mL) 886(1.1~1967) 636.6(6.68~1200) 0.22 >0.05 CEA/(ng/mL) 4.35(0.96~490.51) 5.69(1.40~40.32) 0.27 >0.05 ALT/(U/L) 106(18~542) 149(67~273) 2.16 <0.05 AST/(U/L) 98(19~793) 158(56~347) 2.69 <0.01 ALP/(U/L) 404(102~1990) 685(176~1734) 2.41 <0.05 GGT/(U/L) 406(47~1837) 683(102~2528) 2.22 <0.05 TBIL/(μmol/L) 158(5.8~551.5) 212.4(108.3~706.2) 1.83 <0.05 ALB/(g/L) 34.6(25.1~43.6) 34.3(31.1~40.5) 0.62 >0.05 △示t值;▲示χ2值 表 2 2组病人术后主要生化指标的变化情况
分组 n 术前 术后1月 术后3月 术后6月 F P MS组内 TBIL/(μmol/L) PTBS组 71 198.9±16.8 55.7±13.6* 118.2±32.7* 57.2±37.2*# 443.50 <0.01 730.083 PTBS+腔内灌注化疗组 15 275.4±41.3 45.1±8.9* 20.4±5.9* 28.2±5.5*# 412.40 <0.01 462.491 t — 11.81 2.88 11.49 2.30 — — — P — <0.01 <0.01 <0.01 <0.01 — — — ALB/(g/L) PTBS组 71 34.2±0.5 34.3±0.8 33.2±1.4*■ 31.8±4.0*■# 20.33 0.01 4.713 PTBS+腔内灌注化疗组 15 35.1±0.8 39.6±1.0* 41.1±0.6* 38.5±0.9*# 138.80 <0.01 0.703 t — 5.64 22.29 21.36 6.42 — — — P — <0.01 <0.01 <0.01 <0.01 — — — ALT/(U/L) PTBS组 71 133.4±12.5 43.8±5.4* 90.2±25.6* 52.5±22.1*# 357.71 <0.01 332.295 PTBS+腔内灌注化疗组 15 160.6±16.0 60.8±7.7* 49.8±11.4* 64.3±18.8*# 199.42 <0.01 199.673 t — 7.30 10.23 1.92 0.41 — — — P — <0.01 <0.01 <0.01 >0.05 — — — AST/(U/L) PTBS组 71 130.4±15.2 56.3±9.5* 135.3±49.6 32.1±7.8*# 271.90 0.01 710.573 PTBS+腔内灌注化疗组 15 171.5±19.9 69.1±9.4* 64.2±15.0* 70.6±22.0*■# 135.11 <0.01 298.343 t — 9.00 4.75 5.48 11.82 — — — P — <0.01 <0.01 <0.01 <0.01 — — — 与术前比较*P<0.05;与术后1月比较■P<0.05;与术后3月比较#P<0.05 表 3 影响病人术后OS的单因素和多因素分析
变量 单因素分析 多因素分析 HR(95%CI) P HR(95%CI) P 性别 1.125(0.699~1.811) >0.05 2.285(1.308~3.993) <0.01 年龄 1.197(0.752~1.906) >0.05 DCCA/HCCA 1.040(0.638~1.694) >0.05 CA19-9 2.176(1.426~3.319) <0.01 ALT 1.058(0.688~1.626) >0.05 AST 1.100(0.703~1.724) >0.05 TBIL 1.003(0.954~1.055) >0.05 ALB 1.028(0.834~1.267) >0.05 PTBS+腔内灌注化疗/PTBS 0.454(0.229~0.902) <0.05 0.459(0.230~0.918) <0.05 -
[1] RIZVI S, KHAN SA, HALLEMEIER CL, et al.Cholangiocarcinoma-evolving concepts and therapeutic strategies[J].Nat Rev Clin Oncol, 2018, 15(2):95. doi: 10.1038/nrclinonc.2017.157 [2] PU LZ, SINGH R, LOONG CK.Malignant biliary obstruction:evidence for best practice[J].Gastroenterol Res Pract, 2016, 2016(11):1. [3] SON RC, GWON DI, KO HK, et al.Percutaneous unilateral biliary metallic stent placement in patients with malignant obstruction of the biliary hila and contralateral portal vein steno-occlusion[J].Korean J Radiol, 2015, 16(3):586. doi: 10.3348/kjr.2015.16.3.586 [4] RAZUMILAVA N, GORES GJ.Classification, diagnosis, and management of cholangiocarcinoma[J].Clin Gastroenterol Hepatol, 2013, 11(1):13. [5] LEWIS HL, RAHNEMAI-AZAR AA, DILLHOFF M, et al.Current management of perihilar cholangiocarcinoma and future perspectives[J].Chirurgia, 2017, 112(3):193. doi: 10.21614/chirurgia.112.3.193 [6] PARK K, KIM KP, PARK S, et al.Comparison of gemcitabine plus cisplatin versus capecitabine plus cisplatin as first-line chemotherapy for advanced biliary tract cancer[J].Asia Pac J Clin Oncol, 2017, 13(1):13. doi: 10.1111/ajco.2017.13.issue-1 [7] JUN SY, SEOK YK, KATO T, et al.Hyperthermic intrathoracic chemotherapy with cisplatin for ovarian cancer with pleural metastasis[J].Obstet Gynecol Sci, 2017, 60(3):308. doi: 10.5468/ogs.2017.60.3.308 [8] MAURICE MJ, MADI R, CHUANG DY, et al.Retrograde chemoinfusion of the upper tract:standardizing the delivery of topical adjuvant therapy[J].J Endourol, 2013, 27(5):540. doi: 10.1089/end.2012.0608 [9] CEELEN W, VAN NIEUWENHOVE Y, PATTYN P.Surgery and intracavitary chemotherapy for peritoneal carcinomatosis from colorectal origin[J].Acta Gastroenterol Belg, 2008, 71(4):373. [10] WESTPHAL M, LAMSZUS K, HILT D.Intracavitary chemotherapy for glioblastoma:present status and future directions[J].Acta Neurochir Suppl, 2003, 88:61. doi: 10.1007/978-3-7091-6090-9 [11] 马泰, 潘跃银, 孙国平, 等.恶性胸/腹腔积液病人腔内应用贝伐珠单抗的价值及疗效影响因素分析[J].中华疾病控制杂志, 2017(7):727. [12] 于建全, 冯飞灵, 沈洋, 等.持续腹腔热灌注化疗治疗进展期胆管癌的临床疗效观察[J].第二军医大学学报, 2017, 38(5):570. [13] SAVIER E, AZOULAY D, HUGUET E, et al.Percutaneous isolated hepatic perfusion for chemotherapy:a phase 1 study[J].Arch Surg, 2003, 138(3):325. doi: 10.1001/archsurg.138.3.325 [14] 黄伟, 刘会春, 王远鹏, 等.胆管癌病人腔内综合治疗与姑息性手术疗效比较[J].中华肝胆外科杂志, 2017, 23(6):289. [15] 范恒伟, 刘会春, 李宗狂, 等.经PTCD途径胆道金属支架置入术治疗恶性梗阻性黄疸137例临床疗效分析[J].肝胆外科杂志, 2013, 21(2):94. doi: 10.3969/j.issn.1006-4761.2013.02.005 [16] 王勇, 刘会春, 李宗狂, 等.经皮胆道支架联合125I粒子腔内植入治疗恶性梗阻性黄疸的初步研究[J].中华放射学杂志, 2014, 48(5):403. doi: 10.3760/cma.j.issn.1005-1201.2014.05.011 [17] World Medical Association.World Medical Association Declaration of Helsinki:ethical principles for medical research involving human subjects[J].JAMA, 2013, 310(20):2191. doi: 10.1001/jama.2013.281053 [18] LABIB PL, DAVIDSON BR, SHARMA RA, et al.Locoregional therapies in cholangiocarcinoma[J].Hepat Oncol, 2017, 4(4):99. doi: 10.2217/hep-2017-0014 [19] SQUADRONI M, TONDULLI L, GATTA G, et al.Cholangiocarcinoma[J].Crit Rev Oncol Hematol, 2017, 116:11. doi: 10.1016/j.critrevonc.2016.11.012 [20] 金浩, 刘会春, 李宗狂, 等.肝门胆管癌103例诊治分析[J].蚌埠医学院学报, 2013, 38(11):1402. [21] KOZAREK R.Role of preoperative palliation of jaundice in pancreatic cancer[J].J Hepatobiliary Pancreat Sci, 2013, 20(6):567. doi: 10.1007/s00534-013-0612-4 [22] HASIMU A, GU JP, JI WZ, et al.Comparative study of percutaneous transhepatic biliary stent placement with or without Iodine-125 seeds for treating patients with malignant biliary pbstruction[J].J Vasc Interv Radiol, 2017, 28(4):583. doi: 10.1016/j.jvir.2016.11.038 [23] 毛丽伟, 王阳, 廖国清, 等.腹腔热灌注化疗对晚期胃癌病人外周血和腹水调节性T细胞的影响及意义[J].检验医学与临床, 2016, 13(17):2429. doi: 10.3969/j.issn.1672-9455.2016.17.008 [24] 胡惠, 王宗鼎, 李可洲, 等.氟尿嘧啶联合丝裂霉素通过改变自噬作用抑制胆管癌细胞QBC939衰老并促进凋亡[J].第三军医大学学报, 2013, 35(18):1915.