淋巴结清扫在肝内胆管癌根治术中临床价值的多中心回顾性研究

A multicenter retrospective study on clinical value of lymph node dissection in the radical resection of intrahepatic cholangiocarcinoma

目的探讨淋巴结清扫在肝内胆管癌根治术中的临床价值。方法采用倾向评分匹配及回顾性队列研究方法。收集2011年12月至2017年12月12家医疗中心收治的448例(海军军医大学附属东方肝胆外科医院279例、福建医科大学孟超肝胆医院32例、陆军军医大学第一附属医院21例、中国医学科学院北京协和医学院肿瘤医院20例、四川大学华西医院19例、浙江大学医学院附属第二医院18例、上海交通大学医学院附属仁济医院18例、首都医科大学附属北京友谊医院16例、首都医科大学附属宣武医院10例、华中科技大学同济医学院附属同济医院7例、首都医科大学附属北京天坛医院5例、川北医学院附属医院3例)肝内胆管癌患者的临床病理资料;男281例,女167例;中位年龄为57岁,年龄范围为22~80岁。448例患者中,143例术中常规行淋巴结清扫设为清扫组,305例术中未常规行淋巴结清扫设为对照组。观察指标:(1)倾向评分匹配情况及匹配后两组患者一般资料比较。(2)术中和术后情况。(3)随访情况。(4)生存分析。采用门诊、电话及邮件方式进行随访,了解患者生存和肿瘤复发情况。术后2年内每3个月随访1次,术后2~5年每6个月随访1次,5年后每1年随访1次。随访时间截至2018年10月31日或患者死亡。倾向评分匹配按1∶1最近邻匹配法匹配。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Mann-Whitney U检验;计数资料以绝对数表示,组间比较采用χ2检验或Fisher确切概率法。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。单因素分析采用Log-rank检验,多因素分析采用COX回归模型。结果(1)倾向评分匹配情况及匹配后两组患者一般资料比较:448例肝内胆管癌患者中,286例(清扫组和对照组各143例)配对成功。倾向评分匹配前清扫组患者性别(男、女),合并肝炎,肝功能Child-Pugh分级(A级、B级),切缘距肿瘤距离(<1 cm、≥1 cm),肿瘤分化程度(高分化和中分化、低分化),肝切除方式(解剖性肝切除、非解剖性肝切除)分别为77例、66例,33例,96例、47例,70例、73例,105例、38例,79例、64例,对照组患者上述指标分别为204例、101例,121例,165例、140例,207例、98例,251例、54例,124例、181例,两组患者上述指标比较,差异均有统计学意义(χ2=7.079,11.885,7.098,14.763,5.184,8.362,P<0.05);经倾向评分匹配后清扫组患者上述指标分别为77例、66例,33例,96例、47例,70例、73例,105例、38例,79例、64例,对照组患者上述指标分别为79例、64例,29例,88例、55例,71例、72例,112例、31例,74例、69例,两组患者上述指标比较,差异均无统计学意义(χ2=0.056,0.329,2.158,0.014,0.936,1.400,P>0.05)。(2)术中和术后情况:倾向评分匹配后,清扫组患者手术时间、术中出血量、术中输血例数、术后并发症例数、术后住院时间分别为265 min(160~371 min)、300 mL(200~500 mL)、37例、46例、12 d(9~17 d),对照组患者上述指标分别为59 min(46~250 min)、200 mL(100~400 mL)、24例、25例、9 d(7~11 d),两组患者术中出血量、术中输血例数比较,差异均无统计学意义(Z=1.700,χ2=3.520,P>0.05);两组患者手术时间、术后并发症例数、术后住院时间比较,差异均有统计学意义(Z=6.520,χ2=8.260,Z=4.270,P<0.05)。(3)随访情况:清扫组143例患者获得随访,随访时间为18~26个月。清扫组患者1、3、5年总体生存率分别为66.9%、32.8%、25.0%,中位生存时间为22.0个月(18.0~26.0个月)。对照组143例患者获得随访,随访时间为11~32个月。对照组患者1、3、5年总体生存率分别为71.7%、38.0%、31.0%,中位生存时间为22.0个月(11.0~32.0个月)。两组患者总体生存情况比较,差异无统计学意义(χ2=0.466,P>0.05)。(4)生存分析:单因素分析结果显示切缘距肿瘤距离、肿瘤直径、肿瘤数目、微血管侵犯、病理学检查淋巴结转移是影响肝内胆管癌根治术患者预后的因素(χ2=10.662,9.477,16.944,6.520,11.633,P<0.05)。多因素分析结果显示切缘距肿瘤距离<1 cm、肿瘤直径>5 cm、肿瘤数目为多发、微血管侵犯和病理学检查淋巴结转移阳性是影响肝内胆管癌根治术患者预后的独立危险因素(风险比=0.600,1.571,1.601,1.750,1.723,95%可信区间为0.430~0.837,1.106~2.232,1.115~2.299,1.083~2.829,1.207~2.460,P<0.05)。结论淋巴结转移是影响肝内胆管癌根治术患者预后的独立危险因素。对淋巴结转移患者在肝内胆管癌根治术中行淋巴结清扫十分必要。

Objective To investigate the clinical value of lymph node dissection(LND)in the radical resection of intrahepatic cholangiocarcinoma(ICC).Methods The propensity score matching and retrospective cohort study was conducted.The clinicopathological data of 448 patients with ICC who were admitted to 12 medical centers from December 2011 to December 2017 were collected,including 279 in the Eastern Hepatobiliary Surgery Hospital of Navy Medical University,32 in the Mengchao Hepatobiliary Hospital of Fujian Medical University,21 in the First Hospital Affiliated to Army Medical University,20 in the Cancer Hospital Chinese Academy of Medical Science and Peking Union Medical College,19 in the West China Hospital of Sichuan University,18 in the Second Hospital Affiliated to Zhejiang University School of Medicine,18 in the Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine,16 in the Beijing Friendship Hospital Affiliated to Capital Medical University,10 in the Xuanwu Hospital Affiliated to Capital Medical University,7 in the Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology,5 in the Beijing Tiantan Hospital Affiliated to Capital Medical University,and 3 in the Affiliated Hospital of North Sichuan Medical College.There were 281 males and 167 females,aged from 22 to 80 years,with a median age of 57 years.Of the 448 patients,143 with routinely intraoperative LND were divided into LND group and 305 without routinely intraoperative LND were divided into control group,respectively.Observation indicators:(1)the propensity score matching conditions and comparison of general data between the two groups after matching;(2)intraoperative and postoperative situations;(3)follow-up;(4)survival analysis.Patients were followed up by outpatient examination,telephone interview and email to detect survival of patients and tumor recurrence up to October 31,2018 or death.Follow-up was conducted once every 3 months within postoperative 1-2 years,once every 6 months within postoperative 2-5 years,and once a year after 5 years.The propensity score matching was realized using the nearest neighbor method with 1∶1 ratio.Measurement data with normal distribution were represented as Mean±SD,and comparison between groups was analyzed using the t test.Measurement data with skewed distribution were represented as M(range),and comparison between groups was analyzed using the Mann-Whitney U test.Count data were described as absolute numbers,and comparison between groups was analyzed using the chi-square test or Fisher exact probability.Kaplan-Meier method was used to calculate survival rates and draw survival curve,and Log-rank test was used to perform survival analysis.Univariate analysis and multivaraiate analysis were conducted using the Log-rank test and COX regression model,respectively.Results(1)The propensity score matching conditions and comparison of general data between the two groups after matching:286 of 448 patients had successful matching,including 143 in each group.The number of males and females,cases with hepatitis,cases with grade A and B of Child-Pugh classification,cases with distance from margin to tumor<1 cm and≥1 cm,cases with highly,moderately,and poorly differentiated tumor,cases with anatomical hepatectomy and nonanatomical hepatectomy before propensity score matching were 77,66,33,96,47,70,73,105,38,79,64 in the LND group,and 204,101,121,165,140,207,98,251,54,124,181 in the control group,respectively,showing significant differences in the above indices between the two groups(χ2=7.079,11.885,7.098,14.763,5.184,8.362,P<0.05).After propensity score matching,the above indices were 77,66,33,96,47,70,73,105,38,79,64 in the LND group,and 79,64,29,88,55,71,72,112,31,74,69 in the control group,respectively,showing no significant difference in the above indices between the two groups(χ2=0.056,0.329,2.158,0.014,0.936,1.400,P>0.05).(2)Intraoperative and postoperative situations:the operation time,volume of intraoperative blood loss,cases with intraoperative blood transfusion,cases with postoperative complications,and duration of postoperative hospital stay were 265 minutes(range,160-371 minutes),300 mL(range,200-500 mL),37,46,12 days(range,9-17 days)for the LND group,and 59 minutes(range,46-250 minutes),200 mL(range,100-400 mL),24,25,9 days(range,7-11 days)for the control group,respectively.There was no significant difference in the volume of intraoperative blood loss or cases with intraoperative blood transfusion between the two groups(Z=1.700,χ2=3.520,P>0.05).There were significant differences in the operation time,cases with postoperative complications,and duration of postoperative hospital stay(Z=6.520,χ2=8.260,Z=4.270,P<0.05).(3)Follow-up:143 patients in the LND group was followed up for 18-26 months.The 1-,3-,5-year survival rates were 66.9%,32.8%,25.0%,and the median survival time was 22.0 months(range,18.0-26.0 months).In the control group,143 patients were followed up for 11-32 months.The 1-,3-,5-year survival rates were 71.7%,38.0%,31.0%,and the median survival time was 22.0 months(range,11.0-32.0 months).There was no significant difference in the overall survival between the two groups(χ2=0.466,P>0.05).(4)Survival analysis:results of univariate analysis showed that distance from margin to tumor,tumor diameter,the number of tumors,microvascular tumor thrombus,and lymph node metastasis by pathological examination were related factors for prognosis of patients undergoing radical resection of ICC(χ2=10.662,9.477,16.944,6.520,11.633,P<0.05).Results of multivariate analysis showed that distance from margin to tumor<1 cm,tumor diameter>5 cm,multiple tumors,microvascular tumor thrombus,positive lymph node metastasis by pathological examination were independent risk factors for prognosis of patients undergoing radical resection of ICC(hazard ratio=0.600,1.571,1.601,1.750,1.723,95%confidence interval:0.430-0.837,1.106-2.232,1.115-2.299,1.083-2.829,1.207-2.460,P<0.05).Conclusion Lymph node metastasis is an independent risk factor affecting the prognosis of ICC patients,and it is necessary to perform LND in radical resection for patients with ICC and lymph node metastasis.