腹腔镜远端胃癌D_(2)根治术治疗局部进展期胃癌10年预后及影响因素分析:基于CLASS队列的全国多中心研究

The 10-year outcome and prognostic factors of laparoscopic D2 radical distal gastrectomy for locally advanced gastric cancer:a CLASS multicenter study

目的探讨腹腔镜远端胃癌D2根治术治疗局部进展期胃癌10年预后及影响因素。方法采用回顾性队列研究方法。收集2004年2月至2010年12月中国腹腔镜胃肠外科研究组(CLASS研究组)腹腔镜胃癌外科多中心临床数据库中16家医院收治的652例(陆军军医大学第一附属医院214例、福建医科大学附属协和医院191例、南方医科大学南方医院52例、四川大学华西医院49例、空军军医大学附属西京医院43例、江苏省中医院25例、解放军总医院第一医学中心14例、解放军联勤保障部队第九八九医院12例、中山大学附属第三医院12例、南昌大学第一附属医院10例、佛山市第一人民医院9例、南方医科大学珠江医院7例、福建医科大学附属肿瘤医院7例、复旦大学附属中山医院3例、华中科技大学同济医学院附属协和医院2例、北京大学肿瘤医院2例)局部进展期胃癌患者的临床病理资料;男442例,女210例;年龄为(57±12)岁。患者均行腹腔镜远端胃癌D_(2)根治术。观察指标:(1)手术情况。(2)术后病理学检查情况。(3)术后恢复及并发症情况。(4)随访情况。(5)预后影响因素分析。采用门诊和电话方式进行随访,了解患者术后肿瘤复发转移及生存情况。随访时间截至2020年3月。正态分布的计量资料以x±s表示,偏态分布的计量资料以M(Q_(1),Q_(3))或M(范围)表示。计数资料以绝对数或百分比表示,组间比较采用χ^(2)检验,等级资料比较采用Mann-Whitney U非参数检验。采用寿命表法计算生存率,Kaplan-Meier法绘制生存曲线,Log-Rank检验进行生存分析。采用COX风险回归模型进行单因素和多因素分析。结果(1)手术情况:652例患者中,617例行D2淋巴结清扫术,35例行D2+淋巴结清扫术;348例消化道重建方式为Billroth Ⅱ吻合,218例为Billroth Ⅰ吻合,25例为Roux-en-Y吻合,61例为其他;12例行联合脏器切除;569例术中输血,83例术中未输血。652例患者手术时间为187(155,240)min,术中出血量为100(50,150)mL。(2)术后病理学检查情况:652例患者肿瘤最大径为(4.5±2.0)cm;淋巴结清扫数目为26(19,35)枚,其中>15枚570例,≤15枚82例;淋巴结转移数目为4(1,9)枚;肿瘤近端切缘为(4.8±1.6)cm,肿瘤远端切缘为(4.5±1.5)cm。652例患者中,肿瘤Borrmann分型为Ⅰ~Ⅱ型255例,Ⅲ~Ⅳ型334例,缺失Borrmann分型资料63例;肿瘤分化程度为高-中分化171例,低-未分化430例,缺失肿瘤分化程度资料51例;肿瘤病理学T分期T2期、T3期、T4a期分别为123、253、276例,病理学N分期N0期、N1期、N2期、N3期分别为116、131、214、191例,病理学TNM分期Ⅱ期、Ⅲ期分别为260、392例。(3)术后恢复及并发症情况:652例患者术后首次下床活动间为3(2,4)d,首次肛门排气时间为4(3,5)d,首次进食全流质食物时间为5(4,6)d,术后住院时间为10(9,13)d。652例患者中,69例发生术后并发症,Clavien-Dindo Ⅰ~Ⅱ级、Ⅲa级、Ⅲb级、Ⅳa级并发症患者分别为60、3、5、1例。同1例患者可合并多种并发症。手术并发症和系统并发症中,发生率最高的分别为十二指肠残端瘘(3.07%,20/652)和呼吸系统并发症(2.91%,19/652)。69例患者经治疗后均顺利转归并出院。(4)随访情况:652例患者均获得随访,随访时间为110~193个月,中位随访时间为124个月。298例术后复发转移患者中,255例术后≤5年复发转移,其中远处转移、腹膜转移、局部复发、多处复发转移、其他部位复发转移分别为21、69、37、52、76例;43例术后>5年复发转移,上述指标分别为5、9、10、4、15例;两者复发转移类型比较,差异无统计学意义(χ^(2)=5.52,P>0.05)。术后≤5年和>5年复发转移患者病理学TNM分期Ⅱ期、Ⅲ期分别为62、193例和23、20例,两者病理学TNM分期比较,差异有统计学意义(χ^(2)=15.36,P<0.05);病理学T分期T2期、T3期、T4a期分别为42、95、118例和9、21、13例,两者病理学T分期比较,差异无统计学意义(Z=-1.80,P>0.05),进一步分析,两者病理学T2期、T3期比较,差异均无统计学意义(χ^(2)=0.52,2.08,P>0.05),两者T4a期比较,差异有统计学意义(χ^(2)=3.84,P<0.05);病理学N分期N0期、N1期、N2期、N3期分别为19、44、85、107例和12、5、18、8例,两者病理学N分期比较,差异有统计学意义(Z=-3.34,P<0.05),进一步分析,两者病理学N0期、N3期比较,差异均有统计学意义(χ^(2)=16.52,8.47,P<0.05),两者N1期、N2期比较,差异均无统计学意义(χ^(2)=0.85,1.18,P>0.05)。652例患者术后中位总生存时间为81个月,10年总生存率为46.1%,其中病理学TNM分期Ⅱ期、Ⅲ期患者10年总生存率分别为59.6%、37.5%,两者比较,差异有统计学意义(χ^(2)=35.29,P<0.05)。进一步分析,病理学TNM分期ⅡA期、ⅡB期、ⅢA期、ⅢB期、ⅢC期患者10年总生存率分别为65.6%、55.8%、46.9%、37.1%、24.0%,5者比较,差异有统计学意义(χ^(2)=55.06,P<0.05)。病理学T2期、T3期、T4a期患者10年总生存率分别为55.2%、46.5%、41.5%,3者比较,差异有统计学意义(χ^(2)=8.39,P<0.05)。病理学N0期、N1期、N2期、N3期患者10年总生存率分别为63.7%、56.2%、48.5%、26.4%,4者比较,差异有统计学意义(χ^(2)=54.89,P<0.05)。(5)预后影响因素分析:单因素分析结果显示年龄,肿瘤最大径,肿瘤分化程度(低-未分化),病理学TNM分期,病理学T分期,病理学N分期(N2期、N3期),术后化疗是影响行腹腔镜远端胃癌D2根治术局部进展期胃癌10年总生存率的相关因素(风险比=1.45,1.64,1.37,2.05,1.30,1.68,3.08,0.56,95%可信区间为1.15~1.84,1.32~2.03,1.05~1.77,1.62~2.59,1.05~1.61,1.17~2.42,2.15~4.41,0.44~0.70,P<0.05)。多因素分析结果显示:肿瘤最大径>4 cm,肿瘤分化程度为低-未分化,病理学TNM分期Ⅲ期是影响行腹腔镜远端胃癌D2根治术局部进展期胃癌10年总生存率的独立危险因素(风险比=1.48,1.44,1.81,95%可信区间为1.19~1.84,1.11~1.88,1.42~2.30,P<0.05),术后化疗是影响行腹腔镜远端胃癌D2根治术局部进展期胃癌10年总生存率的独立保护因素(风险比=0.57,95%可信区间为0.45~0.73,P<0.05)。结论腹腔镜辅助远端胃癌D_(2)根治术治疗局部进展期胃癌10年肿瘤学疗效满意。病理学TNM分期Ⅲ期、病理学T4a期、病理学N3期患者术后≤5年复发转移比例高,而病理学TNM分期Ⅱ期、病理学N0期患者术后>5年复发转移比例高。肿瘤最大径>4 cm,肿瘤分化程度为低-未分化,病理学TNM分期Ⅲ期是影响行腹腔镜远端胃癌D2根治术局部进展期胃癌10年总生存率的独立危险因素,术后化疗是影响行腹腔镜远端胃癌D2根治术局部进展期胃癌10年总生存率的独立保护因素。

Objective To investigate the 10-year outcome and prognostic factors of laparoscopic D_(2) radical distal gastrectomy for locally advanced gastric cancer.Methods The retrospective cohort study was conducted.The clinicopathological data of 652 patients with locally advanced gastric cancer who were admitted to 16 hospitals from the multicenter database of laparoscopic gastric cancer surgery in the Chinese Laparoscopic Gastrointestinal Surgery Study(CLASS)Group,including 214 cases in the First Affiliated Hospital of Army Medical University,191 cases in Fujian Medical University Union Hospital,52 cases in Nanfang Hospital of Southern Medical University,49 cases in West China Hospital of Sichuan University,43 cases in Xijing Hospital of Air Force Medical University,25 cases in Jiangsu Province Hospital of Chinese Medicine,14 cases in the First Medical Center of the Chinese PLA General Hospital,12 cases in No.989 Hospital of PLA,12 cases in the Third Affiliated Hospital of Sun Yat-Sen University,10 cases in the First Affiliated Hospital of Nanchang University,9 cases in the First People's Hospital of Foshan,7 cases in Zhujiang Hospital of Southern Medical University,7 cases in Fujian Medical University Cancer Hospital,3 cases in Zhongshan Hospital of Fudan University,2 cases in Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,2 cases in Peking University Cancer Hospital&Institute,from February 2004 to December 2010 were collected.There were 442 males and 210 females,aged(57±12)years.All patients underwent laparoscopic D_(2) radical distal gastrectomy.Observation indicators:(1)surgical situations;(2)postoperative pathological examination;(3)postoperative recovery and complications;(4)follow-up;(5)prognostic factors analysis.Follow-up was conducted by outpatient examination and telephone interview to detect the tumor recurrence and metastasis,postoperative survival of patients up to March 2020.Measurement data with normal distribution were represented as Mean±SD,and measurement data with skewed distribution were represented as M(Q_(1),Q_(3))or M(range).Count data were described as absolute numbers or percentages,and comparison between groups was conducted using the chi-square test.Comparison of ordinal data was analyzed using the rank sum test.The life table method was used to calculate survival rates and the Kaplan-Meier method was used to draw survival curves.Log-Rank test was used for survival analysis.Univariate and multivariate analyses were analyzed using the COX hazard regression model.Results(1)Surgical situations:among 652 patients,617 cases underwent D_(2) lymph node dissection and 35 cases underwent D_(2)+lymph node dissection.There were 348 cases with Billroth Ⅱ anastomosis,218 cases with Billroth Ⅰ anastomosis,25 cases with Roux-en-Y anastomosis and 61 cases with other digestive tract reconstruction methods.Twelve patients had combined visceral resection.There were 569 patients with intraoperative blood transfusion and 83 cases without blood transfusion.The operation time of 652 patients was 187(155,240)minutes and volume of intraoperative blood loss was 100(50,150)mL.(2)Postoperative pathological examination:the maximum diameter of tumor was(4.5±2.0)cm of 652 patients.The number of lymph node dissected of 652 patients was 26(19,35),in which the number of lymph node dissected was>15 of 570 cases and≤15 of 82 cases.The number of metastatic lymph node was 4(1,9).The proximal tumor margin was(4.8±1.6)cm and the distal tumor margin was(4.5±1.5)cm.Among 652 patients,255 cases were classified as Borrmann type Ⅰ-Ⅱ,334 cases were classified as Borrmann type Ⅲ-Ⅳ,and 63 cases had missing Borrmann classification data.The degree of tumor differentiation was high or medium in 171 cases,low or undifferentiated in 430 cases,and the tumor differentiation data was missing in 51 cases.There were 123,253 and 276 cases in pathological stage T2,T3 and T4a,respectively.There were 116,131,214 and 191 cases in pathological stage N0,N1,N2 and N3,respectively.There were 260 and 392 cases in pathological TNM stage Ⅱ and Ⅲ,respectively.(3)Postoperative recovery and complications:the time to postoperative first out-of-bed activities,time to postoperative first flatus,time to the initial liquid food intake,duration of postoperative hospital stay of 652 patients were 3(2,4)days,4(3,5)days,5(4,6)days,10(9,13)days,respectively.Among 652 patients,69 cases had postoperative complications.Clavien-Dindo grade Ⅰ-Ⅱ,grade Ⅲa,grade Ⅲb,and grade Ⅳa complications occurred in 60,3,5 and 1 cases,respectively(some patients could have multiple complications).The duodenal stump leakage was the most common surgical complication,with the incidence of 3.07%(20/652).Respiratory complication was the most common systemic complication,with the incidence of 2.91%(19/652).All the 69 patients were recovered and discharged successfully after treatment.(4)Follow-up:652 patients were followed up for 110-193 months,with a median follow-up time of 124 months.There were 298 cases with postoperative recurrence and metastasis.Of the 255 patients with the time to postoperative recurrence and metastasis≤5 years,there were 21 cases with distant metastasis,69 cases with peritoneal metastasis,37 cases with local recurrence,52 cases with multiple recurrence and metastasis,76 cases with recurrence and metastasis at other locations.The above indicators were 5,9,10,4,15 of the 43 patients with the time to postoperative recurrence and metastasis>5 years.There was no significant difference in the type of recurrence and metastasis between them(χ^(2)=5.52,P>0.05).Cases in pathological TNM stage Ⅱ and Ⅲ were 62 and 193 of the patients with the time to postoperative recurrence and metastasis≤5 years,versus 23 and 20 of the patients with the time to postoperative recurrence and metastasis>5 years,showing a significant difference in pathological TNM staging between them(χ^(2)=15.36,P<0.05).Cases in pathological stage T2,T3,T4a were 42,95,118 of the patients with the time to postoperative recurrence and metastasis≤5 years,versus 9,21,13 of the patients with the time to postoperative recurrence and metastasis>5 years,showing no significant difference in pathological T staging between them(Z=-1.80,P>0.05).Further analysis showed no significant difference in cases in pathological stage T2 or T3(χ^(2)=0.52,2.08,P>0.05)but a significant difference in cases in pathological stage T4a between them(χ^(2)=3.84,P<0.05).Cases in pathological stage N0,N1,N2,N3 were 19,44,85,107 of the patients with the time to postoperative recurrence and metastasis≤5 years,versus 12,5,18,8 of the patients with the time to postoperative recurrence and metastasis>5 years,showing a significant difference in pathological N staging between them(Z=-3.34,P<0.05).Further analysis showed significant differences in cases in pathological stage N0 and N3(χ^(2)=16.52,8.47,P<0.05)but no significant difference in cases in pathological stage N1 or N2(χ^(2)=0.85,1.18,P>0.05).The median overall survival time was 81 months after surgery and 10-year overall survival rate was 46.1% of 652 patients.The 10-year overall survival rates of patients in TNM stage Ⅱ and Ⅲ were 59.6% and 37.5%,respectively,showing a significant difference between them(χ^(2)=35.29,P<0.05).In further analysis,the 10-year overall survival rates of patients in pathological TNM stage ⅡA,ⅡB,ⅢA,ⅢB and ⅢC were 65.6%,55.8%,46.9%,37.1% and 24.0%,respectively,showing a significant difference between them(χ^(2)=55.06,P<0.05).The 10-year overall survival rates of patients in pathological stage T2,T3 and T4a were 55.2%,46.5% and 41.5%,respectively,showing a significant difference between them(χ^(2)=8.39,P<0.05).The 10-year overall survival rates of patients in pathological stage N0,N1,N2 and N3 were 63.7%,56.2%,48.5% and 26.4%,respectively,showing a significant difference between them(χ^(2)=54.89,P<0.05).(5)Prognostic factors analysis:results of univariate analysis showed that age,maximum diameter of tumor,degree of tumor differentiation as low or undifferentiated,pathological TNM staging,pathological T staging,pathological stage N2 or N3,postoperative chemotherapy were related factors for the 10-year overall survival rate of locally advanced gastric cancer patients undergoing laparoscopic D_(2) radical distal gastrectomy(hazard ratio=1.45,1.64,1.37,2.05,1.30,1.68,3.08,0.56,95%confidence interval as 1.15-1.84,1.32-2.03,1.05-1.77,1.62-2.59,1.05-1.61,1.17-2.42,2.15-4.41,0.44-0.70,P<0.05).Results of multivariate analysis showed that maximum diameter of tumor>4 cm,low-differentiated or undifferentiated tumor,pathological TNM stage Ⅲ were independent risk factors for the 10-year overall survival rate of locally advanced gastric cancer patients undergoing laparoscopic D_(2) radical distal gastrectomy(hazard ratio=1.48,1.44,1.81,95%confidence interval as 1.19-1.84,1.11-1.88,1.42-2.30,P<0.05)and postoperative chemotherapy was a independent protective factor for the 10-year overall survival rate of locally advanced gastric cancer patients undergoing laparoscopic D_(2) radical distal gastrectomy(hazard ratio=0.57,95% confidence interval as 045-0.73,P<0.05).Conclusions Laparoscopic assisted D_(2) radical distal gastrectomy for locally advanced gastric cancer has satisfactory 10-year oncologic outcomes.A high proportion of patients in pathological TNM stage Ⅲ,pathological stage T4a,pathological stage N3 have the time to postoperative recurrence and metastasis≤5 years,whereas a high proportion of patients in pathological TNM stage Ⅱ or pathological stage N0 have the time to postoperative recurrence and metastasis>5 years.Maximum diameter of tumor>4 cm,low-differentiated or undifferentiated tumor,pathological TNM stage Ⅲ are independent risk factors for the 10-year overall survival rate of locally advanced gastric cancer patients undergoing laparoscopic D_(2) radical distal gastrectomy.Postoperative chemotherapy is a independent protective factor for the 10-year overall survival rate of locally advanced gastric cancer patients undergoing laparoscopic D_(2) radical distal gastrectomy.