个体化全程营养干预在局部进展期SiewertⅡ型和Ⅲ型食管胃结合部腺癌行新辅助同步放化疗中的应用价值

Application value of individualized full-course nutritional intervention in neoadjuvant concurrent chemoradiotherapy for locally advanced Siewert type Ⅱ and Ⅲ adenocarcinoma of esophagogastric junction

目的探讨个体化全程营养干预在局部进展期SiewertⅡ型和Ⅲ型食管胃结合部腺癌(AEG)行新辅助同步放化疗(nCRT)中的应用价值。方法采用前瞻性随机对照研究方法。选取2012年2月至2018年12月河北医科大学第四医院收治的90例局部进展期SiewertⅡ型和Ⅲ型AEG行nCRT病人的临床资料。病人采用随机数字表法,按1∶1比例随机分为两组。病人行nCRT联合个体化全程营养干预设为试验组,行nCRT联合常规营养干预设为对照组。观察指标:(1)入组病人分组情况。(2)病人nCRT治疗期间和术前等待期营养指标及生命质量变化情况。(3)nCRT疗效评价及不良反应。(4)手术及恢复情况。正态分布的计量资料以x±s表示,组间比较采用t检验。偏态分布的计量资料以M(P25,P75)或M(范围)表示,组间比较采用Mann-Whitney U检验。计数资料以绝对数或百分比表示,组间比较采用χ^(2)检验或Fisher确切概率法。等级资料比较采用非参数秩和检验。重复测量资料采用重复测量方差分析。结果(1)入组病人分组情况:筛选出符合条件的病人90例,男77例,女13例;中位年龄为62岁,年龄范围为26~74岁。90例病人中,试验组和对照组各45例。(2)病人nCRT治疗期间和术前等待期营养指标及生命质量变化情况:①试验组病人nCRT期间(第3、6周)及术前等待期(第9、12、15周)体质量分别为(67±10)kg、(66±9)kg、(67±10)kg、(68±10)kg、(70±10)kg,对照组上述指标分别为(65±9)kg、(59±8)kg、(62±8)kg、(64±8)kg、(66±9)kg,不满足球性检验(χ^(2)=195.010,P<0.05),采用多变量检验结果显示:两组病人体质量变化的时间效应、交互效应、干预效应比较,差异均有统计学意义(F=93.974,60.638,4.144,P<0.05)。②试验组病人nCRT期间(第3、6周)及术前等待期(第9、12、15周)总蛋白分别为(66±4)g/L、(65±4)g/L、(65±4)g/L、(68±4)g/L、(71±5)g/L,对照组上述指标分别为(65±4)g/L、(62±5)g/L、(63±5)g/L、(65±5)g/L、(67±6)g/L,不满足球性检验(χ^(2)=652.524,P<0.05),采用多变量检验结果显示:两组病人总蛋白变化的时间效应、交互效应、干预效应比较,差异均有统计学意义(F=672.507,6.424,5.057,P<0.05)。③试验组病人nCRT期间(第3、6周)及术前等待期(第9、12、15周)白蛋白分别为(40±3)g/L、(38±4)g/L、(38±4)g/L、(39±4)g/L、(40±4)g/L,对照组上述指标分别为(39±4)g/L、(35±5)g/L、(36±4)g/L、(36±4)g/L、(37±5)g/L,不满足球性检验(χ^(2)=289.324,P<0.05),采用多变量检验结果显示:两组病人白蛋白变化的时间效应、交互效应、干预效应比较,差异均有统计学意义(F=4210.683,5.013,7.330,P<0.05)。④试验组病人nCRT期间(第3、6周)及术前等待期(第9、12、15周)前白蛋白分别为(228±41)mg/L、(222±56)mg/L、(223±47)mg/L、(227±46)mg/L、(233±53)mg/L,对照组上述指标分别为(202±49)mg/L、(174±68)mg/L、(179±54)mg/L、(185±51)mg/L、(193±57)mg/L,不满足球性检验(χ^(2)=297.324,P<0.05),采用多变量检验结果显示:两组病人前白蛋白变化的时间效应、交互效应、干预效应比较,差异均有统计学意义(F=871.545,6.111,14.426,P<0.05)。⑤试验组病人nCRT期间(第3、6周)及术前等待期(第9、12、15周)血红蛋白分别为(124±14)g/L、(121±14)g/L、(125±13)g/L、(127±13)g/L、(128±13)g/L,对照组上述指标分别为(121±18)g/L、(114±14)g/L、(116±14)g/L、(117±16)g/L、(118±22)g/L,不满足球性检验(χ^(2)=257.560,P<0.05),采用多变量检验结果显示:两组病人血红蛋白变化的时间效应、交互效应、干预效应比较,差异均有统计学意义(F=2533.553,4.142,4.985,P<0.05)。⑥试验组病人nCRT期间(第3、6周)及术前等待期(第9、12、15周)主观整体营养状况评分分别为(4.4±1.2)分、(6.3±1.4)分、(5.5±1.4)分、(4.3±1.4)分、(3.4±1.7)分,对照组上述指标分别为(4.9±1.2)分、(7.4±1.7)分、(7.3±1.6)分、(6.3±1.4)分、(6.0±1.5)分,不满足球性检验(χ^(2)=289.543,P<0.05),采用多变量检验结果显示:两组病人主观整体营养状况评分变化的时间效应、交互效应、干预效应比较,差异均有统计学意义(F=648.583,41.906,26.098,P<0.05)。⑦试验组病人nCRT期间(第3、6周)及术前等待期(第9、12、15周)胃癌病人生命质量问卷评分分别为(13±3)分、(16±6)分、(16±4)分、(14±4)分、(12±5)分,对照组上述指标分别为(15±4)分、(21±6)分、(20±4)分、(17±4)分、(15±5)分,不满足球性检验(χ^(2)=279.865,P<0.05),采用多变量检验结果显示:两组病人胃癌病人生命质量问卷评分变化的时间效应、交互效应、干预效应比较,差异均有统计学意义(F=710.238,7.261,16.794,P<0.05)。(3)nCRT疗效评价及不良反应:45例试验组病人nCRT后25例部分缓解、20例疾病稳定,客观缓解率和疾病控制率分别为55.6%(25/45)和100.0%(45/45);45例对照组病人中18例部分缓解、27例疾病稳定,客观缓解率和疾病控制率分别为40.0%(18/45)和100.0%(45/45);两组病人nCRT疗效比较,差异无统计学意义(P>0.05)。试验组病人nCRT白细胞减少、中性粒细胞减少、贫血、恶心、食欲减退分别为27例、25例、19例、30例、34例,对照组上述指标分别为37例、34例、29例、39例、42例,两组比较,差异均有统计学意义(χ^(2)=5.409,3.986,4.464,5.031,5.414,P<0.05)。(4)手术及恢复情况:试验组病人nCRT后均成功行手术治疗;对照组2例病人术前腹腔镜探查发现腹膜转移,行转化治疗,未行手术治疗,43例病人行手术治疗。试验组病人术后胃管拔除时间、术后引流管拔除时间、术后首次肛门排气时间、术后首次排便时间、术后住院时间分别为2.0 d(1.5 d,3.0 d)、6.0 d(5.0 d,11.0 d)、2.0 d(1.5 d,2.5 d)、2.0 d(1.5 d,2.5 d)、7.0 d(6.0 d,14.0 d),对照组上述指标分别为3.0 d(2.0 d,4.0 d)、7.0 d(5.5 d,14.0 d)、2.0 d(1.5 d,3.0 d)、3.0 d(2.0 d,3.5 d)、8.0 d(6.0 d,17.0 d),两组比较,差异均有统计学意义(Z=-3.477,-4.398,-3.068,-5.786,-3.395,P<0.05)。结论对于局部进展期SiewertⅡ型和Ⅲ型AEG行nCRT的病人,营养师参与的个体化全程营养干预有利于改善病人营养状况,减少不良反应,提高病人生命质量,促进术后近期恢复。临床试验注册:在美国clinicaltrials.gov注册,注册号为NCT01962246。

Objective To investigate the application value of individualized full-course nutritional intervention in neoadjuvant concurrent chemoradiotherapy[nCRT]for locally advanced Siewert type Ⅱ and HI adenocarcinoma of esophagogastric junction[AEG].Methods The perspective randomized control study was conducted.The clinicopathological data of 90 patients with locally advanced Siewert type Ⅱ and Ⅲ AEG who underwent nCRT in the Fourth Hospital of Hebei Medical University from February 2012 to December 2018 were selected.Patient were divided into two groups with 1:1 according to random number table.Patients undergoing nCRT combined with individualized fall-course nutritional intervention were allocated into experimental group,and patients undergoing nCRT combined with common nutritional intervention were allocated into control group.Observation indicators:[1]grouping situations of the enrolled patients;[2]changing situations of nutritional status and quality of life of patients in nCRT and preoperative waiting period;[3]efficacy evaluation and adverse effects of nCRT;[4]surgical and recovery situations.Measurement data with normal distribution were represented as Mean±SD,and comparison between groups was conducted using the t test.Measurement date with skewed distribution were represented as M[P25,P75]or M[range],and comparison between groups was conducted using the Mann-Whitney U test.Count data were represented as absolute numbers or percentages,and comparison between groups was conducted using the chi-square test or Fisher exact probability.Comparison of ordinal data was conducted using the non-parameter rank sum test.Repeated measurement data were analyzed using the repeated ANOVA.Results[1]Grouping situations of the enrolled patients:a total of 90 patients were selected for eligibility.There were 77 males and 13 females,aged from 26 to 74 years,with a median age of 62 years.Of 90 patients,there were 45 cases in the experimental group and 45 cases in the control group.[2]Changing situations of nutritional status and quality of life of patients in nCRT and preoperative waiting period:①during the nCRT treatment[week 3,week 6]and the preoperative waiting period[week 9,week 12,week 15],the body mass was[67±10]kg,[66±9]kg,[67±10]kg,[68±10]kg,[70±10]kg for the experi-mental group,respectively,and[65±9]kg,[59±8]kg,[62±8]kg,[64±8]kg,[66±9]kg for the control group.The multivariate test was conducted based on the mauchly's test of sphericity for the body mass[χ^(2)=195.010,P<0.05].There were significant differences in the time effect,interaction effect,intervention effect of body mass changing between the two groups[F=93.974,60.638,4.144,P<0.05].②During the nCRT treatment[week 3,week 6]and the preoperative waiting period[week 9,week 12,week 15],the total protein was[66±4]g/L,[65±4]g/L,[65±4]g/L,[68±4]g/L,[71±5]g/L for the experimental group,respectively,and[65±4]g/L,[62±5]g/L,[63±5]g/L,[65±5]g/L,[67±6]g/L for the control group.The multivariate test was conducted based on the mauchly's test of sphericity for the total protein[F=652.524,P<0.05].There were significant differences in the time effect,interaction effect,interven-tion effect of total protein changing between the two groups[F=672.507;6.424,5.057,P<0.05].③During the nCRT treatment[week 3,week 6]and the preoperative waiting period[week 9,week 12,week 15],the albumin was[40±3]g/L,[38±4]g/L,[38±4]g/L,[39±4]g/L,[40±4]g/L for the experimental group,respectively,and[39±4]g/L,[35±5]g/L,[36±4]g/L,[36±4]g/L,[37±5]g/L for the control group.The multivariate test was conducted based on the mauchly's test of sphericity for the albumin[χ^(2)=289.324,P<0.05].There were significant differences in the time effect,interaction effect,intervention effect of albumin changing between the two groups[F=4210.683,5.013,7.330,P<0.05].④During the nCRT treatment[week 3,week 6]and the preoperative waiting period[week 9,week 12,week 15],the prealbumin was[228±41]mg/L,[222±56]mg/L,[223±47]mg/L,C227±46]mg/U[233±53]mg/L for the experimental group,respectively,and[202±49]mg/U[174±68]mg/L,[179±54]mg/L,[185±51]mg/L,[193±57]mg/L for the control group.The multivariate test was conducted based on the mauchly's test of sphericity for the prealbumin [χ^(2)=297.324,P<0.05].There were significant differences in the time effect,interaction effect,intervention effect of prealbumin changing between the two groups[F=871.545,6.111,14.426,P<0.05].⑤During the nCRT treatment[week 3,week 6]and the preoperative waiting period[week 9,week 12,week 15],the hemoglobin was[124±14]g/L,[121±14]g/L,[125±13]g/L;[127±13]g/L;[128±13]g/L for the experimental group,respectively,and[121±18]g/L,[114±14]g/U[116±14]g/L,[117±16]g/L;[118±22]g/L for the control group.The multivariate test was conducted based on the mauchly's test of sphericity for the hemoglobin 0^=257.560,P<0.05].There were significant differences in the time effect,interaction effect intervention effect of hemoglobin changing between the two groups[F=2533.553,4.142,4.985,P<0.05].⑥During the nCRT treatment[week 3,week 6}and the preopera-tive waiting period[week 9,week 12,week 15],the patient-generated subjective global assessment[PG-SGA]score was 4.4±1.2,6.3±1.4,5.5±1.4,4.3±1.4,3.4±1.7 for the experimental group,respec-tively,and 4.9±1.2,7.4±1.7,7.3±1.6,6.3±1.4,6.0±1.5 for the control group.The multivariate test was conducted based on the mauchly's test of sphericity for the PG-SGA score.[χ^(2)=289.543,P<0.05].There were significant differences in the time effect,interaction effect,intervention effect of PG-SGA score changing between the two groups[F=648.583,41.906,26.098,P<0.05].©During the nCRT treatment[week 3,week 6]and the preoperative waiting period[week 9,week 12,week 15],the quality of life questionnaire of stomach[QLQ-ST022]score was 13±3,16±6,16±4,14±4,12±5 for the experimental group,respectively,and 15±4,21±6,20±4,17±4,15±5 for the control group.The multivariate test was conducted based on the mauchly's test of sphericity for the QLQ-ST022[χ^(2)=279.865,P<0.05].There were significant differences in the time effect,interaction effect,intervention effect of QLQ-ST022 changing between the two groups[F=710.238,7.261,16.794,P<0.05].[3]Efficacy evaluation and adverse effects of nCRT:there were 25 patients and 20 cases of the experimental group with partial response and stable disease,showing the objective response rate and disease control rate as 55.6%[25/45]and 100.0%[45/45].There were 18 patients and 27 cases of the control group with partial response and stable disease,showing the objective response rate and disease control rate as 40.0%[18/45]and 100.0%[45/45].There was no significant difference in the nCRT efficacy between the two groups[P>0.05].Cases with leukopenia,neutropenia,anemia,nausea,and loss of appetite were 27,25,19,30,34 for the experimental group,versus 37,34,29,39,42 for the control group,showing significant differences between the two groups[χ^(2)=5.409,3.986,4.464,5.031,5.414,P<0.05].[4]Surgical and recovery situations:patients of the experimental group underwent surgeries successfully.Two patients of the control group diagnosed with peritoneal metastasis after laparoscopic exploration underwent conversion therapy and no surgery,the other 43 patients underwent surgeries.The time to postoperative gastric tube removal,time to postoperative drainage tube removal,time to postoperative first flatus,time to postoperative first defecation,duration of postoperative hospital stay were 2.0 days[1.5 days,3.0 days],6.0 days[5.0 days,11.0 days],2.0 days[1.5 days,2.5 days];2.0 days[1.5 days,2.5 days],7.0 days[6.0 days;14.0 days]for the experimental group,versus 3.0 days[2.0 days,4.0 days],7.0 days[5.5 days,14.0 days],2.0 days[1.5 days,3.0 days],3.0 days[2.0 days,3.5 days],8.0 days[6.0 days,17.0 days]for the control group,showing significant differences between the two groups[Z=-3.477,-4.398,-3.068;-5.786,-3.395,P<0.05].Conclusion For AEG patients undergoing nCRX the individualized full-course nutrition intervention involving nutritionists is beneficial to improve the nutritional status,reduce adverse reactions,and improve the quality of life of the patients,promote postoperative short-term recovery.Registry:this study was registered at clinicaltrials.gov in United States,with the registry number of NCT01962246.