【作者】 李静；

【导师】 王军；

【作者基本信息】 河北医科大学 ， 肿瘤学（专业学位）， 2018， 硕士

【摘要】 目的:分析局部进展期食管-胃结合部腺癌(Adenocarcinoma of Esophagogastric Junction,AEG)经新辅助放化疗(neoadjuvant chemoradiotherapy,nCRT)或新辅助化疗(neoadjuvant chemotherapy,nCT)后的病理反应、生存情况及安全性,探索两种新辅助治疗模式的疗效差异。方法:纳入自2011年1月至2017年1月,于河北医科大学第四医院进行的前瞻性、非随机新辅助治疗研究的AEG患者156例。其中男性133例(85.3%),女性23例(17.3%),男女比例约为5.8:1;中位年龄62岁(26~79岁),平均年龄61.5岁;SiewertII型86例,III型70例;单纯腺癌119例,其他类型腺癌37例;治疗前cTNM分期II期33例,III期123例。行n CRT者66例,n CT者90例。n CT组患者行XELOX方案(卡培他滨1000mg/m~2,口服,2/日d1~14;奥沙利铂130mg/m~2,静点,d1,每21天)化疗,n CRT组采用放疗同步XELOX方案化疗,放疗采用受累野照射,照射剂量为45Gy/25次。新辅助治疗结束后6~8周,查无手术禁忌者进行手术,术式为经腹入路行食管下段及近端/全胃切除+D2淋巴结清扫术。根治术后6~8周继续行原方案化疗6周期。采用倾向性评分匹配法在nCRT组和n CT组之间进行1:1配对。匹配后男性109例(89.3%),女性13例(10.7%),男女比例约为8.4:1;中位年龄63岁(26~79岁),平均年龄62.1岁;SiewertII型76例、III型46例;单纯腺癌92例,其他类型腺癌30例;依据治疗前临床分期可分为II期35例,III期87例。比较匹配后两组患者的近期疗效、病理特征、预后及安全性等。结果:1.匹配前均衡性检验显示组间病例特征分布构成比不均衡。基线资料不均衡的因素有性别、Siewert分型、病理类型、临床T分期和临床N分期。采用倾向性评分匹配法匹配出122例患者,每组各61例,组间构成比均衡。2.近期疗效:新辅助治疗后影像学疗效评价,nCRT组中疾病稳定(SD)13例(21.3%),部分缓解(PR)48例(78.7%)。n CT组中疾病稳定(SD)17例(27.9%),部分缓解(PR)34例(55.7%),疾病进展(PD)10例(16.4%)。n CRT组疾病控制率、客观有效率分别为100%、78.7%,nCT组疾病控制率、客观有效率分别为83.6%、55.7%,nCRT组中疾病控制率、客观有效率显著高于nCT组,存在显著统计学差异(?~2=10.839,P=0.001;?~2=7.290,P=0.007)。3.病理特征1)R0切除率:nCRT组和nCT组R0切除率分别为91.8%和86.9%(?~2=0.775,P=0.379),组间统计学差异不显著。2)肿瘤退缩分级(TRG):nCRT组TRG 0级、1级、2级、3级分别为10例(16.7%)、19例(31.1%)、27例(45.0%)、5例(8.3%),nCT组TRG 0级、1级、2级、3级分别为1例(1.6%)、4例(6.6%)、26例(42.6%)、30例(49.2%)。TRG 0级患者在n CRT组中比率显著升高(?~2=8.093,P=0.004)。3)病理完全缓解(p CR):pCR定义为术后病理证实瘤床无癌细胞且无淋巴结转移(ypT0N0)。nCRT组达p CR者11例(18.0%),n CT组达pCR者1例(1.6%),nCRT组PCR率显著高于nCT组,统计学差异显著(?~2=9.242,P=0.002)。4)淋巴结转移总体情况:nCRT组有27例发生淋巴结转移,淋巴结转移率为44.3%(27/61)。手术共清扫淋巴结1574枚,平均清扫淋巴结26枚(4~59枚),53例(86.9%)患者清扫淋巴结数目≥15枚,其中76枚淋巴结发生转移,淋巴结转移度为4.8%(76/1574)。nCT组有36例发生淋巴结转移,淋巴结转移率为59.0%(36/61)。手术共清扫淋巴结2100枚,平均清扫淋巴结34枚(8~78枚),56例(91.8%)患者清扫淋巴结数目≥15枚,其中293枚淋巴结发生转移,淋巴结转移度为14.0%(293/2100)。两组比较nCRT组淋巴结转移度显著低于nCT组(?~2=82.895,P=0.000);两组间淋巴结转移率未见统计学差异(?~2=2.659,P=0.103)。5)脉管瘤栓:nCRT组脉管瘤栓发生率为8.2%(5/61),nCT组脉管瘤栓发生率为14.8%(9/61),两组比较无显著统计学差异(?~2=1.291,P=0.256)。6)神经受侵:nCRT组神经受侵发生率为11.5%(7/61),nCT组则为19.7%(12/61),两组比较统计学差异不显著(?~2=1.559,P=0.212)。7)术后降期:对比术前治疗前分期与术后分期,nCRT组中T分期降期比例为44.3%(27/61),显著高于nCT组的21.3%(13/61),(?~2=7.290,P=0.007);n CRT组中N分期降期比例为50.8%(31/61),nCT组为36.1%(22/61),N分期降期比例有下降趋势(?~2=2.702,P=0.100)。4.预后分析截止至末次随访时间,全组患者68例生存,41例肿瘤相关性死亡,7例治疗相关性死亡,6例失访。1)远处转移和局部复发情况:nCRT组远处转移发生率为26.2%(16/61),nCT组则为16.4%(10/61),两组未见明显差异(?~2=1.760,P=0.185)。nCRT组局部区域复发率为14.8%(9/61),显著低于nCT组的34.4%(?~2=6.365,P=0.012)。2)无病生存期(disease-free survival,DFS):nCRT组平均DFS为42.0±3.4个月(95%CI:35.30~48.67),1、3年无病生存率分别为82.9%、55.1%。n CT组平均DFS为49.7±4.3个月(95%CI:41.11~58.24),1、3年无病生存率分别为83.5%、58.6%,未见显著统计学差异(?~2=0.014,P=0.905)。单因素分析显示脉管瘤栓、术后有无淋巴结转移是DFS的影响因素。术后病理证实存在脉管瘤栓的患者1、3年无病生存率分别为72.3%、53.3%,显著低于未发生组的84.9%、61.9%(?~2=4.427,P=0.035);术后淋巴结转移阳性者1、3年无病生存率分别为80.5%、44.3%,显著低于淋巴结转移阴性组的87.8%、70.9%(?~2=9.540,P=0.002)。多因素分析显示术后有无淋巴结转移是DFS的独立影响因素(Wald=8.923,P=0.003)。3)总生存(overall survival,OS):nCRT组平均OS为52.5±3.8个月(95%CI:45.85~63.02),1、3年生存率分别为89.4%、63.8%。nCT组平均OS为54.4±4.3个月(95%CI:45.85~63.02),1、3年生存率分别为86.9%、60.1%。组间统计学差异不显著(?~2=0.237,P=0.627)。单因素分析显示术后有无淋巴结转移是OS的影响因素。术后淋巴结转移阳性者的1、3年生存率分别为85.2%、49.9%,显著低于淋巴结转移阴性的89.5%、64.3%(?~2=6.989,P=0.008)。多因素分析显示术后有无淋巴结转移是OS的独立影响因素(Wald=6.573,P=0.010)。4)亚组生存分析:将全组患者按性别(男/女)、年龄(≤60岁/>60岁)、病理类型(单纯腺癌/其他类型)、淋巴结转移状况(N0/N+)、T分期(T3/T4)等基线资料分组,在各亚组中进行OS和DFS的预后分析。未筛选出对两种治疗方式获益的亚组人群。5.安全性分析1)非血液学毒性反应中以消化道反应最为常见。在nCRT组和nCT组发生率分别为73.7%(45/61)和60.7%(37/61),统计学差异不显著(?~2=2.380,P=0.123)。nCRT组急性放射性食管炎或胃炎发生率为31.1%(19/61),1、2、3级反应分别为13例(21.3%)、4例(6.6%)、2例(3.2%),未见4~5级毒副反应发生;放射性肺炎发生率为9.8%(6/61),其中1级4例(6.6%),2级2例(3.2%),未见3级及以上放射性肺炎。2)血液学毒性反应:nCRT组较n CT组的1~2级白细胞计数下降发生率显著增高(49.2%vs.24.6%,?~2=7.922,P=0.005);≥3级反应的发生率组间差异无显著统计学意义(?~2=0.342,P=0.559)。3)围手术期死亡率及住院时间:nCRT组有2例患者出现围手术期死亡,1例死于呼吸衰竭,1例死于多器官功能障碍综合征(呼吸、肾脏),围手术期死亡率为3.3%;nCT组有1例患者死于感染性休克合并MODS(呼吸、循环、肾脏),围手术期死亡率为1.6%,两组围手术期死亡率统计学差异不显著(?~2=0.342,P=0.559)。nCRT组中位住院天数为16(11~37),nCT组中位住院天数16(12~40),统计学差异不显著(P=0.215)。结论:SiewertⅡ、Ⅲ型局部进展期食管-胃结合部腺癌经新辅助放化疗和新辅助化疗后R0切除率均较高;与新辅助化疗相比,新辅助放化疗更易实现肿瘤降期、提高pCR率,并降低淋巴结转移度和局部复发率,但未显著延长患者总生存和无病生存。新辅助放化疗采用累及野照射患者有较好的耐受性,围手术期死亡率无显著增加,住院时间无明显延长。术后有无淋巴结转移是无病生存和总生存的独立影响因素。更多还原

【Abstract】 Objective:To analyze the pathological reaction,survival and safety of neoadjuvant chemoradiotherapy(nCRT)or neoadjuvant chemotherapy(nCT)in patients with locally advanced adenocarcinoma of esophagogastric junction(AEG)and to explore the difference in efficacy between the two neoadjuvant treatment models.Methods:Prospective analysis of 156 patients with AEG received non-randomized neoadjuvant treatment in the Fourth Hospital of Hebei Medical University from January 2011 to January 2017.Among them,there were 133 males(85.3%)and 23 females(17.3%),the ratio of male to female was approximately 5.8:1.The median age was 62(26-79),and the average age was 61.5.There were 86 Siewert II and 70 Siewert III,of which 33 patients were in stage II and 123 patients were in stage III according to the clinical stage.There were 119 patients with adenocarcinoma alone and 37 patients with other types of adenocarcinoma.There were 66 patients in nCRT group and 90 patinets in nCT group.Patients in nCT group received XELOX regimen(capecitabine 1000 mg/m~2,oral,2/day d1~14;oxaliplatin 130 mg/m~2,intravenous infusion,d1,per 21 days)for chemotherapy;patients in nCRT group received XELOX regimen combined with radiotherapy which was performed in the involved field with an irradiation dose of 45 Gy/25 times.Six to eight weeks after the end of neoadjuvant treatment,patients who had no surgical contraindications received operation.The surgical approach consisted of transabdominal approach to the lower esophagus and proximal/total gastrectomy+D2 lymph node dissection.After radical resection,the original protocol was continued for 6 cycles.Using a propensity score matching method,the covariates were 1:1 paired between the nCRT group and the nCT group.109 cases(89.3%)were males and 13(10.7%)were females in the matching cohort.The ratio of male to female was approximately 8.4:1;the median age was 63 years(26-79),the average age was 62.1 years;Siewert type II was 76 cases,type III 46 cases;there were 92 cases of adenocarcinoma alone and 30 cases of other types of adenocarcinoma.According to the clinical stage,there were 35 cases in stage II and 87 cases in stage III.The short-term efficacy,pathological features,prognosis and safety of the two groups after matching were compared.Results:1.Pre-matching equilibrium tests showed that the composition ratios of the distribution of case characteristics between groups did not get balanced.The unbalanced baseline data were gender,Siewert classification,biopsy pathology,clinical T staging,and clinical N staging.122 patients were matched using propensity score matching method,with 61 cases in each group.2.Recist:There were 13 cases(21.3%)with stable disease(SD)and 48cases(78.7%)with partial remission(PR)in the nCRT group.As a comparison,there were 17 cases(27.9%)with stable disease(SD),34 cases(55.7%)with partial remission(PR),and 10 cases(16.4%)with disease progression(PD)in the nCT group.In the nCRT group,the disease control rate and objective effective rate were 100%and 78.7%,respectively.The disease control rate and objective effective rate in the nCT group were 83.6%and 55.7%,respectively,with statistically significant difference(?~2=10.839,P=0.001;?~2=7.290,P=0.007),which suggested that the disease control rate and objective efficiency in the nCRT group were obviously higher than those in the nCT group.3.Pathological features1)R0 resection rate:The R0 resection rates of nCRT group and nCT group were 91.8%and 86.9%,respectively,with no statistically significant difference.2)Tumor regression grade(TRG):In n CRT group,TRG 0,1,2,3 were10(16.7%),19(31.1%),27(45.0%),and 5 cases(8.3%),respectively.In nCT group,TRG 0,1,2,3 were 1(1.6%),4(6.6%),26(42.6%),and 30 cases(49.2%),respectively.The incidence rate of TRG 0 in the nCRT group was significantly higher than nCT group(?~2=8.093,P=0.004).3)Pathologic Complete Remission(pCR):p CR was defined as a postoperative pathologically confirmed tumor bed without cancerous cells or lymph node metastasis(ypT0N0).There were 11 patients(18.0%)with pCR in nCRT group and 1 patient(1.6%)with pCR in nCT group.The statistical difference was significant(?~2=9.242,P=0.002).4)Status of lymph node metastasis:In nCRT group,lymph node metastasis occurred in 27 cases,and the lymph node metastasis rate was 44.3%(27/61).A total of 1,574 lymph nodes were cleared and averagely 26 lymph nodes(4 to 59)were removed.53(86.9%)patients had more than 15 lymph node dissections,of which 76 lymph nodes were metastasized resulting the degree of lymph node metastasis was4.8%(76/1574).In nCT group,lymph node metastasis occurred in 36 cases,and the lymph node metastasis rate was 59.0%(36/61).A total of 2100 lymph nodes were cleared and averagely 34 lymph nodes(8 to 78)were removed.56(91.8%)patients had more than 15 lymph node dissections,of which 293lymph nodes were metastasized resulting the degree of lymph node metastasis was 14.0%(293/2100).The degree of lymph node metastasis in nCRT group was significantly lower than that in nCT group(?~2=82.895,P=0.000).There was no significant difference in the rate of lymph node metastasis between the two groups(?~2=2.659,P=0.103).5)Vessel tumor thrombus:The incidence rate of vascular tumor embolus in n CRT group and nCT group was 8.2%(5/61)and 14.8%(9/61),respectively,with no statistically significant difference(?~2=1.291,P=0.256).6)Nerve invasion:The incidence of nerve invasion in nCRT group and nCT group was 11.5%(7/61)and 19.7%(12/61),respectively,with no statistically significant difference(?~2=1.559,P=0.212).7)Postoperative declination of tumor’s stage:Comparing preoperative with postoperative staging,the proportion of T staging declined in n CRT group was 44.3%(27/61),which was significantly higher than that in nCT group(21.3%)(?~2=7.290,P=0.007).The proportion of N staging declined in nCRT group was 50.8%(31/61),and it was 36.1%(22/61)in nCT group,indicating the proportion of N stage declined had a downward trend(?~2=2.702,P=0.100).4.Prognosis analysisTo the end of the last follow-up,68 patients survived in the whole group,41 patients died of tumor-related deaths,7 patients died of treatment-related deaths,and 6 patients were lost to follow-up.1)Distant metastasis and local recurrence:The incidence rate of distant metastasis in nCRT group and in nCT group was 26.2%(16/61)and 16.4%(10/61),respectively,with no statistically significant difference(?~2=1.760,P=0.185).The local recurrence rate in the nCRT group was 14.8%(9/61),which was significantly lower than that in the n CT group(34.4%)(?~2=6.365,P=0.012).2)Distant metassease-free survival rates in the 1 and 3 years were 82.9%and 55.1%,respectively.In the nCT group,the average DFS was 49.7±4.3months(95%CI:41.11 to 58.24).The 1-and 3-year DFS rates were 83.5%and 58.6%,respectively.There was no significant difference between the two groups(?~2=0.014,P=0.905).Univariate analysis showed that vascular tumor thrombosis and the status of postoperative lymph node metastasis were the influencial factors of DFS.The DFS rates of patients with pathologically confirmed vascular tumor embolism were 72.3%and 53.3%in the 1 and 3years,respectively,which were significantly lower than those of 84.9%and61.9%(?~2=4.427,P=0.035).The 1-and 3-year DFS rates in the patients with positive postoperative lymph node metastasis were 80.5%and 44.3%,which were significantly lower than those in the patients with negative lymph node metastasis group(87.8%and 70.9%).Multivariate analysis showed that the status of postoperative lymph node metastasis was an independent factor for DFS(Wald=8.923,P=0.003).3)Overall survival(OS):The mean OS of the nCRT group was 52.5±3.8months(95%CI:45.85 to 63.02).The 1-and 3-year survival rates were 89.4%and 63.8%,respectively.The mean OS of the nCT group was 54.4±4.3 months(95%CI:45.85 to 63.02).The 1-and 3-year survival rates were 86.9%and60.1%,respectively.There was no statistical difference between the two groups(?~2=0.237,P=0.627).Univariate analysis showed that the status of postoperative lymph node metastasis was an influencial factor for OS.The1-year and 3-year survival rates of patiens with positive postoperative lymph node metastasis group were 85.2%and 49.9%,respectively,which were significantly lower than those of patients with negative lymph node metastasis group(89.5%and 64.3%)(?~2=6.989,P=0.008).Multivariate analysis demonstrated that the status of postoperative lymph node metastasis was an independent influencial factor for OS(Wald=6.573,P=0.010).4)Subgroup survival analysis:Divide the entire patient group into subgroups such as sex(male/female),age(≤60 years and 60 years),pathological type(adenocarcinoma alone/other types),lymph node metastasis(N0/N+),T stage(T3/T4),performing prognostic analysis of OS and DFS,respectively.The results showed that there was no significant difference in survival between the two treatment groups among subgroups above.5.Security analysis1)Gastrointestinal reactions were most common in non-hematological toxic reactions.The incidence rate of it in the nCRT group and nCT group were 73.7%(45/61)and 60.7%(37/61),respectively,with no statistically significant difference(?~2=2.380,P=0.123).The incidence rate of acute radiation esophagitis/gastritis in the nCRT group was 31.1%(19/61),including 13 cases(21.3%)in grade 1,4 cases(6.6%)in grade 2,2 cases(3.2%)in grade 3,and 0 cases in grade 4-5.The incidence rate of radiation pneumonitis was 9.8%(6/61),including 4 cases(6.6%)in grade 1,and 2 cases(3.2%)in grade 2.2)Hematologic toxicities:The incidence rate of grade 1 to 2 leukopenia in nCRT group was significantly higher than that in the nCT group(49.2%vs.24.6%,?~2=7.922,P=0.005).There was no significant difference between groups with higer level response.3)Perioperative mortality and hospital stay:There were 2 cases of perioperative death in nCRT group,1 died of respiratory failure,1 died of multiple organ dysfunction syndrome(respiratory,renal)and the rate of perioperative mortality was 3.3%.In nCT group,1 died of MODS(respiration,circulation,kidney)combined with septic shock,and the rate of perioperative mortality was 1.6%,with no statistically significant difference(?~2=0.342,P=0.559).The median hospital stay was 16d(11 to 37)in nCRT group and16d(12 to 40)in nCT group.with no statistically significant difference(P=0.215).Conclusion:The R0 resection rates of patients with locally advanced AEG in Siewert’s type II and III were both high in the two treatments.Compared to nCT,nCRT could achieve tumor downstaging more easily,reach a higher pCR rate,reduce the degree of lymph node metastasis and get a lower risk of locoregional disease progression,but it did not significantly prolong OS.Patients in nCRT group could tolerate involved-fieid radiotherapy.The perioperative mortality was not significantly increased and the hospital stay was not significantly prolonged.The status of postoperative lymph node metastasis was an independent factor for PFS and OS.更多还原