【作者】 朱焱；

【导师】 徐晓婷；

【作者基本信息】 苏州大学 ， 肿瘤学（放射治疗）（专业学位）， 2022， 硕士

【摘要】 第一部分 成人高级别胶质瘤患者的预后因素研究目的:本研究旨在分析成人高级别脑胶质瘤患者预后相关临床及病理因素,从而为高级别胶质瘤患者的个体化治疗和预后评估提供理论依据。方法:回顾性分析2017年1月至2020年12月于苏州大学附属第一医院收治的122例初诊成人高级别胶质瘤(HGG)患者的临床及病理学资料。分别收集患者的性别、年龄、术前体能状态(KPS)评分、术前癫痫发作情况、肿瘤病理分级、肿瘤最大径、病灶数量、肿瘤偏侧、肿瘤是否累及室管膜下区(SVZ)、手术切除程度、手术穿通侧脑室情况、放疗与手术间隔时间、肿瘤分子标记物IDH1的突变状态、MGMT启动子甲基化状态和Ki-67的表达水平。通过电话及门诊随诊随访病人的生存状况。主要观察终点为无进展生存期(PFS)和总生存期(OS)。采用SPSS26.0软件进行统计学处理;通过Kaplan-Meier法分析比较患者的生存状态和描绘相应的生存曲线,Cox比例风险回归模型用于分析PFS和OS的影响因素。P<0.05认为差异具有统计学意义。结果:1.生存分析:根据纳排标准共纳入122例HGG患者。随访至2021年9月30日,全部病例中位随访时间为26.0个月。所有患者中位无进展生存期(PFS)和总生存期(OS)分别为13.0个月(11.0～15.0)和32.0个月(23.0～41.0);术后1、2、3年的生存率分别为81.1%(99/122)、33.6%(41/122)和 11.5%(14/122)。2.单因素分析结果显示,患者术前KPS评分≥80分(HR=0.559,95%CI:0.354-0.884,P=0.013)、病灶数量多个(HR=3.616,95%CI:2.113-6.186,P<0.001)、病理分级 WHO Ⅳ级(HR=1.915,95%CI:1.151-3.187,P=0.012)、SVZ 受侵(HR=1.801,95%CI:1.145-2.832,P=0.011)、手术次全切除(HR=2.837,95%CI:1.770-4.549,P<0.001)、手术穿通侧脑室(HR=1.835,95%CI:1.097-3.069,P=0.021)、IDH1 突变(HR=0.339,95%CI:0.185-0.620,P<0.001)和 Ki-67 表达量>10%(HR=2.570,95%CI:1.222-5.402,P=0.013)是显著影响PFS的因素;术前KPS评分≥80分(HR=0.535,95%CI:0.294-0.973,P=0.040)、病灶数量多个(HR=2.394,95%CI:1.249-4.589,P=0.009)、SVZ 受侵(HR=2.335,95%CI:1.285-4.244,P=0.005)、手术次全切除(HR=2.080,95%CI:1.126-3.842,P=0.019)、手术穿通侧脑室(HR=2.524,95%CI:1.387-4.593,P=0.002)、IDH1 突变(HR=0.172,95%CI:0.061-0.482,P=0.001)和 Ki-67 表达量>10%(HR=4.616,95%CI:1.421-14.991,P=0.011)是显著影响 OS的因素。3.将单因素分析中P<0.05的因素和重要的临床因素纳入Cox比例风险回归模型进行多因素分析,结果表明,病灶数量多个(HR=2.977,95%CI:1.724-5.140,P<0.001)、手术次全切除(HR=2.178,95%CI:1.349-3.516,P=0.001)、IDH1 突变(HR=0.405,95%CI:0.220-0.744,P=0.004)和 Ki-67 表达量>10%(HR=2.130,95%CI:1.006-4.509,P=0.048)是PFS 的独立预后因素;手术穿通侧脑室(HR=2.144,95%CI:1.179-3.899,P=0.012)、IDH1突变(HR=0.186,95%CI:0.066-0.522,P=0.001)和 Ki-67 表达量>10%(HR=4.137,95%CI:1.271-13.460,P=0.018)是OS的独立预后因素。结论:1.术前KPS评分、病理分级、病灶数量、SVZ是否受侵、手术切除程度、手术是否穿通侧脑室、IDH1突变状态和Ki-67表达量与HGG患者预后相关。其中,病灶数量、手术切除程度、IDH1突变状态和Ki-67表达量是PFS的独立影响因素;手术穿通侧脑室、IDH1野生型和Ki-67表达量>10%是HGG患者OS缩短的独立危险因素。2.肿瘤全切后联合放化疗可以改善HGG患者的预后,但手术穿通侧脑室可能会缩短患者的生存时间。第二部分 室管膜下区受累对放疗靶区勾画的影响研究目的:本研究旨在分析肿瘤累及室管膜下区(SVZ)时,SVZ放疗靶区范围和剂量对高级别胶质瘤(HGG)患者预后的影响,为SVZ受累的HGG患者术后放疗靶区勾画提供参考。方法:从第一部分研究纳入的HGG患者中,选取有充分影像学证据证明术前肿瘤累及SVZ的人群。在靶区勾画软件上复原患者放疗计划,以原靶区为基础分别勾画肿瘤同侧和对侧SVZ,通过剂量-体积直方图(DVH)得出肿瘤同侧和对侧SVZ的平均剂量Dmean以及同侧SVZ的V45和V60,同时收集患者临床及病理学资料。主要观察终点为无进展生存期(PFS)和总生存期(OS)。应用Kaplan-Meier法绘制生存曲线并采用log-rank检验方法对生存曲线进行比较。Cox比例风险回归模型用于分析PFS和OS的影响因素。同侧SVZ靶区范围大小与进展模式的相关性采用卡方检验,P<0.05认为差异具有统计学意义。结果:1.基线资料:根据纳排标准共纳入SVZ累及的HGG患者50例,中位年龄54岁(48.5-62.0)。肿瘤同侧SVZ部位的四分位剂量值分别为49.76Gy、55.56Gy和 58.75G,V45<100%有 27 例(54.0%),V60≥50%有 29 例(58.0%);对侧 SVZ 区域的四分位数剂量值分别为31.14Gy、37.33Gy和45.02Gy。2.单因素分析结果显示,V60≥50%的HGG患者中位PFS明显高于V60<50%的患者(12.0个月vs.9.0个月),但差异没有统计学意义(HR=0.583,95%CI:0.306-1.108,P=0.100)。亚组分析结果表明,V60≥50%的患者在年龄<60岁亚组(18.0个月vs.8.0个月,P=0.006),WHO Ⅳ级(16.0个月vs.8.0个月,P=0.006)和手术穿通侧脑室亚组(12.0个月vs.8.0个月,P=0.034)中的PFS显著高于V60<50%。V60≥50%的HGG患者中位OS明显高于V60<50%的患者(38.0个月vs.24.0个月),但差异没有统计学意义(HR=0.438,95%CI:0.183-1.050,P=0.064)。亚组分析结果表明,V60≥50%的患者在WHO Ⅳ级亚组(38.0个月vs.16.0个月,P=0.035)、手术穿通侧脑室亚组(30.0个月vs.16.0个月,P=0.008)、IDH1野生型亚组(35.0个月vs.16.0个月,P=0.012)和MGMT未甲基化亚组(38.0个月vs.16.0个月,P=0.047)中的OS显著高于V60<50%。3.SVZ靶区范围与进展模式:V60≥50%患者中,局部复发13例(13/29,44.8%),远处转移6例(6/29,20.7%),未进展10例(10/29,34.5%);V60<50%组中,局部复发 13 例(13/21,61.9%),远处转移 6 例(6/21,28.6%),未进展 2 例(2/21,9.5%)。两组患者相比差异无统计学意义(χ2=4.160,P=0.125)结论:1.对于SVZ受累的HGG,同侧SVZ接受60Gy照射剂量的体积≥50%能延长年龄小于60岁、WHO Ⅳ级和手术穿通侧脑室人群的PFS和延长WHO Ⅳ级、手术穿通侧脑室、IDH1野生型和MGMT未甲基化人群的OS。2.同侧SVZ接受60Gy照射剂量的体积≥50%能提高SVZ累及HGG患者局部控制率,减少局部复发的风险。更多还原

【Abstract】 Part Ⅰ Analysis of prognostic factors in adults with high-grade gliomaObjective:Our study aims to analyze the clinical and pathological factors related to the prognosis of adult high-grade glioma,to provide a rationale for the individualized treatment and prognosis evaluation of patients with high-grade glioma.Methods:We retrospectively analyzed clinical and pathological data of 122 patients with newly diagnosed adult high-grade glioma from January 2017 to December 2020 in the First Affiliated Hospital of Soochow University,including patients,age,gender,preoperative karnofsky performance score,preoperative seizure status,tumor pathological grade,maximum tumor diameter,number of lesions,tumor location,contact with or without the subventricular zone,extent of surgical resection,lateral ventricular entry during surgery,duration from surgery to radiotherapy,tumoral molecular biomarkers such as mutation status of IDH1,methylation status of MGMT and expression of Ki67.The survival of patients was followed up by telephone,outpatient follow-up.The primary endpoints were PFS and OS.SPSS26.0 software was used for statistical analysis.Kaplan-Meier method was applied to analyze and compare the survival of patients and plot the corresponding survival curves.Cox proportional risk regression model was used to analyze the relative factors of PFS and OS.P<0.05 was considered statistically significant.Results:1.Survival:A total of 122 HGG patients were included according to inclusion and exclusion criteria.These patients were followed up to September 30,2021,with a median follow-up time of 26.0 months.Median progression-free survival(PFS)and overall survival(OS)were 13.0 months(11.0-15.0)and 32.0 months(23.0 to 41.0),respectively.The survival rates at 1,2 and 3 years after operation were 81.1%(99/122),33.6%(41/122)and 11.5%(14/122),respectively.2.Univariate analysis suggested that preoperative KPS≥80(HR=0.559,95%CI:0.3540.884,P=0.013),number of lesions(HR=3.616,95%CI:2.113-6.186,P<0.001),WHO Ⅳgrade(HR=1.915,95%CI:1.151-3.187,P=0.012),SVZ invasion(HR=1.801,95%CI:1.145-2.832,P=0.011),subtotal resection(HR=2.837,95%CI:1.770-4.549,P<0.001),lateral ventricle entry(HR=1.835,95%CI:1.097-3.069,P=0.021),IDH1 mutation(HR=0.339,95%CI:0.185-0.620,P<0.001)and Ki-67 expression>10%(HR=2.570,95%CI:1.222-5.402,P=0.013)were statistically significant factors that associated with PFS.Preoperative KPS≥ 80(HR=0.535,95%CI:0.294-0.973,P=0.040),number of lesions(HR=2.394,95%CI:1.249-4.589,P=0.009),SVZ invasion(HR=2.335,95%CI:1.2854.244,P=0.005),subtotal resection(HR=2.080,95%CI:1.126-3.842,P=0.019),lateral ventricle entry(HR=2.524,95%CI:1.387-4.593,P=0.002),IDH1 mutation(HR=0.172,95%CI:0.061-0.482,P=0.001)and Ki-67 expression>10%(HR=4.616,95%CI:1.421-14.991,P=0.011)were statistically significant factors that associated with OS.3.Statistically significant factors in univariate analysis and factors found to be relative with prognosis in previous studies were included in the Cox regression model for multivariate analysis,the results showed that the number of lesions(HR=2.977,95%CI:1.724-5.140,P<0.001),subtotal resection(HR=2.178,95%CI:1.349-3.516,P=0.001),IDH1 mutation(HR=0.405,95%CI:0.220-0.744,P=0.004)and Ki-67 expression>10%(HR=2.130,95%CI:1.006-4.509,P=0.048)were factors independently associated with PFS.lateral ventricle entry(HR=2.144,95%CI:1.179-3.899,P=0.012),IDH1 mutation(HR=0.405,95%CI:0.220-0.744,P=0.004)and Ki-67 expression>10%(HR=2.130,95%CI:1.006-4.509,P=0.048)were factors independently associated with OS.Conclusion:1.Preoperative KPS score,pathological grade,number of lesions,SVZ invasion,the extent of tumor resection,lateral ventricular entry during surgery,IDH1 mutation status and Ki67 expression were correlated with prognosis of HGG patients.Among these factors,the number of lesions,extent of surgical resection,IDH1 mutation status and ki67 expression level were independent prognostic factors of PFS.Lateral ventricle entry,IDH1 wild type and the expression of ki-67>10%were independent negative risk factors for OS.2.Gross total resection can improve the prognosis of HGG patients,but lateral ventricular entry during surgery may shorten the survival of patients.Part Ⅱ Impact of SVZ invasion in clinical target delineation of high-grade gliomasObjective:The purpose of this study was to explore the impact of target volume and dose of SVZ on prognosis of high-grade gliomas contacted with the SVZ,and to provide reference for the delineation of postoperative radiotherapy target volume in HGG patients with SVZ invasion.Methods:From the HGG patients included in the first part of the study,we choose those with sufficient imaging evidence of preoperative tumor involvement in SVZ.The patient’s radiotherapy plan was restored on the target mapping software,and ipsilateral and contralateral SVZ of the tumor were plotted respectively based on the original target region.The mean dose(Dmean)of ipsilateral and contralateral SVZ of the tumor and V45 and V60 of ipsilateral SVZ were obtained by dose-volume histogram(DVH),clinical and pathological data of the patients were collected.The primary endpoints were PFS and OS.The survival curves were plotted by Kaplan-Meier method and compared by log-rank test.Cox proportional risk regression model was used to analyze the predictors of PFS and OS.Chi-square test was used to test the correlation between the size of ipsilateral SVZ target range and progression pattern.P<0.05 was considered statistically significant.Results:1.Baseline characteristics:A total of 50 HGG patients(median age 54 years(48.5-62.0)with SVZ involvement were enrolled according to the inclusion and exclusion criteria.The quartile dose values of ipsilateral SVZ were 49.76Gy,55.56Gy and 58.75G,respectively.V45<100%was noted in 27 cases(54.0%)and V60≥50%in 29 cases(58.0%).The quartile dose values in the contralateral SVZ region were 31.14Gy,37.33Gy and 45.02Gy,respectively.2.Univariate analysis showed that the median PFS of HGG patients with V60≥50%was significantly higher than that of patients with V60<50%(12.0 months vs.9.0 months),but the difference was not statistically significant(HR=0.583,95%CI:0.306-1.108,P=0.100).The results of subgroup analysis showed that patients with V60≥50%were age 60<years(18.0 months vs.8.0 months,P=0.006),WHO grade Ⅳ(16.0 months vs.8.0 months,P=0.006),and lateral ventricle entry(12.0 months vs.8.0 months,P=0.034)was significantly higher than those with V60<50%.The median OS of HGG patients with V60≥50%was significantly higher than patients with V60<50%(38.0 months vs.24.0 months),but the difference was not statistically significant(HR=0.438,95%CI:0.183-1.050,P=0.064).The results of subgroup analysis showed that OS in patients with V60≥50%were superior in WHO grade Ⅳ subgroup(38.0 months vs.16.0 months,P=0.035),lateral ventricle entry subgroup(30.0 months vs.16.0 months,P=0.008),IDH1 wild-type subgroup(35.0 months vs.16.0 months,P=0.008)and MGMT unmethylated subgroup(38.0 months vs.16.0 months,P=0.047)than OS in patients with V60<50%.3.SVZ target volume and progression patterns:Among patients with V60≥50%,13 cases(13/29,44.8%)had local recurrence,6 cases(6/29,20.7%)had distant metastasis,and 10 cases(10/29,34.5%)had no progression.In the V60<50%group,13 cases(13/21,61.9%)had local recurrence,6 cases(6/21,28.6%)had distant metastasis,and 2 cases(2/21,9.5%)had no progression.There was no significant difference between the two groups(χ2=4.160,P=0.125).Conclusion:1.For HGG patients with SVZ involvement,V60≥50%of ipsilateral SVZ suggested longer PFS in subgroups with age<60 years,WHO grade Ⅳ,and surgically perforated lateral ventricle,and prolong OS in WHO grade Ⅳ,lateral ventricle entry,IDH1 wild type,and MGMT unmethylated.2.The ipsilateral SVZ V60≥50%indicated higher local control rate of HGG patients with SVZ involvement and lower risk of local recurrence.更多还原