贝伐珠单抗联合化疗对非小细胞肺癌脑转移影响的研究

发布时间：2018-06-21 13:49

本文选题：肺癌脑转移 + 贝伐珠单抗　；参考：《中国人民解放军医学院》2017年博士论文

【摘要】：背景:晚期非小细胞肺癌(NSCLC)脑转移的发生率约30-65%,生存期约1-3个月,严重影响患者的认知功能、生存时间及生活质量,预后极差。化疗联合放疗可以降低晚期非小细胞患者颅外病灶的复发,但并不能降低脑转移的发生率。由于血脑屏障的存在,传统化疗药物难以很好的进入脑组织,对于治疗及预防脑转移作用十分有限。控制及预防脑转移的发生成为延长患者生存时间的重要策略。血管生成与肿瘤发生、转移密切相关,血管内皮生长因子(VEGF)是调节血管生成重要的活性物质,基础研究已经证实肿瘤细胞在脑实质中的播散和生长有赖于VEGF的作用,抑制VEGF通路可以有效地减少脑转移。碳酸酐酶-9(CA9)与肿瘤的增殖、黏附、转移相关,与VEGF关系密切。贝伐珠单抗(Bevacizumab)是VEGF的单克隆抗体,通过阻断VEGF与其受体结合而发挥作用。多项临床研究已经证明贝伐单抗联合化疗对肺癌脑转移的治疗是安全和有效的,对其他肿瘤引起的脑转移也具有肯定的作用。但是以往研究都是在已经发生脑转移的患者中开展,关于贝伐珠单抗是否能降低脑转移发生率少有研究。本课题旨在观察贝伐单抗联合化疗相对于单纯化疗对晚期非小细胞肺癌脑转移的影响,并进一步观察其对VEGF、CA9不同表达的患者脑转移的影响。目的:1、比较贝伐珠单抗联合化疗与单纯化疗对晚期非小细胞肺癌患者的疗效及对脑转移发生率的影响,2、观察不同VEGF表达与贝伐珠单抗联合化疗的疗效及脑转移的关系,3、观察贝伐珠单抗联合化疗对不同CA9水平患者脑转移的影响。方法:第一部分:采用回顾性研究方法,收集、分析患者临床资料,主要观察指标为脑转移累积发生率,次要观察指标为总生存期(Overall survival,OS)。比较脑转移发生的累积风险。采用Kaplan-Meier中的Log-rank检验进行生存分析。采用COX回归模型对影响脑转移发生的相关因素进行分析。第二部分:用免疫组化方法将入组患者进行分组,观察不同VEGF表达与贝伐珠单抗联合化疗疗效及脑转移的关系。第三部分:用ELISA方法检测两组患者治疗前及治疗6周期结束后血清CA9浓度变化,观察贝伐珠单抗联合化疗对不同CA9水平患者脑转移的影响。结果:将2009年1月1日到2010年12月31日共159名患者纳入研究,依据治疗方式不同分为两组,贝伐珠单抗+化疗组(BV + CT)及单纯化疗组(CT),其中BV+CT组110例,CT组49例。收集两组患者的治疗分组、年龄、性别、吸烟史、治疗前PS评分、病理类型、TNM分期、既往治疗史及VEGF表达状态等资料。至随访结束,BV+CT组与单纯CT组均有15例患者发生脑转移(14%vs31%, P0.05),BV+CT组6、12、24月时脑转移发生累积风险分别为:1%、7.5%、14%, CT 组为 6.7%、18.8%、31% (P0.001)。BV+CT组有40例(36%)存活,CT组有11例(22%)存活(P0.05)。BV+CT组中位OS为19.9个月,CT组中位OS为15.7个月(P0.05),提示无论在脑转移发生风险还是总生存方面,BV+CT组均优于单纯化疗组。进一步按VEGF、CA9表达不同进行亚组分析发现,VEGF阳性患者中BV+CT组脑转移发生率降低,总生存延长,疗效明显优于单纯化疗组,而VEGF阴性患者中未观察到显著差异。血清CA9浓度高表达患者中,BV+CT组治疗后血清CA9浓度显著下降(P0.05), CT组血清CA9浓度下降不明显,BV+CT组患者脑转移发生率明显下降(P0.05),血清CA9浓度低表达患者中,两组脑转移发生风险未见明显差异。多因素分析的结果证实贝伐单抗联合化疗可显著降低脑转移风险。结论:1、贝伐珠单抗联合化疗可以降低晚期非小肺癌患者脑转移发生率,延长患者生存期;2、VEGF阳性患者中贝伐珠单抗联合化疗可降低脑转移发生率,延长总生存。提示VEGF表达阳性或可预测贝伐珠单抗的疗效获益。3、血清CA9浓度高表达患者,贝伐珠单抗联合化疗使脑转移发生风险减低,提示CA9与贝伐珠单抗疗效可能有一定的相关性。
[Abstract]:Background: the incidence of brain metastases in advanced non-small cell lung cancer (NSCLC) is about 30-65%. The survival period is about 1-3 months, which seriously affects the cognitive function, survival time and quality of life, and the prognosis is extremely poor. Chemotherapy combined with radiotherapy can reduce the recurrence of extracranial focus in advanced non small cell patients, but it does not reduce the incidence of brain metastases. The traditional chemotherapeutic drugs are difficult to enter the brain tissue. It is very limited for the treatment and prevention of brain metastases. Controlling and preventing the occurrence of brain metastases is an important strategy to prolong the survival time of the patients. Angiogenesis is closely related to the occurrence of tumor and metastasis, and intravascular growth factor (VEGF) is important for regulating angiogenesis. Active substance, basic research has confirmed that the spread and growth of tumor cells in the brain parenchyma depend on the effect of VEGF, inhibiting the VEGF pathway can effectively reduce brain metastasis. Carbonic anhydrase -9 (CA9) is associated with tumor proliferation, adhesion and metastasis, and is closely related to VEGF. Bevacizumab (Bevacizumab) is a monoclonal antibody to VEGF by blocking VEG. F is associated with its receptor. A number of clinical studies have shown that bevacizumab combined with chemotherapy is safe and effective in the treatment of brain metastases from lung cancer, and has a positive effect on brain metastases caused by other tumors. However, previous studies have been conducted in patients with brain metastases and whether bevacizumab can be reduced. The purpose of this study is to observe the effect of bevacizumab combined with chemotherapy on brain metastases of advanced non-small cell lung cancer and to further observe the effects of chemotherapy on the brain metastases of patients with different expressions of VEGF and CA9. Objective: 1. Comparison of bevacizumab combined with chemotherapy and simple chemotherapy on advanced non-small cell lung cancer The effect of the patients and the incidence of brain metastases, 2, observe the relationship between the different VEGF expression and the effect of bevaco monoclonal antibody combined with chemotherapy and brain metastasis. 3, observe the effect of bevac monoclonal antibody combined with chemotherapy on the brain metastasis of patients with different CA9 levels. The observation index was the cumulative incidence of brain metastases, the secondary observation index was the total survival period (Overall survival, OS). The cumulative risk of brain metastases was compared. The Log-rank test in Kaplan-Meier was used to analyze the survival analysis. The COX regression model was used to analyze the related factors affecting the occurrence of brain metastases. The second part: immunohistochemical method will be used. Group patients were grouped to observe the relationship between different VEGF expressions and the effect of bevacizumab combined with chemotherapy and brain metastases. The third part: the changes of serum CA9 concentration in two groups of patients before and after the end of 6 cycle were detected by ELISA method, and the effect of bevacizumab combined with chemotherapy on the brain metastasis of patients with different CA9 levels was observed. Results: 2009 From January 1st to 31 December 2010, a total of 159 patients were divided into two groups, including two groups, bevacizumab + chemotherapy group (BV + CT) and simple chemotherapy group (CT), including 110 cases in group BV+CT and 49 cases in group CT. The group of treatment, age, sex, smoking history, preoperative PS score, pathological type, TNM staging, history of treatment and the history of treatment were also collected. At the end of the follow-up, 15 patients in group BV+CT and group CT had brain metastases (14%vs31%, P0.05). The cumulative risk of brain metastases in group BV+CT 6,12,24 months were respectively: 1%, 7.5%, 14%, CT group 6.7%, 18.8%, 31% (P0.001).BV+CT group were 40 (36%) surviving, CT group was 11 (22%) survival (P0.05) group 1 In 9.9 months, the median OS of group CT was 15.7 months (P0.05). It was suggested that the group BV+CT was better than the chemotherapy group in both the risk of brain metastasis and the total survival. Further, the subgroup analysis according to VEGF and CA9 expression showed that the incidence of brain metastases in BV+CT group decreased and the total survival was prolonged in VEGF positive patients, and the curative effect was obviously better than that of chemotherapy alone, but VE was significantly better than that in the chemotherapy group. There was no significant difference in the GF negative patients. In the patients with high serum CA9 concentration, serum CA9 concentration in BV+CT group decreased significantly (P0.05), the decrease of serum CA9 concentration in CT group was not obvious, and the incidence of brain metastases in group BV+CT patients decreased significantly (P0.05), and the risk of brain metastases in the two groups was not significantly different. The results of multifactor analysis confirm that bevacizumab combined with chemotherapy can significantly reduce the risk of brain metastases. Conclusion: 1, bevacizumab combined with chemotherapy can reduce the incidence of brain metastases in patients with advanced non small lung cancer and prolong the survival period of the patients; 2, the combined therapy of bevac mAb in VEGF positive patients can reduce the incidence of brain metastases and prolong the total survival. Prompt VEG The effect of F expression positive or predictability of bevac monoclonal antibody benefit.3, the patient with high serum CA9 concentration, bevacizumab combined with chemotherapy to reduce the risk of brain metastases, suggesting that the effect of CA9 and bevac monoclonal antibody may have a certain correlation.
【学位授予单位】：中国人民解放军医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R734.2

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