本文選題：肺癌腦轉(zhuǎn)移 + 貝伐珠單抗�。� 參考：《中國人民解放軍醫(yī)學(xué)院》2017年博士論文

【摘要】：背景:晚期非小細(xì)胞肺癌(NSCLC)腦轉(zhuǎn)移的發(fā)生率約30-65%,生存期約1-3個月,嚴(yán)重影響患者的認(rèn)知功能、生存時間及生活質(zhì)量,預(yù)后極差�；熉�(lián)合放療可以降低晚期非小細(xì)胞患者顱外病灶的復(fù)發(fā),但并不能降低腦轉(zhuǎn)移的發(fā)生率。由于血腦屏障的存在,傳統(tǒng)化療藥物難以很好的進入腦組織,對于治療及預(yù)防腦轉(zhuǎn)移作用十分有限。控制及預(yù)防腦轉(zhuǎn)移的發(fā)生成為延長患者生存時間的重要策略。血管生成與腫瘤發(fā)生、轉(zhuǎn)移密切相關(guān),血管內(nèi)皮生長因子(VEGF)是調(diào)節(jié)血管生成重要的活性物質(zhì),基礎(chǔ)研究已經(jīng)證實腫瘤細(xì)胞在腦實質(zhì)中的播散和生長有賴于VEGF的作用,抑制VEGF通路可以有效地減少腦轉(zhuǎn)移。碳酸酐酶-9(CA9)與腫瘤的增殖、黏附、轉(zhuǎn)移相關(guān),與VEGF關(guān)系密切。貝伐珠單抗(Bevacizumab)是VEGF的單克隆抗體,通過阻斷VEGF與其受體結(jié)合而發(fā)揮作用。多項臨床研究已經(jīng)證明貝伐單抗聯(lián)合化療對肺癌腦轉(zhuǎn)移的治療是安全和有效的,對其他腫瘤引起的腦轉(zhuǎn)移也具有肯定的作用。但是以往研究都是在已經(jīng)發(fā)生腦轉(zhuǎn)移的患者中開展,關(guān)于貝伐珠單抗是否能降低腦轉(zhuǎn)移發(fā)生率少有研究。本課題旨在觀察貝伐單抗聯(lián)合化療相對于單純化療對晚期非小細(xì)胞肺癌腦轉(zhuǎn)移的影響,并進一步觀察其對VEGF、CA9不同表達(dá)的患者腦轉(zhuǎn)移的影響。目的:1、比較貝伐珠單抗聯(lián)合化療與單純化療對晚期非小細(xì)胞肺癌患者的療效及對腦轉(zhuǎn)移發(fā)生率的影響,2、觀察不同VEGF表達(dá)與貝伐珠單抗聯(lián)合化療的療效及腦轉(zhuǎn)移的關(guān)系,3、觀察貝伐珠單抗聯(lián)合化療對不同CA9水平患者腦轉(zhuǎn)移的影響。方法:第一部分:采用回顧性研究方法,收集、分析患者臨床資料,主要觀察指標(biāo)為腦轉(zhuǎn)移累積發(fā)生率,次要觀察指標(biāo)為總生存期(Overall survival,OS)。比較腦轉(zhuǎn)移發(fā)生的累積風(fēng)險。采用Kaplan-Meier中的Log-rank檢驗進行生存分析。采用COX回歸模型對影響腦轉(zhuǎn)移發(fā)生的相關(guān)因素進行分析。第二部分:用免疫組化方法將入組患者進行分組,觀察不同VEGF表達(dá)與貝伐珠單抗聯(lián)合化療療效及腦轉(zhuǎn)移的關(guān)系。第三部分:用ELISA方法檢測兩組患者治療前及治療6周期結(jié)束后血清CA9濃度變化,觀察貝伐珠單抗聯(lián)合化療對不同CA9水平患者腦轉(zhuǎn)移的影響。結(jié)果:將2009年1月1日到2010年12月31日共159名患者納入研究,依據(jù)治療方式不同分為兩組,貝伐珠單抗+化療組(BV + CT)及單純化療組(CT),其中BV+CT組110例,CT組49例。收集兩組患者的治療分組、年齡、性別、吸煙史、治療前PS評分、病理類型、TNM分期、既往治療史及VEGF表達(dá)狀態(tài)等資料。至隨訪結(jié)束,BV+CT組與單純CT組均有15例患者發(fā)生腦轉(zhuǎn)移(14%vs31%, P0.05),BV+CT組6、12、24月時腦轉(zhuǎn)移發(fā)生累積風(fēng)險分別為:1%、7.5%、14%, CT 組為 6.7%、18.8%、31% (P0.001)。BV+CT組有40例(36%)存活,CT組有11例(22%)存活(P0.05)。BV+CT組中位OS為19.9個月,CT組中位OS為15.7個月(P0.05),提示無論在腦轉(zhuǎn)移發(fā)生風(fēng)險還是總生存方面,BV+CT組均優(yōu)于單純化療組。進一步按VEGF、CA9表達(dá)不同進行亞組分析發(fā)現(xiàn),VEGF陽性患者中BV+CT組腦轉(zhuǎn)移發(fā)生率降低,總生存延長,療效明顯優(yōu)于單純化療組,而VEGF陰性患者中未觀察到顯著差異。血清CA9濃度高表達(dá)患者中,BV+CT組治療后血清CA9濃度顯著下降(P0.05), CT組血清CA9濃度下降不明顯,BV+CT組患者腦轉(zhuǎn)移發(fā)生率明顯下降(P0.05),血清CA9濃度低表達(dá)患者中,兩組腦轉(zhuǎn)移發(fā)生風(fēng)險未見明顯差異。多因素分析的結(jié)果證實貝伐單抗聯(lián)合化療可顯著降低腦轉(zhuǎn)移風(fēng)險。結(jié)論:1、貝伐珠單抗聯(lián)合化療可以降低晚期非小肺癌患者腦轉(zhuǎn)移發(fā)生率,延長患者生存期;2、VEGF陽性患者中貝伐珠單抗聯(lián)合化療可降低腦轉(zhuǎn)移發(fā)生率,延長總生存。提示VEGF表達(dá)陽性或可預(yù)測貝伐珠單抗的療效獲益。3、血清CA9濃度高表達(dá)患者,貝伐珠單抗聯(lián)合化療使腦轉(zhuǎn)移發(fā)生風(fēng)險減低,提示CA9與貝伐珠單抗療效可能有一定的相關(guān)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.
【學(xué)位授予單位】：中國人民解放軍醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R734.2

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