本文選題：靶向治療 + 阿帕替尼　； 參考：《山東大學》2017年碩士論文

【摘要】：研究背景:惡性腫瘤危害著人們的康健和生活,其在全球范圍內(nèi)的死亡率和發(fā)病率均在逐步上升。惡性腫瘤的治療一直備受關(guān)注,也是醫(yī)學工作者努力的重要方向。惡性腫瘤的診療是多學科的綜合性治療,目前針對惡性病變的診治方法大致包含外科手術(shù)、內(nèi)科治療、放射治療、介入等。然而如今現(xiàn)有的各種診療方法依舊無法滿足臨床工作的需求。近十幾年來靶向抗腫瘤藥物不斷地被探索并取得突破,取得越來越大的臨床獲益,為惡性病變的治療和控制帶來了新的希望。分子靶向治療是針對惡性病變發(fā)生及發(fā)展過程中細胞信號轉(zhuǎn)導及其他生物學途徑的治療手段,將腫瘤相關(guān)分子作為靶點,通過對特定靶點的作用,直接遏制病變的生長、遷移等過程。與傳統(tǒng)化療藥物相比,對腫瘤細胞更具針對性,減少對正常細胞的損傷,其針對特異性靶點的特征也有利于實現(xiàn)個體化治療。依照抗腫瘤靶向藥物的作用機理,可把它們劃分成兩個大類:小分子化合物(主要是小分子酪氨酸激酶抑制劑)和大分子單克隆抗體。甲磺酸阿帕替尼(艾坦)為2014年經(jīng)國家食品藥品管理監(jiān)督總局(CFDA)批準上市的一種小分子酪氨酸激酶抑制劑,用于晚期胃癌或胃食管結(jié)合部腺癌三線及三線以上治療。阿帕替尼的作用機制主要為高度選擇性抑制血管內(nèi)皮生長因子受體-2(VEGFR-2)酪氨酸激酶,阻斷VEGF與其受體結(jié)合之后的胞內(nèi)信號轉(zhuǎn)導,因而阻止腫瘤新生血管的形成,達到抗腫瘤的作用。上市前幾項臨床試驗顯示阿帕替尼有較好的安全性,嚴重毒副作用發(fā)生率較低。目前阿帕替尼用于多種實體瘤的幾項臨床試驗正在進行。在臨床工作中,必要時阿帕替尼也用于除胃癌之外的其他瘤種。目的:進一步觀察并分析阿帕替尼在臨床應用中的安全性;初步探討基因多態(tài)性與阿帕替尼不良反應的相關(guān)性。材料與方法:將2016年7月至12月期間在山東大學齊魯醫(yī)院應用阿帕替尼治療惡性腫瘤的患者的臨床資料進行收集和分析。收集的信息包括:姓名、性別、年齡、疾病、治療線數(shù)、ECOG評分、藥物劑量。對這部分病人進行定期電話隨訪等方式監(jiān)測其不良反應,并將不良反應按照CTCAE4.03進行分級。納入標準:經(jīng)病理證實為惡性腫瘤;阿帕替尼單藥治療;服用阿帕替尼之前無明顯的血象、肝腎功能的異常。排除標準:用藥時間小于10天;用藥后未定期監(jiān)測血常規(guī)和肝腎功。對發(fā)生嚴重不良反應(3-4級)的患者,在取得患者同意的情況下,抽取靜脈血檢測其CYP3A4*1B、CYP3A5*3、CYP2C9*3的基因多態(tài)性。統(tǒng)計學處理采用SPSS17.0軟件。多因素分析采用logistic回歸分析,組間比較采用x 2檢驗。以P0.05為差異具有統(tǒng)計學意義。結(jié)果:1、患者基本資料最終納入患者49人。之中包含:肺癌14人,胃惡性腫瘤9人,卵巢癌6人,結(jié)直腸癌4人,乳腺癌4人,肉瘤3人,食管癌2人,十二指腸癌2人,胰腺癌2人,膽管癌2人,牙齦癌1人。男性24人,女性25人。中位年齡53歲。ECOG評分:0分17人,1分19人,2分13人。治療線數(shù)在3線以下:20人,3線及3線以上29人。初始劑量:250mg5人,425mg2人,500mg32人,675mg 6 人,850mg4 人。2、不良反應統(tǒng)計不良反應發(fā)生率為100%,嚴重不良反應發(fā)生率為59.2%。不良反應發(fā)生率前五位分別為:高血壓(57.1%)、手足綜合征(42.9%)、食欲減退(42.9%)、乏力(40.8%)、蛋白尿(37.1%),嚴重不良反應(3-4級)發(fā)生率前四位為:高血壓(32.7%)、手足綜合征(12.2%)、口腔炎(8.2%)、腹瀉(8.2%)。嚴重不良反應的發(fā)生與腫瘤的部位有關(guān),消化系統(tǒng)高于非消化系統(tǒng)(x 2=5.408,P0.05),與其他因素無關(guān)。嚴重高血壓這一不良反應的發(fā)生和ECOG評分有關(guān),ECOG評分低者,嚴重高血壓的發(fā)生率高(P0.05),和其它因素無關(guān)。嚴重手足綜合征的發(fā)生與年齡、性別等因素均無關(guān)。3、單核苷酸位點基因多態(tài)性將10名發(fā)生嚴重不良反應的患者的血樣進行CYP3A4*1B、CYP3A5*3、CYP2C9*3單核苷酸位點的基因多態(tài)性檢測。CYP3A4*1B的基因頻率為0%,CYP3A5*3的基因頻率為75%,CYP2C9*3基因頻率為0%。結(jié)論:1、阿帕替尼的不良反應發(fā)生率和嚴重不良反應發(fā)生率均較高。高血壓、手足綜合征的發(fā)生率最高。2、消化系統(tǒng)腫瘤患者嚴重不良反應的發(fā)生率高于非消化系統(tǒng)的患者。3、ECOG評分低的患者嚴重高血壓的發(fā)生率較高。4、阿帕替尼嚴重不良反應的發(fā)生可能與CYP3A4*1B、CYP3A5*3、CYP2C9*3無關(guān)。
[Abstract]:Background: malignant tumor is harmful to people's Kang Jian and life. The mortality and incidence of the malignant tumor are increasing gradually. The treatment of malignant tumor has been paid much attention to. It is also an important direction of medical workers. The diagnosis and treatment of malignant tumor is a multidisciplinary and comprehensive treatment. At present, the diagnosis and treatment of malignant diseases It includes surgery, medical treatment, radiotherapy, and intervention. However, all the existing methods of diagnosis and treatment are still unable to meet the needs of clinical work. In the past decade, the target of anti-tumor drugs has been continuously explored and made a breakthrough, and more and more clinical benefits have been obtained, which bring new hope for the treatment and control of malignant lesions. Molecular targeting therapy is a therapeutic means for cell signal transduction and other biological pathways in the occurrence and development of malignant lesions. It takes the tumor related molecules as a target and directly controls the growth and migration of the lesions through the action of specific targets. Compared with the traditional chemotherapeutic drugs, the tumor cells are more targeted and reduced to the tumor cells. Normal cell damage, and its specific targets are also beneficial to individualized treatment. According to the mechanism of antitumor targeting drugs, they can be divided into two major categories: small molecular compounds (mainly small molecule tyrosine kinase inhibitors) and macromolecular monoclonal antibodies. Amapinii mesylate (atan) is the 2014 classics A small molecule tyrosine kinase inhibitor was approved by the State Administration of food and Drug Administration (CFDA) for the treatment of three lines and more than three lines of adenocarcinoma in advanced gastric or gastroesophageal junction. The action mechanism of apatinib is highly selective inhibition of vascular endothelial growth factor receptor -2 (VEGFR-2) tyrosine kinase, blocking VEGF and A number of clinical trials of apatinib are currently being carried out. Several clinical trials of apatinib are currently being conducted. Clinical trials are ongoing. Atapatinib is also used in other tumors other than gastric cancer. Objective: to further observe and analyze the safety of apatinib in clinical application; to explore the correlation between genetic polymorphism and atapinib adverse reactions. Materials and methods: the use of apatinib between July 2016 and December in Qilu Hospital of Shandong University. The clinical data of patients with malignant tumors were collected and analyzed. The information collected included: name, sex, age, disease, number of treatment lines, ECOG score, dose of drug. The adverse reactions were monitored by regular telephone follow-up, and the adverse reactions were classified according to CTCAE4.03. Malignant tumor; abatinib single drug treatment; no apparent hematology, abnormal liver and kidney function before taking apatinib. Exclusion criteria: medication time was less than 10 days; blood routine and liver and kidney functions were not regularly monitored after drug use. Patients with severe adverse reactions (grade 3-4) were extracted with venous blood to detect CYP3A4*1B, CYP3A5*3, CYP2C9*3 gene polymorphism. SPSS17.0 software was used for statistical treatment. Logistic regression analysis was used in multifactor analysis and x 2 test was used among groups. The difference was statistically significant with P0.05. Results: 1, the basic data of the patients were included in 49 patients, including 14 lung cancer, 9 gastric malignant tumors, 6 ovarian cancer, and straight line. Colon cancer 4, breast cancer 4, sarcoma 3, esophageal cancer 2, twelve colon cancer 2, pancreatic cancer 2, bile duct cancer 2, gingival cancer 1. 24 men and 25 women. Median age 53 years.ECOG score: 0 minutes below the line: initial dose: 250mg5, 425mg2, 500mg32, 675mg 6 people, 850mg4 people.2, the incidence of adverse reaction statistical adverse reactions was 100%, the incidence of severe adverse reactions was five before the incidence of 59.2%. adverse reactions: hypertension (57.1%), hand foot syndrome (42.9%), anorexia (42.9%), fatigue (40.8%), proteinuria (37.1%), and the incidence of severe adverse reactions (3-4 grade): hypertension (32.7%). Hand foot syndrome (12.2%), stomatitis (8.2%), diarrhoea (8.2%). The occurrence of severe adverse reactions is related to the site of the tumor. The digestive system is higher than the non digestive system (x 2=5.408, P0.05) and has nothing to do with other factors. The occurrence of severe hypertension is related to the ECOG score, the low ECOG score, the high incidence of high blood pressure (P0.05), and Other factors are irrelevant. The occurrence of severe hand foot syndrome is not related to age, sex, and other factors. The single nucleotide polymorphism of the gene polymorphisms of 10 patients with severe adverse reactions take CYP3A4*1B, CYP3A5*3, and CYP2C9*3 single nucleotide polymorphisms to detect the gene frequency of.CYP3A4*1B with the frequency of 0%, and the gene frequency of CYP3A5*3. For 75%, the CYP2C9*3 gene frequency was 0%. conclusion: 1, the incidence of ADR and the incidence of severe adverse reactions were higher. The incidence of hypertension, hand foot syndrome was the highest, and the incidence of severe side effects in the digestive system tumor patients was higher than that of the non digestive system patients with.3, and the incidence of severe hypertension in the patients with low ECOG score was severe. A higher rate of.4, the occurrence of severe adverse reactions of apatinib may not be related to CYP3A4*1B, CYP3A5*3 and CYP2C9*3.

【學位授予單位】：山東大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R730.5

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