阿帕替尼治疗恶性肿瘤不良反应的单中心观察性研究

发布时间：2018-05-10 12:40

本文选题：靶向治疗 + 阿帕替尼　；参考：《山东大学》2017年硕士论文

【摘要】：研究背景:恶性肿瘤危害着人们的康健和生活,其在全球范围内的死亡率和发病率均在逐步上升。恶性肿瘤的治疗一直备受关注,也是医学工作者努力的重要方向。恶性肿瘤的诊疗是多学科的综合性治疗,目前针对恶性病变的诊治方法大致包含外科手术、内科治疗、放射治疗、介入等。然而如今现有的各种诊疗方法依旧无法满足临床工作的需求。近十几年来靶向抗肿瘤药物不断地被探索并取得突破,取得越来越大的临床获益,为恶性病变的治疗和控制带来了新的希望。分子靶向治疗是针对恶性病变发生及发展过程中细胞信号转导及其他生物学途径的治疗手段,将肿瘤相关分子作为靶点,通过对特定靶点的作用,直接遏制病变的生长、迁移等过程。与传统化疗药物相比,对肿瘤细胞更具针对性,减少对正常细胞的损伤,其针对特异性靶点的特征也有利于实现个体化治疗。依照抗肿瘤靶向药物的作用机理,可把它们划分成两个大类:小分子化合物(主要是小分子酪氨酸激酶抑制剂)和大分子单克隆抗体。甲磺酸阿帕替尼(艾坦)为2014年经国家食品药品管理监督总局(CFDA)批准上市的一种小分子酪氨酸激酶抑制剂,用于晚期胃癌或胃食管结合部腺癌三线及三线以上治疗。阿帕替尼的作用机制主要为高度选择性抑制血管内皮生长因子受体-2(VEGFR-2)酪氨酸激酶,阻断VEGF与其受体结合之后的胞内信号转导,因而阻止肿瘤新生血管的形成,达到抗肿瘤的作用。上市前几项临床试验显示阿帕替尼有较好的安全性,严重毒副作用发生率较低。目前阿帕替尼用于多种实体瘤的几项临床试验正在进行。在临床工作中,必要时阿帕替尼也用于除胃癌之外的其他瘤种。目的:进一步观察并分析阿帕替尼在临床应用中的安全性;初步探讨基因多态性与阿帕替尼不良反应的相关性。材料与方法:将2016年7月至12月期间在山东大学齐鲁医院应用阿帕替尼治疗恶性肿瘤的患者的临床资料进行收集和分析。收集的信息包括:姓名、性别、年龄、疾病、治疗线数、ECOG评分、药物剂量。对这部分病人进行定期电话随访等方式监测其不良反应,并将不良反应按照CTCAE4.03进行分级。纳入标准:经病理证实为恶性肿瘤;阿帕替尼单药治疗;服用阿帕替尼之前无明显的血象、肝肾功能的异常。排除标准:用药时间小于10天;用药后未定期监测血常规和肝肾功。对发生严重不良反应(3-4级)的患者,在取得患者同意的情况下,抽取静脉血检测其CYP3A4*1B、CYP3A5*3、CYP2C9*3的基因多态性。统计学处理采用SPSS17.0软件。多因素分析采用logistic回归分析,组间比较采用x 2检验。以P0.05为差异具有统计学意义。结果:1、患者基本资料最终纳入患者49人。之中包含:肺癌14人,胃恶性肿瘤9人,卵巢癌6人,结直肠癌4人,乳腺癌4人,肉瘤3人,食管癌2人,十二指肠癌2人,胰腺癌2人,胆管癌2人,牙龈癌1人。男性24人,女性25人。中位年龄53岁。ECOG评分:0分17人,1分19人,2分13人。治疗线数在3线以下:20人,3线及3线以上29人。初始剂量:250mg5人,425mg2人,500mg32人,675mg 6 人,850mg4 人。2、不良反应统计不良反应发生率为100%,严重不良反应发生率为59.2%。不良反应发生率前五位分别为:高血压(57.1%)、手足综合征(42.9%)、食欲减退(42.9%)、乏力(40.8%)、蛋白尿(37.1%),严重不良反应(3-4级)发生率前四位为:高血压(32.7%)、手足综合征(12.2%)、口腔炎(8.2%)、腹泻(8.2%)。严重不良反应的发生与肿瘤的部位有关,消化系统高于非消化系统(x 2=5.408,P0.05),与其他因素无关。严重高血压这一不良反应的发生和ECOG评分有关,ECOG评分低者,严重高血压的发生率高(P0.05),和其它因素无关。严重手足综合征的发生与年龄、性别等因素均无关。3、单核苷酸位点基因多态性将10名发生严重不良反应的患者的血样进行CYP3A4*1B、CYP3A5*3、CYP2C9*3单核苷酸位点的基因多态性检测。CYP3A4*1B的基因频率为0%,CYP3A5*3的基因频率为75%,CYP2C9*3基因频率为0%。结论:1、阿帕替尼的不良反应发生率和严重不良反应发生率均较高。高血压、手足综合征的发生率最高。2、消化系统肿瘤患者严重不良反应的发生率高于非消化系统的患者。3、ECOG评分低的患者严重高血压的发生率较高。4、阿帕替尼严重不良反应的发生可能与CYP3A4*1B、CYP3A5*3、CYP2C9*3无关。
[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.

【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R730.5

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