發(fā)布時(shí)間：2018-05-08 05:37

  本文選題：克唑替尼 + 肺腫瘤　； 參考：《安徽醫(yī)科大學(xué)》2017年碩士論文

【摘要】：目的Crizotinib在中國(guó)患者中的臨床療效及其不良反應(yīng)尚缺乏大樣本臨床實(shí)驗(yàn)。本研究的研究目的為:1、研究克唑替尼(Crizotinib)對(duì)棘皮動(dòng)物微管結(jié)合蛋白樣-4-間變性淋巴瘤激酶(echinoderm microtubule-assciated protein-like-4-Anaplastic lymphoma kinase,EML4-ALK)融合基因陽性的非小細(xì)胞肺癌(non-small cell lung cancer,NSCLC)患者的療效以及毒副作用。2、對(duì)比傳統(tǒng)的標(biāo)準(zhǔn)化療方案,研究Crizotinib對(duì)EML4-ALK融合基因陽性的NSCLC患者的療效和不良反應(yīng)的嚴(yán)重程度以及耐受情況。3、研究Crizotinib對(duì)已經(jīng)發(fā)生腦轉(zhuǎn)移的EML4-ALK融合基因陽性晚期NSCLC患者的臨床療效以及毒副作用。方法1、入組符合本研究要求的45例EML4-ALK融合基因陽性的NSCLC患者,隨后給予Crizotinib 250mg/次,2/日,口服治療,直到病情進(jìn)展(progressive disease,PD)或者發(fā)生不可耐受的毒副反應(yīng),隨訪周期為12個(gè)月,觀察Crizotinib療效及其耐受情況。2、篩選符合本研究要求的EML4-ALK融合基因陽性的NSCLC患者86例,Crizotinib組和傳統(tǒng)的標(biāo)準(zhǔn)化療組每組各43例,隨訪周期為12個(gè)月,分析Crizotinib組相較于傳統(tǒng)標(biāo)準(zhǔn)化療組的療效優(yōu)劣以及毒副作用的大小。3、入組符合本研究要求的腦轉(zhuǎn)移的EML4-ALK融合基因陽性的晚期NSCLC患者20例,隨后給予Crizotinib 250mg/次,2/日,口服治療,直到病情進(jìn)展(progressive disease,PD)或者發(fā)生不可耐受的毒副反應(yīng),隨訪周期為12個(gè)月,觀察Crizotinib療效及其毒副作用。結(jié)果1、Crizotinib在EML4-ALK融合基因陽性的NSCLC中的治療效果45例EML4-ALK融合基因陽性的NSCLC患者給予Crizotinib治療至少一個(gè)月,一個(gè)月后給予療效評(píng)價(jià)。服用Crizotinib患者部分緩解(partial response,PR)為60%(27/45),疾病穩(wěn)定(stable disease,SD)為33.3%(15/45),疾病進(jìn)展為6.7%(3/45),客觀緩解率(Objective Response Rate,ORR)為60%(27/45),疾病控制率(disease control rate,DCR)為93.3%(42/45),中位無進(jìn)展生存期(progression-free survival,PFS)為7.0個(gè)月。年齡、性別、吸煙史、EGFR基因狀態(tài)以及是否一線服用Crizotinib對(duì)PFS的影響無顯著統(tǒng)計(jì)學(xué)差異。而入組本實(shí)驗(yàn)前已行化療的患者口服Crizotinib的療效明顯優(yōu)于入組本實(shí)驗(yàn)前未行化療的患者(中位PFS分別為8個(gè)月和5個(gè)月,兩組差異有統(tǒng)計(jì)學(xué)意義)。服用Crizotinib的不良反應(yīng)發(fā)生率是40%(18/45),主要不良反應(yīng)為視覺障礙、惡心、便秘以及谷丙轉(zhuǎn)氨酶升高,本組研究患者中有1例患者在口服Crizotinib治療期間出現(xiàn)了III度的骨髓抑制,后經(jīng)對(duì)癥治療后血象恢復(fù)正常并繼續(xù)口服Crizotinib,所有入組的患者均能耐受至治療終止。2、Crizotinib對(duì)比化療在NSCLC患者中的療效分析Crizotinib組:CR為0,PR為60.5%(26/43),SD為32.6%(14/43),PD為7%(3/43),ORR是60.5%(26/43),DCR是93%(40/43),中位PFS是7.0個(gè)月�；熃M:CR為0,PR為25.6%(11/43),SD為20.9%(9/43),PD為53.5%(23/43),ORR是25.6%(11/43),DCR是46.5%(20/43),m PFS(medial progression-free survival,PFS)是3.0個(gè)月。Crizotinib組患者的療效明顯要優(yōu)于傳統(tǒng)標(biāo)準(zhǔn)化療組的患者,P=0.015,兩組之間的差異具有統(tǒng)計(jì)學(xué)意義。Crizotinib組的不良反應(yīng)發(fā)生率是41.8%(18/43),主要的不良反應(yīng)為視覺障礙、惡心等消化道反應(yīng)、便秘以及谷丙轉(zhuǎn)氨酶升高,本組研究患者中有1例患者在口服Crizotinib治療期間出現(xiàn)了III度的骨髓抑制,后經(jīng)對(duì)癥治療血象恢復(fù)正常并繼續(xù)口服Crizotinib,所有患者均能耐受至治療終止。而標(biāo)準(zhǔn)化療組的主要不良反應(yīng)為脫發(fā)、惡心、嘔吐、腹瀉及谷丙轉(zhuǎn)氨酶升高,化療組有4名患者因?yàn)閲?yán)重的化療反應(yīng)不能耐受,從而更改其它方案化療。1例患者在化療間歇期猝死。3、Crizotinib對(duì)EML4-ALK融合基因陽性的晚期NSCLC患者腦轉(zhuǎn)移的療效分析20例已經(jīng)發(fā)生腦轉(zhuǎn)移的EML4-ALK融合基因陽性的晚期NSCLC患者給予Crizotinib至少一個(gè)月后的療效分析顯示:CR 0例(0%),PR 60%(12/20),SD 45%(9/20),PD 5%(1/20)。ORR為60%(12/20),DCR為95%(19/20)。截止隨訪時(shí)間,有16例患者進(jìn)展,其中首發(fā)進(jìn)展是顱內(nèi)進(jìn)展的為62.5%(10/16)。本組患者未放療20%(4/20),行放療或腦轉(zhuǎn)移瘤手術(shù)80%(16/20),未行放療患者SD為75%(3/4),PR為25%(1/4)例,ORR為25%(1/4),DCR為100%(4/4)。在行放療或腦轉(zhuǎn)移瘤手術(shù)的16名患者中,SD 31.2%(5/16)例,PR 62.5%(10/16),PD 6.25%(1/16),ORR為62.5%(10/16),DCR為93.8%(15/16)。本組入組患者中行放療或者腦轉(zhuǎn)移瘤手術(shù)患者的中位無進(jìn)展生存期為7個(gè)月(95%CI 5.70-8.30個(gè)月),顯著長(zhǎng)于于未行放療及手術(shù)治療患者的3個(gè)月(P=0.003)。Crizotinib治療前接受過腦伽馬刀治療13例患者,包括全腦放療(Whole brain radiotherapy,WBRT)、立體定向放療(Stereotactic radiotherapy,SBRT)以及手術(shù),中位PFS為7個(gè)月(95%CI4.74-9.26月),服用Crizotinib后放療3例,m PFS 6個(gè)月。服用Crizotinib前后放療未見明顯統(tǒng)計(jì)學(xué)差異(P=0.951)。Crizotinib不良反應(yīng)發(fā)生率為40%(8/20),主要有視覺障礙、惡心等消化道反應(yīng)、便秘以及谷丙轉(zhuǎn)氨酶升高,本組研究患者中有1例患者在口服Crizotinib治療期間出現(xiàn)了III度的骨髓抑制,后經(jīng)對(duì)癥治療血象恢復(fù)正常并繼續(xù)口服Crizotinib,所有患者均能耐受并堅(jiān)持治療結(jié)束。結(jié)論1、Crizotinib作為第一個(gè)被國(guó)際上批準(zhǔn)用于EML4-ALK融合基因陽性的NSCLC患者的靶向治療藥物,具有良好的療效,不良反應(yīng)在可耐受范圍。2、相較于傳統(tǒng)標(biāo)準(zhǔn)的化療方案,Crizotinib治療EML4-ALK融合基因陽性的非小細(xì)胞患者的療效顯著,可明顯延長(zhǎng)患者的中位PFS并且提高晚期NSCLC患者的生存質(zhì)量,毒副作用也明顯小于化療。針對(duì)EML4-ALK融合基因陽性的非小細(xì)胞患者,應(yīng)優(yōu)先考慮行Crizotinib靶向治療。3、對(duì)于已經(jīng)發(fā)生腦轉(zhuǎn)移的EML4-ALK融合基因陽性的NSCLC患者,Crizotinib亦表現(xiàn)出較好的控制率。
[Abstract]:Objective the clinical efficacy and adverse reactions of Crizotinib in Chinese patients are still lacking large sample clinical trials. The purpose of this study was to study the study of kazolinib (Crizotinib) on microtubule binding protein like -4- anakinase (echinoderm microtubule-assciated protein-like-4-Anaplastic lymphoma kinase, EM) in acanthopanzia (EM). L4-ALK) the efficacy and toxic side effects of non-small cell lung cancer (NSCLC) patients with fusion gene positive, and the toxic and side effects.2, compared with the traditional standard chemotherapy scheme, the effect of Crizotinib against EML4-ALK fusion gene positive NSCLC patients and the severity of adverse reactions and tolerance condition.3 were studied, and Crizotinib pairs have been studied. The clinical efficacy and toxic side effects of EML4-ALK fusion gene positive NSCLC patients with positive brain metastases. Method 1, 45 cases of NSCLC patients with EML4-ALK fusion gene positive, followed by Crizotinib 250mg/ times, 2/ day, oral treatment, or intolerance (progressive disease, PD), or intolerance in the disease progression (progressive disease, PD). The follow-up period was 12 months. The efficacy and tolerance of Crizotinib were observed and.2 was observed. 86 cases of NSCLC patients with EML4-ALK fusion gene positive, 43 cases in group Crizotinib and traditional standard chemotherapy group, followed up for 12 months, and the effect of Crizotinib group compared with the traditional standard chemotherapy group was analyzed. And the size of the toxic side effects of.3, 20 cases of advanced NSCLC patients with EML4-ALK fusion gene positive in the brain metastases, followed by Crizotinib 250mg/ times, 2/ day, oral treatment, until the disease progression (progressive disease, PD) or an untolerable toxic and side reaction, the follow-up period was 12 months, observe Crizotinib. Effect and toxic and side effects. Results 1, Crizotinib in EML4-ALK fusion gene positive NSCLC, 45 cases of EML4-ALK fusion gene positive NSCLC patients were given Crizotinib treatment for at least one month, and one month later, the curative effect was evaluated. The partial relief of Crizotinib patients (partial response, PR) was 60% (27/45), and the disease was stable (stabl). E disease, SD) was 33.3% (15/45), the disease progressed to 6.7% (3/45), the objective remission rate (Objective Response Rate, ORR) was 60% (27/45), and the disease control rate (disease control) was 93.3%, and the median progression free survival was 7 months. Age, sex, smoking history, gene state and a first-line dress. There was no significant difference in the effect of Crizotinib on PFS. The efficacy of oral Crizotinib in patients who had undergone chemotherapy before the experiment was significantly better than those who did not undergo chemotherapy before the experiment (median PFS was 8 months and 5 months respectively, and the two groups were statistically significant). The incidence of adverse reactions to Crizotinib was 40% (18/45). The adverse reactions were visual disorder, nausea, constipation, and elevated alanine aminotransferase. In this group, 1 patients had a III degree of bone marrow depression during the oral Crizotinib treatment. After symptomatic treatment, the hematogram returned to normal and continued to take Crizotinib. All the patients in the group were tolerated to terminate.2, Crizotinib The efficacy of chemotherapy in NSCLC patients was analyzed in group Crizotinib: CR was 0, PR was 60.5% (26/43), SD was 32.6% (14/43), PD was 7% (3/43), ORR was 60.5% (26/43), DCR was 93%, 7 months. The effect of ion-free survival, PFS) was 3 months in group.Crizotinib patients better than those in the traditional standard chemotherapy group. P=0.015, the difference between the two groups was statistically significant, the incidence of adverse reactions in group.Crizotinib was 41.8% (18/43), and the main adverse reactions were visual disturbance, nausea and other digestive tract reactions, constipation, and glutamic acid conversion. In this group, 1 patients in this group had a III degree of myelosuppression during the oral Crizotinib treatment. After symptomatic treatment, the hematogram returned to normal and continued to take Crizotinib. All the patients were able to tolerate the termination of the treatment. The main adverse reactions in the standard chemotherapy group were alopecia, nausea, vomiting, diarrhoea and alanine transaminase. High, 4 patients in the chemotherapy group were intolerant of the severe chemotherapy response, thus changing the other regimens in.1 patients with sudden death in the intermission of chemotherapy,.3, and the effect of Crizotinib on the brain metastases of advanced NSCLC patients with positive EML4-ALK fusion gene. 20 cases of advanced NSCLC patients with EML4-ALK fusion gene positive brain metastases were given C. The efficacy analysis of rizotinib at least one month showed: CR 0 cases (0%), PR 60% (12/20), SD 45% (9/20), PD 5% (1/20).ORR 60% (12/20), DCR 95% (19/20). There were 16 patients progressing at the end of the follow-up time, and the first progression was 62.5% (20%). The patients were treated with radiotherapy or brain metastases surgery. SD was 75% (3/4), and PR was 25% (1/4), ORR was 25% (1/4), and DCR was 100% (4/4). In 16 patients undergoing radiotherapy or brain metastases surgery, SD 31.2% (5/16), PR 62.5% (10/16), 62.5% (62.5%), 93.8% (93.8%). The group entered the group with no progress in radiotherapy or brain metastases. The survival period was 7 months (95%CI 5.70-8.30 months), which was significantly longer than 3 months (P=0.003).Crizotinib treatment for 13 patients before the treatment of radiotherapy and surgery, including whole brain radiotherapy (Whole brain radiotherapy, WBRT), stereotactic radiotherapy (Stereotactic radiotherapy, SBRT), and surgery, and median PFS was 7 months ( 95%CI4.74-9.26 months), 3 cases of radiotherapy after taking Crizotinib, m PFS for 6 months. There was no significant difference between radiotherapy and radiotherapy before and after Crizotinib (P=0.951) the incidence of.Crizotinib adverse reaction was 40% (8/20), mainly with visual disturbance, nausea and digestive tract reaction, constipation and elevated alanine transaminase, 1 patients in this group were in oral Cri. Zotinib had a III degree of bone marrow depression during the treatment. After symptomatic treatment, the hematogram returned to normal and continued to take Crizotinib. All patients were able to tolerate and adhere to the end of the treatment. Conclusion 1, Crizotinib is the first targeted therapy for NSCLC patients who have been approved by the world for EML4-ALK fusion gene positive, which has good curative effect. The adverse reaction is in the tolerable range of.2. Compared with the traditional standard chemotherapy regimen, Crizotinib has a significant effect on non small cell patients with EML4-ALK fusion gene positive. It can significantly prolong the patient's median PFS and improve the quality of life of patients with advanced NSCLC, and the toxic and side effects are significantly less than chemotherapy. The negative effect of the EML4-ALK fusion gene is less than that of the chemotherapy. Crizotinib targeting therapy.3 should be given priority in small cell patients. Crizotinib also shows good control rate for patients with NSCLC positive EML4-ALK fusion genes that have undergone brain metastases.

【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R734.2

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