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中国真实世界中ALK阳性晚期非小细胞肺癌患者临床特征、治疗现状及克唑替尼总生存获益的研究
中文摘要

第一部分 真实世界中ALK阳性晚期非小细胞肺癌患者临床特征及治疗现状的研究 背景:既往研究表明大约有3%-7%的非小细胞肺癌(Non-small-cell lung cancer, NSCLC)患者具有间变性淋巴瘤激酶基因(Anaplastic Lymphoma Kinase,ALK)重排。针对具有该靶点的患者,克唑替尼已经被证明取得良好的疗效并被广泛采纳为标准一线治疗。然而在中国真实世界下此患者群体的临床特征和治疗现状并不为人所知。因此,我们拟开展一项着眼于ALK基因重排阳性晚期NSCLC的真实世界回顾性临床研究,以探索其临床特征及治疗现状。 方法:本部分研究收集291例来自中山大学肿瘤防治中心的晚期NSCIC患者,其中ALK阳性患者97例,对照组ALK及表皮生长因子受体(Epidermal growth factor receptor,EGFR)基因突变均阴性患者194例。同时收集包括年龄、性别、吸烟状况及饮酒情况、病理类型、转移部位在内的基线临床资料及确诊后治疗经过资料。利用卡方检验、t检验探索ALK基因融合状态基线特征的关系,利用单因素及多因素Logistic回归分析比较不同治疗策略对ALK阳性NSCLC患者生存的影响。 结果:无论是在治疗前基线(26.5%vs.16.5%,P=0.038)还是在治疗开展过程中(25.8%vs.11.9%,P=0.003),ALK阳性患者脑转移发生率均显著高于ALK及EGFR均阴性的患者,然而胸水发生率则相反(治疗前基线:6.2%vs.26.9%, P<0.001;治疗开展过程中:3.1%vs.10.3%,P=0.031)。53.6%的ALK阳性患者曾接受过克唑替尼治疗,37.1%的患者仅接受过化学治疗,9.3%的患者仅接受过支持治疗。对于无进展生存时间(Progression Free Survival,PFS),接受过克唑替尼治疗的ALK阳性患者的优于仅接受过化学治疗的ALK阳性患者(中位PFS 17.6个月vs.4.8个月,P<0.001)。 结论:相比于ALK及EGFR均阴性的晚期NSCLC患者,ALK阳性患者的脑转移发生率更高而胸水发生率更低。相比于化学治疗,任何一线的克唑替尼治疗均能延长ALK阳性晚期NSCLC患者的无进展生存时间。虽然克唑替尼疗效显著,但是在中国真实世界中仍有约一半的ALK阳性晚期NSCLC患者从未接受过克唑替尼治疗,这一治疗现状十分残酷并有待提高。 关键词:非小细胞肺癌,ALK基因,真实世界,临床基线特征,治疗现状 第二部分 ALK阳性晚期非小细胞肺癌患者克唑替尼治疗总生存获益及ALK基因预后价值的回顾性研究 背景:间变性淋巴瘤激酶(Anaplastic Lymphoma Kinase,ALK)是非小细胞肺癌(Non-Small-Cell Lung Cancer,NSCLC)治疗中常用的酪氨酸激酶靶点之一。克唑替尼(Crizotinib)作为目前唯一国内上市的针对ALK抑制剂已在众多临床实践中展示出其良好的疗效。然而迄今尚无大型中国人群研究揭示克唑替尼治疗对晚期NSCLC患者0S的贡献。因此,我们在中国克唑替尼上市前、后的晚期NSCLC人群中开展了一项回顾性研究,来阐明克唑替尼治疗带来的0S获益、ALK基因状态本身能否预测患者的生存获益等问题。 方法:共有1170例在中山大学肿瘤防治中心治疗的晚期NSCLC患者被纳入研究。包括克唑替尼中国上市前患者454例(A组)和上市后患者716例(B组)。研究统计比较组间患者基线特征的一致性,利用生存分析阐明克唑替尼治疗带来的0S获益、ALK基因状态的预后价值。 结果:克唑替尼上市后患者比克唑替尼上市前患者0S显著延长(中位生存时间Median Survival Time,MST:18.3个月vs.11.5个月,HR:0.643;95%CI: 0.457-0.879;P<0.001),且在ALK阳性亚组中差异更明显(MST:42.9个月vs. 12.3个月,HR:0.142;95%CI:0.089-0.475;P<0.001),在ALK阴性患者中无差异。在克唑替尼中国上市前患者中,ALK阳性患者与ALK阴性患者预后无明显差别(MST:10.3个月vs.9.5个月,HR:1.135;95%CI:0.743-1.484;P=0.258),且经年龄、治疗史、病理类型、转移部位校正后仍无区别(MST:9.8个月vs. 9.6个月,HR:1.067;95%CI:0.893-1.257;P=0.760)。 结论:克唑替尼在中国的上市使用为ALK阳性晚期NSCLC患者带来了巨大的总生存获益。ALK基因状态本身并不是一个独立预后因素。 关键词:非小细胞肺癌,ALK基因,总生存获益,预后价值

英文摘要

Part One. A large, single-center, real-world study of clinicopathological characteristics and treatment in advanced ALK-positive non-small-cell lung cancer Background: Crizotinib has achieved astonishing success in advanced non-small-cell lung cancer (NSCLC) patients harboring anaplastic lymphoma kinase (ALK) rearrangement. However, no real-world studies described the clinicopathological characteristics and treatment of such patients in China. Methods: Patients were consecutively collected from Sun Yat-sen University Cancer Center. Chi-square test was applied to explore the relationship between ALK fusion status and metastasis sites. Kaplan-Meier methods and multivariable analyses were used to estimate progression-free survival (PFS). Results: A total of 291 advanced NSCLC patients (ALK (+), N = 97; both ALK & epidermal growth factor receptor (EGFR) (-), N = 194) were enrolled. The occurrence of brain metastasis in ALK-positive patients was significantly higher than double-negative ones both at baseline (26.5% vs. 16.5%, P = 0.038) and during treatment (25.8% vs. 11.9%, P = 0.003), but opposite for pleural effusion (6.2% vs. 26.9%, P < 0.001 at baseline; 3.1% vs. 10.3%, P = 0.031 during treatment). ALK-positive patients of 53.6% used crizotinib, whereas others only received chemotherapy (37.1%) or supportive care (9.3%). Usage of crizotinib prolonged PFS compared with chemotherapy in ALK-positive patients (median PFS 17.6 m vs. 4.8 m, P< 0.001). Conclusion: ALK-positive NSCLC had more brain metastasis and less pleural effusion than double-negative ones. Crizotinib showed better PFS than chemotherapy in advanced ALK-positive NSCLC at any line. However, half advanced ALK-positive patients never received crizotinib, which was grim and need improving. Keywords: NSCLC, ALK, Real-world, clinical characteristics, treatment Part Two. Overall survival benefit of crizotinib among ALK-positive advanced NSCLC patients and prognostic value of ALK gene Background: Anaplastic Lymphoma Kinase (ALK) is one of the most common tyrosine-kinase targets in non-small-cell lung cancer (NSCLC). Crizotinib, as the only available ALK inhibitor in China, showed marked antitumor activity in patients with advanced, ALK-positive NSCLC. However, there is no study focus on crizotinib overall survival (OS) benefit among Chinese population. In order to assess OS benefit of crizotinib and determine whether ALK gene status is an independent prognostic factor, we carried a retrospective study to compare OS between patients before and after crizotinib approval in China. Methods: A total of 1170 advanced NSCLC patients from Sun Yat-sen University Cancer Center were consecutively enrolled in the study. Patients were divided into 2 parts: 454 patients before crizotinib approval in China (group A) and 716 patients after approval (Group B). Baseline characteristics were collected for comparison between groups. Survival analyses were used for assessing OS benefit of crizonitib and prognostic value of ALK status. Results: Patients’ OS of group B was significantly longer than OS of group A in whole patients (Median Survival Time, MST: 18.3 months vs. 11.5 months, HR: 0.643; 95%CI: 0.457-0.879; P<0.001) and in ALK+ subgroup (MST: 42.9 months vs. 12.3 months, HR: 0.142; 95%CI: 0.089-0.475; P﹤0.001), but not in ALK- subgroup. Within patients before crizotinib approval in China, OS was similar between ALK+ patients and ALK- patients (MST: 10.3 months vs. 9.5 months, HR: 1.135; 95%CI: 0.743-1.484; P=0.258), even after adjusted for age, treatment history, pathology type and metastasis site (MST: 9.8 months vs. 9.6 months, HR: 1.067; 95%CI: 0.893-1.257; P=0.760). Conclusion: Approval and usage of crizotinib bring huge OS benefit for ALK-positive, advanced NSCLC in China. ALK gene status itself is not an independent prognostic factor. Key words: NSCLC, ALK, OS, Prognostic value

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