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Efficacy and safety of erlotinib combined with bevacizumab in the treatment of non-small cell lung cancer: A systematic review and meta-analysis.

厄洛替尼联合贝伐单抗治疗非小细胞肺癌疗效和安全性的系统评价和meta分析 [j].

  • 影响因子:1.95
  • DOI:10.1097/MD.0000000000018771
  • 作者列表:"Zhou K","Zhao S","Guo W","Ding L
  • 发表时间:2020-01-01

BACKGROUND:Non-small cell lung cancer (NSCLC) has a poor prognosis despite conventional treatments of surgery, radiotherapy, and chemotherapy. Small-molecule tyrosine kinase inhibitors acting on epidermal growth factor receptor (EGFR) have shown high efficacy and low toxicity for NSCLC. In particular, combining erlotinib with the VEGF antibody bevacizumab has therapeutic value in NSCLC, but the drugs' separate effects as monotherapy and any adverse outcomes of combination therapy remain unclear. OBJECTIVES:To determine the efficacy and safety of erlotinib and bevacizumab for NSCLC, we conducted a meta-analysis and systematic review of randomized controlled trials. DATA SOURCES:PubMed, Embase, Web of Science, and Cochrane databases were searched using keywords and manual review. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS:We reviewed randomized controlled trials on the use of erlotinib combined with bevacizumab in adult patients with NSCLC, including data on outcome measures of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events. STUDY APPRAISAL AND SYNTHESIS METHODS:After quality assessment, datasets were evaluated for heterogeneity. In the event of significant heterogeneity, a random-effects model was used to assess the overall outcome measures as a result of treatments. Subgroup analysis was conducted to evaluate the source of heterogeneity on PFS. RESULTS:Compared with erlotinib or bevacizumab alone, the combined treatment did not significantly prolong OS (95% confidence interval [CI] = 0.84-1.11; P = .62) or increase the ORR (95% CI = 0.91-1.20; P = .52), but significantly improved PFS (95% CI = 0.58-0.73; P < .001). This improvement was especially notable in patients with the following characteristics: Eastern Cooperative Oncology Group Performance Status score of 0 or 1, female, no smoking history, adenocarcinoma, and EGFR Exon19 deletion or Exon21 Leu858Arg mutation. Combination therapy significantly increased incidence of grade 1-2 hypertension (20.3% vs 6.3%, 95% CI 1.73-5.88; P < .01) and severe diarrhea (10% vs 3.2%, 95% CI 1.36-6.60; P = .01). LIMITATIONS:The low number of available randomized controlled trials could influence interpretation. CONCLUSIONS:Compared with erlotinib or bevacizumab monotherapy, their combination effectively prolongs PFS but increases incidence of adverse events in NSCLC patients.


背景: 非小细胞肺癌 (NSCLC) 尽管有手术、放疗和化疗等常规治疗,但预后较差。作用于表皮生长因子受体 (EGFR) 的小分子酪氨酸激酶抑制剂已显示出对NSCLC的高效和低毒性。特别是,厄洛替尼联合VEGF抗体贝伐单抗在NSCLC中具有治疗价值,但这些药物作为单一疗法的单独作用和联合疗法的任何不良结局仍不清楚。 目的: 为了确定厄洛替尼和贝伐单抗治疗非小细胞肺癌的有效性和安全性,我们对随机对照试验进行了荟萃分析和系统评价。 数据来源: PubMed、Embase、Web of Science和Cochrane数据库使用关键词和人工审查进行搜索。 研究纳入标准、参与者和干预措施: 我们回顾了在成年NSCLC患者中使用厄洛替尼联合贝伐单抗的随机对照试验,包括总生存期 (OS) 结局指标的数据,无进展生存期 (PFS) 、客观缓解率 (ORR) 和不良事件。 研究评估和合成方法: 在质量评估之后,评估数据集的异质性。在存在显著异质性的情况下,使用随机效应模型来评估作为治疗结果的总体结果指标。进行亚组分析以评估PFS的异质性来源。 结果: 与单独使用厄洛替尼或贝伐单抗相比,联合治疗未显著延长OS (95% 可信区间 [CI]  =   0.84-1.11; P   =  .62) 或增加ORR (95% ci = 0.91-1.20; P =.52),但显著改善PFS (95% ci = 0.58-0.73; P <.001)。这种改善在具有以下特征的患者中尤其显著: 东部肿瘤协作组表现状态评分为 0 或 1,女性,无吸烟史,腺癌,和EGFR Exon19 缺失或Exon21 Leu858Arg突变。联合治疗显著增加 1-2 级高血压 (20.3% vs 6.3%,95% CI 1.73-5.88; P <.01) 和严重腹泻 (10% vs 3.2%,95% CI 1.36-6.60; P   =  .01)。 局限性: 可用的随机对照试验数量少可能影响解释。 结论: 与厄洛替尼或贝伐单抗单药治疗相比,联合用药可有效延长NSCLC患者的PFS,但增加不良事件的发生率。



作者列表:["Mammana M","Zuin A","Serra E","Bellini A","Rea F"]

METHODS::Pulmonary artery sling is a rare congenital anomaly of the origin and course of the left pulmonary artery. Patients with this condition typically present with respiratory failure in young infancy, and asymptomatic cases are uncommon. We describe the case of an adult patient with a lung adenocarcinoma of the right upper lobe, extending into the hilum and superior mediastinum, and with a previously unknown pulmonary artery sling anomaly. The local invasiveness of the tumor and the peculiar vascular anatomy contributed to a unique surgical scenario, wherein multiple reconstructive procedures were required.

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作者列表:["Hata A","Nakajima T","Matsusaka K","Fukuyo M","Morimoto J","Yamamoto T","Sakairi Y","Rahmutulla B","Ota S","Wada H","Suzuki H","Matsubara H","Yoshino I","Kaneda A"]

METHODS::Patients with idiopathic pulmonary fibrosis (IPF) have higher risk of developing lung cancer, for example, squamous cell carcinoma (SCC), and show poor prognosis, while the molecular basis has not been fully investigated. Here we conducted DNA methylome analysis of lung SCC using 20 SCC samples with/without IPF, and noncancerous lung tissue samples from smokers/nonsmokers, using Infinium HumanMethylation 450K array. SCC was clustered into low- and high-methylation epigenotypes by hierarchical clustering analysis. Genes hypermethylated in SCC significantly included genes targeted by polycomb repressive complex in embryonic stem cells, and genes associated with Gene Ontology terms, for example, "transcription" and "cell adhesion," while genes hypermethylated specifically in high-methylation subgroup significantly included genes associated with "negative regulation of growth." Low-methylation subgroup significantly correlated with IPF (78%, vs. 17% in high-methylation subgroup, p = 0.04), and the correlation was validated by additional Infinium analysis of SCC samples (n = 44 in total), and data from The Cancer Genome Atlas (n = 390). The correlation between low-methylation subgroup and IPF was further validated by quantitative methylation analysis of marker genes commonly hypermethylated in SCC (HOXA2, HOXA9 and PCDHGB6), and markers specifically hypermethylated in high-methylation subgroup (DLEC1, CFTR, MT1M, CRIP3 and ALDH7A1) in 77 SCC cases using pyrosequencing (p = 0.003). Furthermore, low-methylation epigenotype significantly correlated with poorer prognosis among all SCC patients, or among patients without IPF. Multivariate analysis showed that low-methylation epigenotype is an independent predictor of poor prognosis. These may suggest that lung SCC could be stratified into molecular subtypes with distinct prognosis, and low-methylation lung SCC that significantly correlates with IPF shows unfavorable outcome.

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作者列表:["Zhang L","Yang Y","Chai L","Bu H","Yang Y","Huang H","Ran J","Zhu Y","Li L","Chen F","Li W"]

METHODS::The role of Fyn-related kinase (FRK) in malignant tumors remains controversial. Our study investigated the function of FRK in lung cancer. Immunohistochemistry staining and generating a knockout of FRK by CRISPR/Cas9 in H1299 (FRK-KO-H1299) cells were strategies used to explore the role of FRK. Immunohistochemistry staining indicated that FRK expression was elevated in 223 lung cancer tissues compared to 26 distant normal lung tissues. FRK contributed to poor survival status in lung cancer patients and acted as a predictor for poor prognosis of lung cancer. Knockout of FRK by CRISPR/Cas9 markedly inhibited proliferation, invasion, colony formation and epithelial-mesenchymal transition (EMT) process in the lung cancer cell line H1299. Further exploration indicated that FRK-KO damaged the stemness phenotype of H1299 by inhibiting CD44 and CD133 expression. Seahorse detection and a U-13 C flux assay revealed that FRK-KO induced metabolism reprogramming by inhibiting the Warburg effect and changing the energy type in H1299 cells. Epidermal growth factor stimulation recovered the expression of FRK and biological functions, metabolic reprogramming and stemness phenotype of H1299 cells. FRK plays an oncogenic role in lung cancer cells via a novel regulation mechanism of enhancing the stemness of H1299 cells by inducing metabolism reprogramming, which finally promotes EMT and metastasis. Our study also indicates that FRK could be used as a potential therapeutic target for drug development.

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