吉非替尼治疗伴有表皮生长因子受体基因突变的非小细胞肺癌的研究进展

肺癌为恶性肿瘤死亡首位原因,而非小细胞肺癌(NSCLC)约占其中的80%。NSCLC中85%以上属中晚期肺癌,5年生存率仅有15%。吉非替尼主要用于晚期非小细胞肺癌(NSCLC)患者经化疗后进展的单用疗法,2003年5月经FDA批准上市。本文对其作用机制、药代动力学进行了概述。     

Anti-growth factor therapy for lung cancer

Lung cancers are the leading cause of cancer death in developed countries. In the USA, lung cancer accounts for 29% of all cancer deaths. The cure rate for lung cancer is low (14%) because the cancer spreads early and because chemotherapy cannot cure metastatic disease. In small cell lung cancer (SCLC) two-thirds of patients present with metastatic disease in a distant organ (stage IV). In non-small cell lung cancers (adenocarcinoma, squamous carcinoma, large cell carcinoma) one-third present with metastatic disease. Initial chemotherapy produces high response rates in both SCLC (85%-90% response rate) and NSCLC (50% response rate) but response duration is short and drug resistance develops rapidly. Growth factors play an important role in the pathogenesis and the progression of lung cancers. Knowledge of the role of these growth factors, their receptors and their signal pathways has produced new therapeutic targets. Compounds developed toward these targets have completed preclinical testing and are now in clinical trials. Some of these compounds are active in both drug sensitive and drug resistant lung cancers. They also produce synergistic growth inhibition when combined with cytotoxic chemotherapeutic agents. Thus, these compounds may provide a new way to overcome drug resistance in lung cancer.     

晚期非小细胞肺癌的药物治疗进展

肺癌目前仍是死亡率较高的恶性肿瘤。近年来随着分子靶向治疗的进展,非小细胞肺癌的治疗已经取得了长足的进步。许多转化性临床研究结果带来近期疗效、生活质量尤其是生存的显著提高。传统的化疗是非小细胞肺癌治疗的基石,是野生型以及突变未知患者治疗的首选;分子靶向治疗则为敏感突变的患者带来了革命性的转变,是目前治疗的中流砥柱;而免疫治疗在免疫检查点抑制剂上的突破也结束了长期混沌的状态,成为非小细胞肺癌治疗的新兴力量。而无论是化疗、靶向治疗还是免疫治疗,基于肿瘤分子病理改变的精确治疗是目前非小细胞肺癌治疗发展的趋势。     

非小细胞肺癌表皮生长因子受体–酪氨酸激酶抑制剂的研究进展及其耐药后治疗策略

肺癌是全球死亡率最高的癌症之一,非小细胞肺癌占肺癌总人群的85%以上。约2/3的非小细胞肺癌患者在诊断时已为晚期,内科治疗是晚期非小细胞肺癌患者的主要治疗手段。近些年随着靶向治疗药物表皮生长因子受体–酪氨酸激酶抑制剂（EGFR-TKI）分子治疗的出现,非小细胞肺癌患者的治疗取得了明显的成效。但是EGFR-TKI耐药问题也接踵而至,总结了非小细胞肺癌患者EGFR-TKI治疗进展以及耐药后的治疗策略,为临床选择适合患者个体化治疗方案提供参考。     

The role of EGFR tyrosine kinase inhibitors in the first-line treatment of advanced non small cell lung cancer patients harboring EGFR mutation

Lung cancer continues to be the leading cause of cancer death worldwide. Among lung cancers, 80% are classified as nonsmall- cell lung cancer (NSCLC) and are mostly diagnosed at an advanced stage (either locally advanced or metastatic disease). In the last years, the discovery of the pivotal role in tumorigenesis of the Epidermal Growth Factor Receptor (EGFR) has provided a new class of targeted therapeutic agents: the EGFR tyrosine kinase inhibitors (EGFR-TKIs). Since the first reports of an association between somatic mutations in EGFR exons 19 and 21 and response to EGFR-TKIs, treatment of advanced NSCLC has changed dramatically. Histologic profile, clinical characteristics, and mutational profile of lung carcinoma have all been reported as predictive factors of response to EGFR-TKIs and other targeted therapies. In advanced NSCLC patients harboring EGFR mutations, the use of EGFR TKIs in first-line treatment has provided an unusually large progression-free survival (PFS) benefit with a negligible toxicity when compared with cytotoxic chemotherapy in phase III randomized trials. Considering the findings regarding the excellent benefit and better safety profile of EGFR TKIs in EGFR mutation positive patients, these targeted therapeutic agents can be now considered as first-line treatment in this setting of patients. This review will discuss the new evidences in the role of EGFR-TKIs in the first-line treatment of advanced NSCLC and their implication in the current clinical decision-making.     

晚期非小细胞肺癌EGFR-TKIs获得性耐药后治疗策略研究进展

肺癌是癌症相关死亡的首要原因。非小细胞肺癌（NSCLC）约占肺癌的85%,且患者在诊断时大多为晚期。随着表皮生长因子受体（EGFR）在肺癌中被发现,针对特定基因突变的靶向治疗成为晚期NSCLC的重要治疗方式,并显著延长了患者生存期。尽管第一、二、三代EGFR-酪氨酸激酶抑制剂（TKI）蓬勃发展,但随着治疗时间的推移,患者都可能面临耐药和进展。为克服这一难题,基于耐药机制的相关治疗策略正在研究中。本文旨在对近年来EGFR-TKIs,特别是在疗效及安全性上作为指南更优推荐的第三代EGFR-TKIs的耐药机制和治疗策略的研究进展进行综述。     

晚期非小细胞肺癌病人一线治疗的优化策略

肺癌是全球头号癌症杀手,合理优化晚期非小细胞肺癌病人的药物治疗策略,有望改善病人的生存预后。至今,含铂两药化疗仍是非小细胞肺癌群体有效率最高的治疗首选;对于选择性人群,如表皮生长因子受体突变者,靶向药物表皮生长因子受体酪氨酸激酶抑制剂更具优势。两者应用新模式和策略仍在进一步研究和完善中。     

PI3K/Akt信号转导通路在非小细胞肺癌中的作用

肺癌是当今世界严重威胁人类健康和生命的疾病,其中85%是非小细胞肺癌(NSCLC)。PI3K/Akt通路在NSCLC的发生、发展中具有重要的作用,可以调控细胞存活、增殖、抗凋亡、血管生成等影响肿瘤的发生发展,而且某些蛋白的表达还是NSCLC不良预后的标志。在此我们对PI3K/Akt通路在NSCLC中的分子机制进行总结,并进一步讨论NSCLC的多靶点治疗。     

Safety profiles of first-line therapies for metastatic non-squamous non-small-cell lung cancer

ABSTRACT

Introduction: Lung cancer still represents the leading cause of death for cancer. About the 70% of diagnosis are in advanced-stage. Non-small-cell lung cancer (NSCLC) represents the 85% of all diagnosed lung cancers and non-squamous histology represents the 40% of all NSCLC. First-line therapies increase survival, control symptoms and improve quality of life, compared with best supportive care. It is crucial to choose a treatment with a low impact on patient’s life considering the related toxicities.

Areas covered: Adverse events (AEs) of first-line therapies for non-squamous NSCLC are here reviewed and discussed, from evidences in clinical trials conducting to drugs approval.

Expert opinion: For advanced disease, palliation and preserving patients QoL are still the primary goal of treatment. Therefore, differing toxicity profiles are often a deciding factor in first-line and also maintenance setting for non-squamous NSCLC.

Special attention is necessary to renal function and drugs’ nephrotoxicity. Moreover, it is to consider the specific AEs of drugs classes: hypertension, bleeding, and proteinuria, for anti-VEGF therapy; skin toxicity, diarrhea, interstitial lung disease for TKIs; vision disorders, and hepatotoxicity for ALK-inhibitor. It is important to select patients for a treatment on the basis of their comorbidities and the presence of risk factors.     

Docetaxel in non-small cell lung cancer: impact on quality of life and pharmacoeconomics

Lung cancer is one of the leading causes of cancer-related deaths in industrialised countries, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. A large proportion of patients present with advanced disease and are >65 years of age at the time of diagnosis. Systemic chemotherapy may be offered in an effort to improve survival and quality of life (QOL). Chemotherapy with platinum-based compounds has been shown to modestly improve survival and QOL, and is considered the standard of care as first-line treatment in patients with a good performance status. The last decade has seen the emergence of newer generation chemotherapy agents for the treatment of all cancer types. We review the evidence for the use of docetaxel, an antimicrotubular agent, in patients with advanced NSCLC. In this review, we evaluate not only the effects of docetaxel on survival, but also its impact on QOL and economic issues. Docetaxel is a potent anticancer agent with activity both as a single agent or in combination, and is used both as a first- and second-line treatment in advanced NSCLC. The improvements observed in patients' QOL and the cost effectiveness of docetaxel make it a very reasonable choice in older patients with good performance status and advanced disease who are candidates for chemotherapy.     

非小细胞肺癌分子靶向治疗的研究进展

肺癌作为对人类健康与生命造成威胁的一种常见恶性肿瘤,具有较高的发病率与死亡率。肺癌临床属性分为非小细胞肺癌与小细胞肺癌,其中非小细胞肺癌在全部肺癌发病中的占比高达80%~85%,且多数肺癌患者在确诊阶段已处于中晚期,加剧了临床治疗的难度。在医疗技术的不断发展下,手术、放疗、化疗、靶向治疗以及免疫治疗等方式的出现与发展为非小细胞肺癌患者的临床治疗带来新的希望,而分子靶向治疗药物的涌现,为非小细胞肺癌患者的治疗提供了新的选择。     

Insights into angiogenesis in non-small cell lung cancer: molecular mechanisms, polymorphic genes, and targeted therapies

Lung cancer is a highly prevalent disease worldwide. Currently, there are more than 150 million patients with lung cancer in the world, with more than 1 million new cases diagnosed per year. Tumoral angiogenesis is an important hallmark of this disease, but despite being extensively studied, the complete angiogenic mechanisms are not fully elucidated. Recent studies have reported a correlation between pharmacological inhibition of these angiogenic mechanisms and improvement of overall survival in lung cancer patients, mainly for those in advanced stages. The family of vascular endothelial growth factor (VEGF) proteins has critical roles in tumoral angiogenesis. An interaction between VEGF-A and VEGF receptor 2 (VEGFR-2) is the main pathway of activation and maintenance of angiogenesis. In tumors, this process is intimately correlative with progression and metastasis. Some studies suggested that serum levels of VEGF are higher in patients with lung cancer, especially in some types of non-small cell lung cancer (NSCLC). Other studies revealed that genetic polymorphisms of VEGF correlate with susceptibility, prognosis, and therapeutic response of some patients with NSCLC. This paper aims to review the impact of angiogenesis, especially on VEGF pathways, in NSCLC, and highlights the relevance of known and new patents disclosed of anti-angiogenic therapies in these patients.     

肺癌常用化疗药物基因组学概述

目的：对NSCLC化疗药物基因组学方面的研究做一概述．并初步展望NSCLC化疗药物基因组学未来的发展。方法：回顾近年来NSCLC化疗药物基因组学方面的研究进展。结果和结论：肺癌是引起癌症患者死亡的主要原因之一．大约85％的肺癌患者为非小细胞肺癌,化疗是主要治疗手段。NSCLC化疗药物基因组学逐渐成为研究热点．并极有可能对肺癌的化疗产生重大改进。本文就NSCLC化疗药物基因组学方面的研究做一概述．并初步展望NSCLC化疗药物基因组学未来的发展。     

EGFR-directed therapies to treat non-small-cell lung cancer

Lung cancer is the leading cause of cancer death in men and women. In 2008, in the US > 200,000 patients were diagnosed with lung cancer and > 160,000 died from their disease. Over 80% of lung cancers are of the non-small cell type, for which chemotherapy has demonstrated modest survival benefits at all stages of disease. Agents that alter critical molecular cell growth pathways are a growing area of research and development including targeted therapies directed at the EGFR. Downstream effects of EGFR dimerization and activation include cell proliferation, differentiation and angiogenesis, key events in the malignant process. Two main classes of drugs have been developed, small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies directed against the extracellular domain of the receptor. This review discusses clinical studies with several new therapies and the plans for drug development.     

Bevacizumab in non-small cell lung cancer

Lung cancer continues to be the leading cause of cancer death in Western countries. The median survival time for advanced non-small cell lung cancer (NSCLC) remains poor and chemotherapy is the treatment of choice for most patients with metastatic NSCLC. Platinum-based chemotherapy has long been the standard of care for advanced NSCLC. The formation of new blood vessels (angiogenesis) is needed for the growth and invasiveness of primary tumours, and plays an important role in metastatic growth. Vascular endothelial growth factor (VEGF) has emerged as a key potential target for the pharmacological inhibition of tumour angiogenesis. This review discusses current data and the future potential of bevacizumab, a recombinant humanized monoclonal antibody that binds VEGF, in the treatment of NSCLC. Results from a phase II study showed that the addition of bevacizumab to the first-line chemotherapy with paclitaxel and carboplatin (CP) may increase the overall survival (OS) and the time to progression in advanced NSCLC. Based on these promising results, a randomized phase III trial compared the combination of bevacizumab with CP versus CP alone in the treatment of advanced non-squamous NSCLC. The combination of CP plus bevacizumab led to a statistically significant increase in median OS and progression-free survival (PFS) compared with CP alone, with a response rate (RR) in the CP arm of 15% compared with 35% in the bevacizumab plus CP arm (p < 0.001). More recently, the randomized AVAIL (Avastin in Lung Cancer) study, which evaluated cisplatin with gemcitabine plus bevacizumab in two different dosages versus chemotherapy alone in 1043 patients with recurrent or advanced non-squamous NSCLC, reported a significant increase of PFS, RR and duration of response for both of the bevacizumab-containing arms. Bevacizumab has also been investigated in combination with erlitonib as second-line treatment in two small early phase trials, with interesting results. Bevacizumab was generally well tolerated in clinical trials; the main treatment-associated adverse events were neutropenia and haemorrhage, especially in the lung, but also at other sites. Several trials that incorporate bevacizumab in combination with new active drugs in NSCLC are ongoing and should further help to define the place of bevacizumab in the therapy of NSCLC.     

Angiotensin II-induced micro RNA-21 culprit for non-small-cell lung adenocarcinoma

Lung cancer is among the most complicated cancers, with an estimated 1.6 million deaths each year for both men and women. However, the proportion of lung cancer patients in developing nations has increased from 31% to 49.9% in the last two decades. There are two main subtypes of lung cancer, small-cell lung carcinoma and non-small-cell lung carcinoma (NSCLC), accounting for 15% and 85% of all lung cancer, respectively. Adenocarcinoma is the most common type of lung cancer in smokers and nonsmokers in men and women regardless of their age. Chemicals in cigarette smoke and nicotine enter our bloodstream and can then affect the entire body and finally lead to the activation of several important, pro-survival signaling pathways. The biologically active peptide of RAAS on overstimulation enhance Ang II mediates cell proliferation, fibrosis and inflammatory effects via AT1 receptor. Very few studies highlight the diagnostic and therapeutic potential of miRNAs with the EGFR-regulated miRNA-21.     

HER2基因突变晚期非小细胞肺癌治疗进展

肺癌是全球范围内一种高发病率和高死亡率的恶性肿瘤,非小细胞肺癌（NSCLC）是最常见的亚型,发生率约85%。人表皮生长因子受体2（HER2）是受体酪氨酸激酶（RTK）的重要成员之一,NSCLC中HER2基因主要表现为HER2突变、HER2扩增和HER2过表达三种形式。目前,靶向HER2突变的酪氨酸激酶抑制剂、单克隆抗体和抗体偶联药物在HER2突变的NSCLC中显示出一定的临床疗效,但相关免疫治疗疗效有限。本文就HER2突变相关NSCLC的治疗进展进行综述,以期为进一步完善HER2突变晚期NSCLC临床诊疗策略提供理论依据。     

Gefitinib in non-small cell lung cancer

Gefitinib (Iressa^TM), an orally-active tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), is the first approved molecular-targeted drug for the management of patients with advanced non-small cell lung cancer (NSCLC). Two Phase II trials (IDEAL [Iressa Dose Evaluation in Advanced Lung Cancer]-1 and -2), evaluated the efficacy of gefitinib in advanced NSCLC patients who received ≤ 2 (IDEAL1) or ≥ 2 (IDEAL2) previous chemotherapy regimens. The response rate and disease control rate in IDEAL1 and -2 was 18/12% and 54/42%, respectively. The median survival time and one-year survival rate in both studies were ~ 7 months and 30%, respectively. As gefitinib has demonstrated antitumour activity and an acceptable tolerability profile not typically associated with cytotoxic adverse events, such as hematological toxicities, combinations with cytotoxic drugs have been evaluated. Disappointingly, in chemotherapy-naive patients with advanced NSCLC, gefitinib 250 and 500 mg/day combined with platinum-based chemotherapy (gemcitabine/cisplatin or paclitaxel/carboplatin) did not produce prolonged survival, compared with chemotherapy alone in two large, randomised, placebo-controlled, multi-centre Phase III trials (INTACT [Iressa NSCLC Trial Assessing Combination Treatment]-1 and -2). Furthermore, in a recent randomised, placebo-controlled, Phase III trial (ISEL: IRESSA Survival Evaluation in Lung cancer), gefitinib failed to prolong survival compared with placebo in patients with advanced NSCLC who had failed one or more lines of chemotherapy. Subgroup analysis of ISEL suggested improved survival in patients of Asian origin and non-smokers. In addition, subset analyses of IDEAL and several retrospective studies have indicated that female gender, adenocarcinoma histology (especially bronchial alveolar carcinoma), non-smoker status and Asian ethnicity are factors which predict to response to gefitinib. Two types of somatic mutation clustered around the ATP binding pocket in the tyrosine kinase domain of the EGFR gene have been reported as possible surrogate biological markers for predicting response to gefitinib. Appropriate patient selection by clinical characteristics or genetical information is needed, both for future clinical trials of gefitinib and its routine use in the clinic among patients with advanced NSCLC.     

吉非替尼单药一线治疗晚期非小细胞肺癌临床研究

目的评价吉非替尼单药一线治疗在未经化疗的Ⅳ期非小细胞肺癌(NSCLC)患者中的有效性和耐受性。方法23例经组织学或细胞学确诊的未经化疗的Ⅳ期NSCLC患者,予以吉非替尼单药250mg/d口服,直到疾病进展或因严重不良反应不能耐受治疗。2月后评价疗效与不良反应,并随访1年生存率。结果客观有效率为26%,疾病控制率为61%;不良反应轻微,主要是皮疹、乏力、腹泻和肝功能异常。无间质性肺疾病(ILD)发生。1年生存率为58%。结论研究证实了吉非替尼单药一线治疗晚期NSCLC有效并具有良好的耐受性。