The potential of antiangiogenic therapy in non-small cell lung cancer.

The long-term prognosis for patients with advanced non-small cell lung cancer (NSCLC) remains poor despite the availability of several cytotoxic chemotherapy regimens. The use of targeted therapies, particularly those against the key mediator of angiogenesis vascular endothelial growth factor (VEGF), has the potential to improve outcomes for NSCLC patients. Bevacizumab, a recombinant humanized monoclonal anti-VEGF antibody, is the most clinically advanced antiangiogenic agent in NSCLC. In a phase III study, bevacizumab showed significantly improved overall and progression-free survival when used in combination with standard first-line chemotherapy in patients with advanced NSCLC. Bevacizumab was generally well tolerated in patients with NSCLC; however, tumor-related bleeding adverse events have been noted in some patients, predominantly those with squamous cell histology or centrally located tumors. Several small-molecule VEGF receptor tyrosine kinase inhibitors have also shown promise in phase I and II trials in NSCLC. This review summarizes the most important findings of angiogenesis inhibitors in NSCLC and discusses the potential for the use of these novel agents in different settings of NSCLC.     

生物标志物指导下的非小细胞肺癌靶向治疗

 肺癌是最常见的恶性肿瘤之一。分子靶向治疗在21世纪非小细胞肺癌治疗中具有里程碑的意义。基于分子标志检测的靶向治疗更是为肺癌个体化治疗提供了坚实的基础。主要就EGFR突变检测在非小细胞肺癌个体化表皮生长因子受体酪氨酸激酶抑制（EGFR-TKI）一线、二线及维持治疗中的指导意义进行综述。同时介绍EGFR FISH检测在EGFR TKI治疗研究的现状、抗肿瘤血管药物潜在的分子预测标志以及抗EGFR单克隆抗体的个体化治疗现状。     

非小细胞肺癌抗血管生成治疗的预测及预后指标

目前,非小细胞肺癌（non-small-cell lung cancer,NSCLC）已成为癌症相关死亡的首要原因。血管生成（angiogenesis）,即新生血管形成,是一个严格而复杂的调控过程,可促进肺癌及其它恶性肿瘤疾病进展和远处转移。抗血管生成治疗（anti-an? giogenic therapy）是以新生血管为靶点的抗肿瘤方法。目前临床上常用的细胞毒药物作用于所有快速分裂的细胞,可导致严重治疗副作用如免疫抑制、胃肠道反应和脱发等。而除子宫内膜外新生血管形成很少发生于健康成年人,因此相对而言,抗血管生成治疗理论上副作用较少,在临床上应用具有良好的前景。由于不同个体发生的肿瘤其血管生成可能是由不同的血管生成因子调控,因此,在抗血管生成药物越来越多的今天,正确地选择患者个体,选择有针对性的治疗非常重要。本文回顾了非小细胞肺癌抗血管生成药物的预测及预后指标的临床研究及相关指标基本原理的临床前研究。      

晚期非小细胞肺癌疗效监测的研究进展

晚期非小细胞肺癌（NSCLC）具有高度异质性,其临床治疗强调个体化和综合性。随着肺癌分子机制的深入研究和不断阐明,以及分子靶向、单克隆抗体、免疫制剂和抗血管生成等多种新型药物的临床应用,晚期NSCLC患者疗效评价已不再局限于基于瘤体大小变化的实体瘤疗效评价标准,基于蛋白质和核酸水平的分子影像学、分子病理学和液体活检将是晚期NSCLC患者疗效监测新的发展方向。     

Gefitinib therapy for non-small cell lung cancer

Opinion statement Gefitinib is a small molecule that specifically inhibits the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) type 1 by interfering with the adenosine triphosphate (ATP) binding site. At doses that maximally inhibit EGFR tyrosine kinase activity chosen for phase II trials, the most common side effects of gefitinib are low-grade rash or diarrhea. An infrequent but serious side effect of gefitinib is interstitial lung disease (ILD). The Iressa dose evaluation for advanced lung cancer phase II trials (IDEAL 1 and IDEAL 2) of single agent gefitinib, 250 or 500 mg orally per day in pretreated patients with non-small cell lung cancer (NSCLC), found about 20% of patients on IDEAL-1 and 10% of patients on IDEAL-2 had major objective responses and improvement of symptoms. The data from the IDEAL trials and the extensive experience from the 21,000 patients treated on the expanded access program, suggests that the patients who have a major objective response probably have a significant survival benefit in addition to palliative benefit. In addition, approximately 40% of patients on the IDEAL trials experienced improvement in symptoms. Gefitinib was approved for third line treatment of NSCLC. Gefitinib is effective, safe, and well-tolerated single-agent therapy in previously treated NSCLC. Although there have been no direct comparisons, the small molecule inhibitors of EGFR gefitinib and erlotinib appear to have similar efficacy. Erlotinib has been shown to produce a survival advantage compared to best supportive care in an unselected group of previously treated patients with NSCLC. Until similar trials are completed comparing gefitinib to best supportive care, there is a similar survival advantage for gefitinib. Nonsmokers, women, and patients with adenocarcinoma, are more likely to have major objective responses than other patients. Bronchioalveolar lung cancer is a subtype of NSCLC that is more likely to respond to gefitinib. Several groups have now reported that most, but not all, tumors experiencing a major objective response to gefitinib have mutations associated with the ATP-binding site of EGFR. It is reasonable to move gefitinib in to second-line therapy for patients who are known to have a tumor that is more likely to respond to gefitinib. Also, I would treat such patients with gefitinib as first-line therapy on an appropriate clinical trial approved by the Institutional Review Board (IRB). Outside of a clinical trial, patients with advanced disease should initially be treated with a combination of doublet chemotherapy. There is strong evidence that there is no benefit to concurrent chemotherapy and gefitinib. Gefitinib should not be given concurrently with cytotoxic chemotherapy as initial treatment for NSCLC. Sequential therapy combining chemotherapy and gefitinib in advanced disease or as adjuvant therapy should only be done in the context of a clinical trial approved by the IRB. There is preclinical evidence suggesting that gefitinib is a radiosensitizer. Early results from trials combining radiation, or chemoradiotherapy with gefitinib have shown that these combinations are without excessive additive toxicity. There is no proven clinical benefit for concurrent Gefitinib and radiation. Gefitinib should only be given with radiation as part of an appropriate clinical trial approved by the IRB.     

非小细胞肺癌生物标志物新热点

 生物标志物是近年肺癌研究的热点之一,可为非小细胞肺癌（NSCLC）患者的个体化治疗提供可靠的依据。随着分子生物学研究的深入,其在临床上已显示出广阔的应用前景。文章结合近年来的研究对NSCLC生物标志物的新热点进行阐述。     

Targeted therapy in non-small cell lung cancer

Cytotoxic chemotherapy for advanced non-small cell lung cancer (NSCLC) offers only modest benefits over best supportive care alone by modestly prolonging survival, reducing symptoms, and improving quality of life. Despite the introduction of a number of new agents over the past decade, we have seen no convincing improvements in efficacy and safety with platinum-based regimens. It appears that a plateau has been reached in the development of traditional cytotoxic chemotherapy and a new paradigm is needed. Novel treatment modalities have emerged from advances in the understanding of tumor cell biology. These sophisticated new agents home in on and neutralize specific targets in the biologic pathway of cancer. This "targeted therapy" represents a new generation of anticancer treatment and a chance to revitalize the moribund state of NSCLC treatment.     

Targeted therapy in non-small cell lung cancer

Recent progress in molecular biology has enabled us to better understand the molecular mechanism underlying pathogenesis of human malignancy including lung cancer. Sequencing of human genome has identified many oncogenes and tumor suppressor genes, giving us a better understanding of the molecular events leading to the formation, progression, metastasis, and the development of drug resistance in human     

Adjuvant therapy for resected non-small cell lung cancer

Surgery remains the initial treatment for patients with early-stage non-small cell lung cancer (NSCLC). The frequent occurrence of distant metastases and local regional failure after surgical resection would indicate that additional treatment is necessary. Early trials of adjuvant chemotherapy and postoperative radiation were often plagued by small patient sample size, inadequate surgical staging, and ineffective or antiquated treatment. A 1995 meta-analysis found a nonsignificant reduction in risk of death for postoperative cisplatin-based chemotherapy. This was followed by a new generation of randomized phase III trials some of which have reported a benefit for chemotherapy in the adjuvant setting. Based on the results of these trials, platin-based chemotherapy has become the standard of care for resected stages II and IIIA NSCLC. The role of postoperative radiation therapy remains to be defined. In the future, improvement in survival outcomes from adjuvant treatment is likely to result from the evaluation of novel agents, identification of tumor markers predictive of disease relapse, and definition of factors that determine sensitivity to therapeutic agents. Some of the molecularly targeted agents such as the angiogenesis and epidermal growth factor receptor inhibitors are being incorporated into clinical trials. Gene expression profiles and proteomics are techniques being used to create prediction models to identify patients at risk for disease relapse. Molecular markers such as ERCC1 may determine response to treatment. Increasing the understanding of the molecular makeup of lung cancer will hopefully increase cure rates for patients by maximizing the efficacy of the adjuvant therapy.     

Induction therapy for non-small cell lung cancer]

Induction therapy for non-small cell lung cancer was reviewed. Surgical therapy remains the treatment of choice for resectable non-small cell lung cancer. However, postoperative survival of the patients with locally advanced NSCLC is far from acceptable. Several phase II and phase III trials have been attempted to define whether surgical resection after induction therapy provides better local control and survival than surgery alone. Most studies have reported high response and resectability rates, and long-term follow up of two randomized trials shows that patients having cisplatin-based induction chemotherapy prior to surgical resection were significantly more likely to have better 5-year survival than patients operated without preoperative treatment. However, the results of the randomized trials are still controversial owing to the relatively small and inhomogeneous population used. To identify the future direction of effort in improving the therapy of NSCLC, more sophisticated randomized prospective trials should be conducted.     

非小细胞肺癌的分子靶向药物治疗

肺癌是一种高发病率的肿瘤。目前已知表皮生长因子受体（EGFR）、血管内皮生长因子（VEGF）在非小细胞肺癌中有过表达，这种存在于肿瘤组织的过表达通过下游的信号传导能导致肿瘤细胞的增生、血管的生长，凋亡受抑制。表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI）通过抑制酪氨酸激酶，抗EGFR单克隆抗体通过和EGFR自身配体竞争受体及抗VEGF单克隆抗体通过和其形成复合物而阻断其信号通路的传导来达到控制肿瘤增生和发展的目的，仅有少许可耐受的不良反应。TKI对东方人NSCLC疗效，腺癌、不吸烟和女性的疗效好可能和其EGFR基因的高突变率相关。但其和化疗合用未显示增加化疗的效果。抗EGFR及VEGF单克隆抗体与化疗合用均显示了一定的效果。就非小细胞肺癌来说，靶向治疗已成为了另一种有效的全身治疗。     

Impact of biomarkers on non-small cell lung cancer treatment

Chemotherapy represents the mainstay of non-small cell lung cancer (NSCLC) treatment, but response is usually observed in only one out of three patients. Massive efforts have been carried out to identify biomarkers that might help clinicians to choose appropriate drugs, by identifying potentially sensitive subjects and spare toxicities in patients who are unlikely to benefit from treatment. Low excision repair cross-complementation group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) levels have been associated with increased sensitivity to cisplatin and gemcitabine, respectively, while reduced class III β-tubulin expression has been associated with taxane activity. Initial prospective studies showed the feasibility of a customized approach based on biomarker assessment, and phase III trials will hopefully provide further validation of this approach. The impact of biomarkers for patient selection has now been well established for tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), with EGFR mutations emerging as the most reliable predictor for improved outcome. Relevant clinical issues are represented by the identification of patients who can be reasonably excluded from treatment and by the development of therapeutic approaches able to overcome acquired resistance to anti-EGFR strategies.     

Role of imaging biomarkers in mutation-driven non-small cell lung cancer

Lung cancer remains the leading cause of cancer-related deaths worldwide. The treatment of non-small cell lung cancer (NSCLC), which accounts for a vast majority of lung cancers, has shifted to personalized, targeted therapy following discoveries of several targetable oncogenic mutations. Targeting of specific mutations has improved outcomes in many patients. This success has led to several target-specific agents replacing chemotherapy as first-line treatment in certain mutated NSCLC. Several researchers have reported that there may be imaging biomarkers that may be predictive of the presence of these mutations. These features, when present, have the potential in triaging patients into the most appropriate diagnostic and treatment algorithms. Distinct imaging features and patterns of metastases that have been associated with NSCLC with various targetable oncogenic mutations are presented in this review.     

Clinical trials of antiangiogenic therapy in non-small cell lung cancer: focus on bevacizumab and ZD6474

Lung cancer is the leading cause of cancer deaths in the USA. Despite the development of new chemotherapy regimens, the prognosis remains poor. Several studies comparing various platinum-based regimens failed to produce a significant impact in the outcomes for patients with non-small cell lung cancer and this therapeutic modality appears to be reaching a plateau. It has become clear that further advances will require the addition of agents with a different mechanism of action. Bevacizumab is the antiangiogenic agent at the most advanced stage of development in the treatment of cancer. Bevacizumab is synergistic with chemotherapy and usually well tolerated. The addition of bevacizumab to chemotherapy improved survival in patients with metastatic non-small cell lung cancer in a randomized clinical trial. Several small molecule antiangiogenic agents are in development. In this article, currently available data from clinical trials of antiangiogenic compounds in advanced non-small cell lung cancer are reviewed.     

Clinical trials of antiangiogenic therapy in non-small cell lung cancer: focus on bevacizumab and ZD6474

Lung cancer is the leading cause of cancer deaths in the USA. Despite the development of new chemotherapy regimens, the prognosis remains poor. Several studies comparing various platinum-based regimens failed to produce a significant impact in the outcomes for patients with non-small cell lung cancer and this therapeutic modality appears to be reaching a plateau. It has become clear that further advances will require the addition of agents with a different mechanism of action. Bevacizumab is the antiangiogenic agent at the most advanced stage of development in the treatment of cancer. Bevacizumab is synergistic with chemotherapy and usually well tolerated. The addition of bevacizumab to chemotherapy improved survival in patients with metastatic non-small cell lung cancer in a randomized clinical trial. Several small molecule antiangiogenic agents are in development. In this article, currently available data from clinical trials of antiangiogenic compounds in advanced non-small cell lung cancer are reviewed.     

非小细胞肺癌个体化治疗：分子标志的现状和未来

尽管非小细胞肺癌（ＮＳＣＬＣ）的治疗已有较大的进展,但总体而言肺癌患者的预后仍然较差。个体化治疗能选择最有效的治疗策略使疗效最大化,最大程度降低毒性。对生物因子能否指导治疗决策的预测是个体化治疗的关键,最终将改善患者预后。基因组学和蛋白质组学研究针对ＮＳＣＬＣ患者的肿瘤组织进行分子检测,为每一个患者提供最有效的治疗。尽管在临床实践中,应用基因组学和蛋白质组学检测技术仍有很大的困难,但新技术的快速发展能克服这些障碍。     

进展期非小细胞肺癌的维持治疗

4～6周期联合化疗达到"化疗疗效平台"后,进一步维持治疗能否改善进展期非小细胞肺癌患者的生存,是目前临床关注的热点.随着一些具有良好耐受性的化疗药物和分子靶向药物的介入,一些临床研究已经证实,在疾病控制的患者,维持治疗能带来进一步的临床获益,主要表现为无进展生存期的延长,并有改善总生存的趋势.     

非小细胞肺癌靶向治疗药物的研究进展

以吉非替尼（gefitinib）和埃罗替尼（erlotinib）为代表的小分子表皮生长因子受体酪氨酸激酶抑制剂治疗非小细胞肺癌是近年研究的热点,部分患者对药物反应良好,但几项大规模临床研究并没有得出这类药物可延长生存期的结论。研究表明,西妥昔单抗（cetuximab）和贝伐单抗（bevacizumab）等单克隆抗体可能提高患者的治疗反应率,延长生存期。不同人种、不同发病机制肿瘤的药物作用靶点不同,因此应根据临床状态、病理分型等影响因素指导患者接受个体化靶向药物治疗。