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.     

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.     

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.     

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.     

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     

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.     

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.     

晚期非小细胞肺癌维持治疗的研究进展

目的:总结维持治疗在晚期非小细胞肺癌中的研究进展,探讨维持治疗的意义。方法:应用PubMed和CNKI期刊全文数据库检索系统,以"NSCLC maintenancetherapy及非小细胞肺癌,维持治疗"为关键词,共检索到2001-2011年相关文献284篇,纳入分析25篇。结果:维持治疗是近年来为延长晚期NSCLC患者生存期并提高其生存质量而出现的新的治疗观点,目前已有多项临床试验证实标准一线化疗结束使疾病获得控制后,继续给予维持治疗可以显著延长患者的无疾病进展生存期(progression-free survival,PFS),部分药物可以显著延长总生存(overall survival,OS),患者耐受良好。结论:维持治疗可以使晚期NSCLC患者获益,但是其最终疗效和患者的病理类型、EGFR突变状况、体力状况和对药物的耐受情况密切相关,结合患者的实际情况,进行个体化治疗,是NSCLC患者未来治疗的方向。     

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。     

Considerations for second-line therapy of non-small cell lung cancer

For patients with advanced non-small cell lung cancer and a good functional status, platinum-based first-line chemotherapy improves quality of life, reduces disease-related symptoms, and improves survival. The addition of bevacizumab to carboplatin and paclitaxel in the first-line setting has been shown to produce a higher response rate and longer progression-free survival and overall survival times than with carboplatin and paclitaxel. Despite these therapies, all patients inevitably experience disease progression. There are currently three agents approved for treating patients who progress after one prior regimen: docetaxel, pemetrexed, and erlotinib. Erlotinib is also indicated for patients who progress after two prior regimens. These agents appear to have similar efficacies in terms of response and overall survival, but have significantly different toxicity profiles. Currently, the choice of agent depends on a number of factors, including the patient's comorbidities, toxicity from previous treatments, the risk for neutropenia, smoking history, and patient preference. A better understanding of prognostic factors in the second-line setting may allow clinicians to better select patients for second-line therapy, and lead to better-designed second-line trials. Patients with a good performance status in second-line trials have a median survival duration of approximately 9 months, and may receive two second-line therapies during the course of their treatment. Several new agents have shown activity in phase II trials, and may be integrated into second-line therapy as single agents or in combination with current agents in the future.     

Adjuvant therapy in resectable non-small cell lung cancer

In order to improve the management of lung cancer at various stages, we analyzed results of treatment in 928 of 1024 patients who were registered at our Hospital Tumor Registry of 1952-1983 with a pathological diagnosis of TNM for carcinoma of the lung after pulmonary resection. The 5-year-survival rate was 43% in 928 patients excluded the cases who were lost follow-up or succumbed within post-operative 1 month. The 5-year-survival rate was 77% for the stage I, 54.7% for the stage II, 17% for the stage III and 4% for the stage IV. The 5-year-survival rate by therapeutic modality was as follows: 52% for the group with chemotherapy, 35% for the one without adjuvant therapies, 29% for the one with irradiation and 15% for the one with radiochemotherapy. Patients with adenocarcinoma who underwent curative surgery showed improvement of survival by postoperative chemotherapy. No increase in survival time was noticed in the irradiated group with N2.     

吉非替尼靶向治疗非小细胞肺癌

吉非替尼(gefitinib)是用于靶向治疗非小细胞肺癌(NSCLC)的二线或三线药物,是表皮生长因子受体(EGFR)酪氨酸激酶(PTK)抑制剂,能选择性阻断EGFR的PTK,有效地"切断"EGFR向细胞内发出信号.gefitinib具有减慢和降低癌细胞增殖的作用,虽不能完全治愈NSCLC,但可以长期使用,能有效延缓病情恶化,减少并发症,改善患者的生活质量,延长患者生存期,为NSCLC患者提供了一种重要的新型治疗方法.现综述gefitinib的作用机制及其临床应用.     

Remediastinoscopy after neoadjuvant therapy for non-small cell lung cancer

Despite technical difficulties due to mediastinal fibrosis, remediastinoscopy can be a valuable tool in the restaging of non-small cell lung cancer after neoadjuvant therapy. The aim of our study was to evaluate the feasibility, sensitivity and accuracy of remediastinoscopy. From November 1994 to July 2001 we performed a remediastinoscopy in 27 patients after neoadjuvant therapy. Their age ranged from 35 to 80 years (mean 61.9+/-11.9). In all 27 patients it was possible to perform a remediastinoscopy without major technical difficulties and take biopsies of the lymph nodes that were initially invaded by tumour. Remediastinoscopy was positive in 11 patients (40.7%) and negative in 16 (59.3%). In the 11 patients with a positive remediastinoscopy a complete resection was not judged possible and therefore, an unnecessary thoracotomy was avoided. In four patients, remediastinoscopy turned out to be false negative. So, in our series, sensitivity was 73%, specificity 100% and accuracy 85%. The positive and negative predictive values were 100 and 75%, respectively. Previous mediastinoscopy is no contra-indication for a repeat one after neoadjuvant therapy. Although sensitivity and accuracy are lower than that of a first mediastinoscopy, remediastinoscopy is useful to select patients for surgical resection after induction therapy.