Role of bevacizumab for the treatment of non-small-cell lung cancer

Advanced-stage non-small-cell lung cancer (NSCLC) is a lethal disease that is treated with combination chemotherapy. Although modest survival benefit has been documented with various platinum-based, two-drug combination chemotherapy regimens, an efficacy plateau has been reached. Bevacizumab, a monoclonal antibody against the vascular endothelial growth factor, is the first molecularly targeted agent that has demonstrated survival advantage when combined with chemotherapy for the treatment of advanced nonsquamous NSCLC. Improvements in all efficacy parameters, including response rate, progression-free survival and overall survival, were noted for advanced nonsquamous NSCLC patients when bevacizumab was added to the combination of carboplatin-paclitaxel compared with the same chemotherapy regimen alone. This has opened the door for expanding the role of bevacizumab in earlier stages of the disease with chemotherapy or radiotherapy. The anti-angiogenesis agents, including the monoclonal antibody and vascular endothelial growth factor tyrosine kinase inhibitors, will be among the most important drugs of the present decade. This article discusses the recent data with bevacizumab in NSCLC and its potential application at various stages of NSCLC.     

Update on antiangiogenic treatment of advanced non-small cell lung cancer (NSCLC)

Bevacizumab is a monoclonal antibody that specifically inhibits vascular endothelial growth factor, and is the first antiangiogenic agent to be approved for first-line treatment of advanced non-small cell lung cancer (NSCLC). Evidence from two large phase III trials demonstrates that bevacizumab combined with chemotherapy improves outcomes for patients with non-squamous NSCLC. In patients with adenocarcinoma without epidermal growth factor receptor (EGFR) mutation, a median overall survival of 18.0 months is achieved. Several post-registration phase IV studies have confirmed bevacizumab’s efficacy and tolerability profile and have clarified the eligibility criteria. Clinical research is still ongoing to define the role of bevacizumab in different settings, such as single-agent bevacizumab for continuation maintenance therapy in advanced disease, treatment beyond disease progression, adjuvant therapy in early-stage NSCLC, or bevacizumab in combination with other targeted agents. A number of antiangiogenic tyrosine kinase inhibitors (TKI) have also been investigated in phase II and III trials. None of these drugs has proven significant clinical benefit in unselected patient populations. This article reviews the extensive information from randomized trials and large observational studies for bevacizumab in advanced NSCLC, and shortly describes the current clinical development of antiangiogenic monoclonal antibodies, TKIs and related compounds.     

Emerging Data with Antiangiogenic Therapies in Early and Advanced Non–Small-Cell Lung Cancer

Lung cancer is the leading cause of cancer-related mortality in the United States. Patients treated with adjuvant chemotherapy have a 5-year survival rate of 25% to 70% depending on stage, whereas those with advanced disease have a median survival of approximately 8 months when treated with standard platinum-based therapy. Improvements in our understanding of cancer biology have led to the development of novel agents that more precisely affect the target of interest, allowing for a more rational approach to clinical trial design. Angiogenesis, the growth of new vessels from preexisting vessels, is a fundamental step in tumor growth and progression. Inhibition of tumor-related angiogenesis has become an attractive target for anticancer therapy. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), is the most studied antiangiogenic agent in patients with Non—Small-cell lung cancer (NSCLC). There was an improvement in overall survival when bevacizumab was combined with paclitaxel and carboplatin in patients with advanced NSCLC that was not seen when bevacizumab was combined with cisplatin and gemcitabine. Studies with bevacizumab in the adjuvant and advanced setting are ongoing in patients with NSCLC. Small-molecule inhibitors targeting the VEGF receptor and the tyrosine kinase receptor have also shown promise when combined with standard chemotherapy, but their role in the treatment of patients with NSCLC remains to be determined. This article reviews clinical trials that have incorporated antiangiogenic agents in the treatment of patients with NSCLC.     

贝伐单抗治疗晚期非小细胞肺癌的疗效与安全性临床研究进展

抗血管生成治疗是肿瘤常见的治疗方式之一。贝伐单抗作为抗血管内皮生长因子的单克隆抗体,是目前唯一被批准用于晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）一线治疗的抗血管生成制剂。为了扩大贝伐单抗用于晚期NSCLC的适应证,大量研究继续探索贝伐单抗在一线治疗的联合形式外,还致力于探索其在后线及跨线治疗的疗效和安全性。本文就近年来贝伐单抗用于晚期NSCLC治疗的疗效与安全性临床研究进展进行综述。      

Targeted therapy in colorectal cancer

Adjuvant therapy can reduce the risk of disease recurrence in patients with stage II-IV colorectal cancer. Recently, 3 monoclonal antibodies have been shown to improve clinical outcome in this group of patients. Bevacizumab is an antiangiogenesis agent that has been shown in clinical and preclinical models to reverse the effects of proangiogenic molecules. Bevacizumab is active in the adjuvant setting and in the treatment of metastatic disease. Cetuximab is targeted to the epidermal growth factor receptor. Panitumumab is a fully human immunoglobulin G2 antibody that also binds to the epidermal growth factor receptor. Combination therapies of monoclonal therapies and chemotherapy have resulted in better clinical outcomes than with either modality alone.     

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.     

Advanced non-small cell lung cancer therapy: historical and future perspectives

Before the 1980s, radiotherapy was the principal treatment for advanced non-small cell lung cancer (NSCLC). Radiotherapy is primarily effective for local disease control and in early stage disease, or as palliative therapy in inoperable disease. Prior to 1990, only a few cytotoxic drugs had confirmed activity against NSCLC, but a series of trials had established platinum-based chemotherapy as the most effective treatment regimen. Since then, newer chemotherapeutic agents have been found to be effective, and superior to traditional platinum combinations. Recently, chemotherapy-based regimens appear to have reached a therapeutic plateau, and effective, better-tolerated treatments are needed. Improved understanding of the molecular biology and genetics of the tumor has led to the development of more selective, less toxic, targeted therapies. Vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor both play a key role in tumor growth and proliferation, and are logical targets for therapy. Bevacizumab, a monoclonal antibody against VEGF, has demonstrated significant improvements in survival and response rates when combined with chemotherapy (versus chemotherapy alone) as first-line therapy. In the second-line setting, the tyrosine kinase inhibitor erlotinib has demonstrated improved survival compared with placebo. This paper reviews the principal treatments used for NSCLC in the past two decades, provides an overview of current treatment options and considers future challenges. Prolongation of survival, reduced toxicity and improved quality of life are the main objectives. Key challenges for the future are patient-specific tailored therapy and expansion of the eligible patient population for novel therapies.     

From radiotherapy to Targeted therapy: 20 years in the management of non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Before 1980, radiotherapy was considered the only real recourse in advanced disease. In 1995, a landmark meta-analysis of trials conducted in the 1980s and early 1990s demonstrated a survival benefit with platinum-based chemotherapy. Newer chemotherapy agents and improved supportive care measures have allowed more patients to benefit from chemotherapy with reduced toxicity. Concurrent platinum-based chemotherapy and radiotherapy has improved the survival in stage III disease, and recently chemotherapy has also demonstrated improved survival in resected early-stage disease. The majority of patients still present with advanced unresectable disease for whom the prognosis remains poor, but for key subpopulations the outlook has improved markedly since the emergence of targeted therapies directed against the epidermal growth factor receptor and vascular endothelial growth factor receptor pathways. Patient selection and the incorporation of targeted therapies with cytotoxic chemotherapy are the focus of many ongoing studies, and there is an abundance of new agents undergoing clinical trials. Together, these developments have moved us away from the nihilism of 20 years ago into an era of unprecedented optimism in taking on the many remaining challenges of managing NSCLC in the 21st century.     

Docetaxel in the treatment of advanced non-small-cell lung cancer

Systemic chemotherapy provides improvement in both survival and quality of life for patients with advanced non-small-cell lung cancer (NSCLC). Docetaxel is the only agent currently approved for both first- and second-line treatment of advanced NSCLC. Multiple randomized clinical trials have established the efficacy of platinum-docetaxel regimens for the first-line treatment of advanced NSCLC. Carboplatin-based regimens and nonplatinum combinations with docetaxel also have proven efficacy in first-line therapy. Combinations of docetaxel with various novel targeted agents have produced encouraging data in Phase II trials. This review article summarizes recent studies of docetaxel as a single agent and in combination regimens with cytotoxic or targeted therapies in the management of patients with advanced NSCLC.     

Docetaxel in the treatment of advanced non-small-cell lung cancer

Systemic chemotherapy provides improvement in both survival and quality of life for patients with advanced non-small-cell lung cancer (NSCLC). Docetaxel is the only agent currently approved for both first- and second-line treatment of advanced NSCLC. Multiple randomized clinical trials have established the efficacy of platinum–docetaxel regimens for the first-line treatment of advanced NSCLC. Carboplatin-based regimens and nonplatinum combinations with docetaxel also have proven efficacy in first-line therapy. Combinations of docetaxel with various novel targeted agents have produced encouraging data in Phase II trials. This review article summarizes recent studies of docetaxel as a single agent and in combination regimens with cytotoxic or targeted therapies in the management of patients with advanced NSCLC.     

Optimizing chemotherapy for advanced non-small cell lung cancer: focus on docetaxel

Systemic chemotherapy with platinum-based combinations provides modest improvements in both survival and quality of life for patients with advanced non-small cell lung cancer (NSCLC). For first-line treatment of advanced NSCLC patients with a good performance status, the accepted standard of care is a platinum agent combined with docetaxel, paclitaxel, gemcitabine, vinorelbine or irinotecan. Several studies have attempted to identify an optimal platin-based regimen, however, all regimens offer some combination of clinical benefit with characteristic toxicities and no regimen appears clearly superior. Non-platinum regimens have also shown equivalent efficacy compared to platinum combinations, but again, none are clearly superior. Most recently, the existing standard of care is being amended to reflect the survival advantage gained from adding a new targeted agent, bevacizumab, to traditional platinum-doublet therapy for patients with non-squamous NSCLC. Docetaxel is the only agent currently approved for both first- and second-line treatment of advanced NSCLC. Multiple randomized clinical trials have established the efficacy of platin-docetaxel regimens for first-line treatment of advanced NSCLC. Improvements in various lung cancer related symptoms and global quality of life indices have also been noted with docetaxel-based regimens. Based on the efficacy of platin-docetaxel regimens in advanced disease, they are now being incorporated into the adjuvant and neoadjuvant treatment of early-stage disease.     

EGFR inhibitors with concurrent thoracic radiation therapy for locally advanced non-small cell lung cancer

Currently, a combination of chemotherapy and radiotherapy is the standard treatment approach for locally advanced non-small cell lung cancer (NSCLC). However, the clinical outcomes are still disappointing, with the 5-year survival rate being only approximately 20%. Further improvement in treatment outcome for patients with locally advanced NSCLC will require the development of more effective combined-modality therapies. Increasing attention has focused on the integration of targeted agents into current therapies. Many preclinical studies in this area have targeted the epidermal growth factor receptor (EGFR) signaling pathway to increase radiosensitivity. The in vitro rationale for targeting EGFR and concurrent ionizing radiation is well established, but to date, rare clinical data could provide proof-of-principle. In this review article, we briefly discuss pre-clinical data and the rationale and report all the different published clinical trials focusing on efficacy and toxicity in order to clarify and to summarize the present state-of-the-art of this particular combination in NSCLC.     

贝伐珠单抗在非小细胞肺癌中应用的研究现状

目前非小细胞肺癌化疗疗效已经达平台期,亟需寻找新的方法提高疗效。贝伐珠单抗是一种重组抗VEGF单克隆抗体,是首个证实与化疗联合可提高晚期NSCLC 患者生存的靶向治疗药物。近年来许多关于贝伐珠单抗在NSCLC 一线、二线、辅助、新辅助治疗、联合放化疗,安全性及预测标志物的临床研究,现将其研究现状做一综述。      

晚期非小细胞肺癌维持治疗的临床研究进展

 4～6个周期含铂类的一线化疗方案是晚期非小细胞肺癌目前的标准治疗,但对一线治疗后有效和稳定的患者,如何选择安全有效的药物来拓展一线治疗疗效及带来进一步的临床获益是目前值得关注的问题。文章就以化疗和分子靶向药物作维持治疗的临床进展作一介绍。     

宣白承气汤加味联合铂类化疗治疗中晚期非小细胞肺癌痰热蕴肺证的临床观察

目的观察宣白承气汤加味联合铂类化疗治疗中晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)痰热蕴肺证的疗效。方法收治中晚期NSCLC痰热蕴肺证患者40例,随机分为两组。治疗组20例给予宣白承气汤加味口服联合含铂类方案化疗,对照组20例给予单纯含铂类方案化疗。连续观察2个周期,比较治疗前、后两组瘤体大小及变化、临床主要症状评分、Karnofsky体力状况评分及毒副反应等情况。结果治疗组的临床疗效明显优于对照组,在瘤体大小及变化方面,治疗组的瘤体稳定率明显高于对照组(P<0.05),但两组有效率的差异无统计学意义(P>0.05);治疗组的临床症状改善情况、生活质量的提高及卡氏评分均显著高于对照组(P<0.05),治疗组毒副反应明显少于对照组(P<0.05)。结论宣白承气汤加味联合含铂类方案化疗治疗中晚期NSCLC痰热蕴肺证,可控制瘤体生长,改善患者临床症状,提高生活质量,减轻化疗毒副反应。中医"宣肺通腑,肺肠同治"法联合化疗治疗中晚期NSCLC痰热蕴肺证具有一定增效、减毒的作用。     

Place des thérapeutiques biologiques ciblées

Two targeted therapies are approved by the FDA-for the treatment of non-small cell lung cancer (NSCLC). Bévacizumab (Avastin®) is an anti-angiogenic drug; it is a monoclonal antibody directed against the vascular endothelial growth factor (VEGF). Combined with standard first-line chemotherapy in two phase III studies in advanced or metastatic, non squamous non-small cell lung cancers, it induced an improvement in response rates and progression-free survival compared to chemotherapy alone, and a significant advantage as regards survival in combination with a carboplatin paclitaxel-based chemotherapy. Toxic effects limit its use. Erlotinib (Tarceva®), the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, demonstrated a benefit in survival in a randomized phase III trial comparing Erlotinib to best supportive care in second or third line treatment after failure of a platinum-based chemotherapy in patients with advanced or metastatic NSCLC. Its toxicity profile is more favourable and its use needs to be better defined compared to the two other drugs approved as second line treatment for advanced or metastatic NSCLC.     

Gefitinib in the treatment of advanced non-small-cell lung cancer

Most patients with non-small-cell lung cancer (NSCLC) present with advanced disease and their long-term prognosis remains poor, even after platinum-based chemotherapy. EGF receptor (EGFR)-targeted therapies, such as gefitinib, have been subject to comprehensive clinical development. Several Phase II and III trials have evaluated the clinical efficacy of gefitinib as monotherapy in pretreated patients with advanced NSCLC, as well as both monotherapy and combined with chemotherapy in chemo-naive patients. A Phase III trial in heavily pretreated advanced NSCLC patients, 90% of whom were refractory, demonstrated some improvement in survival with gefitinib compared with placebo; however, the difference was not statistically significant in the overall population. A second large Phase III trial in patients with pretreated advanced NSCLC (INTEREST) demonstrated the noninferiority of gefitinib in comparison with docetaxel for overall survival together with an improved quality of life and tolerability profiles. As a result, gefitinib is expected to have a large impact in the management of pretreated patients with NSCLC.     

Advanced Non–Small-Cell Lung Cancer in the Elderly

Systemic chemotherapy provides improvement in both survival and quality of life for patients with advanced non–small-cell lung cancer (NSCLC). Elderly patients have more comorbidities and tend to tolerate more poorly aggressive chemotherapy and radiation therapy than younger individuals. Our purpose in this article is to summarize recent studies of single-agent chemotherapy and combination regimens with cytotoxic or targeted therapies in the management of elderly patients with advanced NSCLC. We have reviewed the available evidence in the literature to gauge the results of therapy for elderly patients with lung cancer. We found that single-agent chemotherapy remains the standard of care for nonselected elderly patients. Retrospective analyses suggest that the efficacy of platinum-based combination chemotherapy is similar in fit older and younger patients, with increased but acceptable toxicity for elderly patients. Therefore, the outcomes in the fit elderly mirror results observed in younger patients, although toxicity is generally greater.     

老年晚期非小细胞肺癌化疗进展

超过47%非小细胞肺癌(NSCLC)患者在诊断时年龄大于70岁,由于老年患者常常合并其他疾病,所以与年轻人相比对化疗耐受性差.尽管化疗在年轻群体中能够得到很多临床证据,但不能盲目的不经选择的应用于老年NSCLC中.目前有大量的关于老年非小细胞肺癌患者的化疗和靶向治疗的前瞻性研究数据.在老年非小细胞肺癌中,基于Ⅱ期和Ⅲ期临床试验,单药化疗主要为第三代化疗药物(长春瑞滨,吉西他滨,紫杉醇),认为是所有患者的常规治疗方案,Ⅱ期临床试验同时也显示出以铂类为基础联合方案的可行性和有效性.同样在相关的Ⅱ期临床中也显示了靶向治疗表皮生长因子酪氨酸激酶抑制剂(厄洛替尼和吉非替尼)及抗血管生成药物(贝伐单抗)作为老年患者一线治疗的可行性.本文对老年晚期非小细胞肺癌化疗新进展进行综述.     

挽救性化疗治疗化疗及表皮生长因子受体酪氨酸激酶抑制剂治疗失败的晚期非小细胞肺癌的疗效和安全性

目的 探讨一线含铂方案及表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗失败后的晚期非小细胞肺癌(NSCLC)患者接受挽救性化疗的疗效和安全性.方法 对55例一线含铂方案及后续EGFR-TKI治疗失败的晚期NSCLC患者行挽救性化疗,其中培美曲塞单药化疗24例,多西他塞单药化疗21例,其他方案化疗10例.至疾病进展或患者拒绝继续治疗.评价挽救性化疗的客观缓解率(ORR)、疾病控制率(DCR)及患者的无进展生存时间(PFS).结果 55例患者均可评价疗效,其中部分缓解(PR)7例(12.7%),稳定(SD)21例(38.2%),进展(PD)27例(49.1%),无完全缓解(CR)患者.ORR为12.7%,DCR为50.9%.全组患者的中位随访时间为5.5个月,中位PFS为2.0个月.不同性别、PS评分及化疗方案患者的近期疗效及PFS差异均无统计学意义(均P＞0.05).EGFR-TKI治疗时间≥6个月患者的ORR(21.1%)和DCR(73.7%)均明显高于EGFR-TKI治疗时间＜6个月的患者(ORR为8.3%,DCR为38.9%;均P＜0.05);EGFR-TKI治疗时间≥6个月患者与＜6个月患者的中位PFS分别为4.5月和2.0个月,差异亦有统计学意义(P=0.008).55例患者均可评价不良反应,主要表现为骨髓抑制,患者均能耐受.全组未发生治疗相关性死亡.结论 一线含铂方案及EGFR-TKI治疗失败后的晚期NSCLC患者能从挽救性化疗中获益,尤其是对EGFR-TKI治疗时间≥6个月的患者.晚期NSCLC患者对于挽救性化疗的耐受性良好.