Treating advanced non-small cell lung cancer in the elderly

More than 40% of cases of all lung cancers are diagnosed in patients over the age of 70?years. Elderly patients have more comorbidities and tend to be less tolerant to toxic medical treatments than their younger counterparts. Thus, clinical data obtained in a younger population cannot be automatically extrapolated to the great majority of nonselected elderly patients with non-small cell lung cancer (NSCLC). The bulk of prospective clinical data regarding chemotherapy and molecularly targeted therapy for elderly NSCLC patients come from studies in advanced disease. In elderly advanced NSCLC patients, single-agent chemotherapy with third-generation agents (vinorelbine, gemcitabine, taxanes) is to be considered the routine standard of care for unselected patients, based on phase II and III trials specifically designed for this special population. Cisplatin-based chemotherapy with cisplatin at attenuated doses has been demonstrated to be an active and feasible option in phase II trials. Among targeted therapies, the epidermal growth factor receptor tyrosine kinase inhibitors, erlotinib and gefitinib, have relevant phase II prospective data showing activity and good tolerability as first-line treatment in this population. Concerning the antivascular endothelial growth factor monoclonal antibody, bevacizumab, combined with chemotherapy, particular care must be taken for elderly patients because of the higher incidence of cardiovascular comorbidities. The lack of data on octogenarians suggest that clinicians should exercise caution when applying the existing data on chemotherapy and targeted therapies for patients aged 70-79 years to those aged >80 years. Further specifically designed clinical trials are needed to optimize medical treatment of NSCLC in elderly patients.     

Potential role of molecularly targeted therapy in the management of advanced nonsmall cell lung carcinoma in the elderly

BACKGROUND: More than 50% of all lung carcinoma cases are diagnosed in patients age > 65 years, and approximately 30% are diagnosed in patients age > 70 years. Elderly patients do not tolerate chemotherapy as well as their younger counterparts do, primarily because of the increased prevalence of comorbid conditions and organ failure. Thus, at present, the majority of elderly patients with malignant disease do not receive aggressive chemotherapy. For such elderly patients, alternatives to conventional chemotherapy, such as novel molecularly targeted therapy regimens, are of interest. METHODS: The current review summarizes contemporary approaches to and recent advances in the treatment of elderly patients with nonsmall cell lung carcinoma (NSCLC) and offers perspectives on the future of molecularly targeted therapy in this population. Inhibitors of epidermal growth factor receptor, vascular endothelial growth factor, and cyclooxygenase-2 are discussed in the current report, with such inhibitors being, in our opinion, among the best candidates for clinical development in the setting of interest. RESULTS: Novel biologic agents with putative activity against advanced NSCLC are at various stages of clinical development. Some of these agents have yielded benefits in terms of disease-related symptom reduction, quality of life, and survival. For elderly patients, the potential advantages of such agents include improved tolerability compared with conventional chemotherapy. This feature also makes these novel agents attractive alternatives for younger patients who cannot tolerate or are reluctant to receive conventional chemotherapy. CONCLUSIONS: Current studies are investigating the safety and efficacy of these novel biologic agents administered alone, in combination with other noncytotoxic agents, and in combination with conventional chemotherapy. These studies will help elucidate the role of targeted therapy in the management of elderly patients with advanced NSCLC.     

老年晚期非小细胞肺癌的靶向治疗

老年肺癌发病及死亡呈上升趋势,但老年患者整体接受积极治疗的人数却明显少于非老年患者。随着分子靶向治疗药物,如人表皮生长因子受体酪氨酸激酶抑制剂、新生血管抑制剂、抗肿瘤单克隆抗体及多靶点药物的出现,老年晚期非小细胞肺癌患者的总生存时间得到显著延长,生活质量得到明显改善。靶向治疗已成为最有希望且能显著改善老年患者预后的治疗方法。     

Combination epidermal growth factor receptor inhibition and radical radiotherapy for NSCLC

Non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related death in the developed world. Despite advances in therapy with conventional modalities, over 85% of patients will die from their disease within 5 years of diagnosis. For patients with inoperable lung cancer, the addition of chemotherapy to radical radiotherapy yields a small but significant 10% survival benefit at 3 years. However, the systemic toxicity of chemotherapy is common and may be severe. Over the past 20 years, dramatic improvements in our understanding of the molecular etiology of cancer have enabled the development of novel targeted therapies. Overexpression of the epidermal growth factor receptor (EGFR) in lung cancer correlates with an aggressive disease course and poor tumor response to radiotherapy. Strategies to inhibit this molecular switch have become a focus for drug development. Preclinical efficacy has been repeatedly demonstrated with anti-EGFR monoclonal antibodies and small molecule tyrosine kinase inhibitors, and responses have been documented in the clinic with acceptable toxicity. Phase III trials combining EGFR tyrosine kinase inhibitors with radical chemoradiation are recruiting at present. This review addresses the current challenges of discovering how best to use these new anticancer therapies, with particular emphasis on the enhancement of existing therapeutic strategies such as radical radiotherapy, factors relating to patient selection and prediction of clinical response.     

Combination epidermal growth factor receptor inhibition and radical radiotherapy for NSCLC

Non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related death in the developed world. Despite advances in therapy with conventional modalities, over 85% of patients will die from their disease within 5 years of diagnosis. For patients with inoperable lung cancer, the addition of chemotherapy to radical radiotherapy yields a small but significant 10% survival benefit at 3 years. However, the systemic toxicity of chemotherapy is common and may be severe. Over the past 20 years, dramatic improvements in our understanding of the molecular etiology of cancer have enabled the development of novel targeted therapies. Overexpression of the epidermal growth factor receptor (EGFR) in lung cancer correlates with an aggressive disease course and poor tumor response to radiotherapy. Strategies to inhibit this molecular switch have become a focus for drug development. Preclinical efficacy has been repeatedly demonstrated with anti-EGFR monoclonal antibodies and small molecule tyrosine kinase inhibitors, and responses have been documented in the clinic with acceptable toxicity. Phase III trials combining EGFR tyrosine kinase inhibitors with radical chemoradiation are recruiting at present. This review addresses the current challenges of discovering how best to use these new anticancer therapies, with particular emphasis on the enhancement of existing therapeutic strategies such as radical radiotherapy, factors relating to patient selection and prediction of clinical response.     

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.     

Current management of advanced non-small cell lung cancer: targeted therapy

Lung cancer is one of the most frequent causes of cancer-related death in the United States. For patients with advanced non-small cell lung cancer (NSCLC), chemotherapy, alone or in combination with radiation therapy, is considered the standard treatment. Although this treatment may result in a modest improvement in patient survival, overall prognosis of these patients remains dismal, and the treatment is nonspecific, nonselective, and toxic. Therefore, new therapeutic strategies are needed. During the past decade, several molecules that contribute to lung cancer progression and metastasis have been identified. Growth factors and proangiogenic factors have been the focus of intense research in cancer since therapeutic approaches for their inhibition do exist. The role of these factors was studied in different organs and tumors and was found to be phenotypically distinct. Several molecular targeted therapies have shown efficacy and had been approved for treatment of specific cancers. Most advanced in clinical research for lung cancer are targeted therapies that inhibit the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) signaling pathways. Others are signaling pathway inhibitors. The first targeted therapy for lung cancer is gefitinib, an EGFR inhibitor, which was approved in several countries in 2003. Goals of molecular targeted therapy studies include the following: better understanding of the exact role of particular growth factors in specific tumors; establishment of new clinical study designs for biological agents; and tailoring appropriate combinations of conventional chemotherapy and/or radiotherapy with biological therapy for specific patients. Achievement of these goals will hopefully lead to incorporation of biological therapy into the current anticancer arsenal, for the benefit of lung cancer patients.     

晚期肺鳞癌的治疗

肺癌是全世界肿瘤死亡的首要原因,肺鳞癌（squamous cell lung cancer, SQCLC）作为肺癌的一种常见的病理类型,全世界每年约40余万人因其致死。其常规治疗方法主要包括手术治疗、化学治疗和分子靶向治疗。但是大多数患者确诊的时候已经是晚期,失去了手术的机会。尽管分子靶向治疗在肺腺癌的治疗中具有里程碑式的作用,但是对肺鳞癌而言,尚无特异性的分子靶标药物,因此,对于晚期肺鳞癌的标准治疗仍是含铂双药方案。而大多数患者经历了一线、二线治疗失败后都面临无药可用的状态。本文旨在对晚期肺鳞癌的常规治疗进行系统性的综述,探讨晚期肺鳞癌的治疗方案以及发展方向。     

Agents in the preclinical development stage for non-small cell lung cancer

Despite recent advancements in identifying distinct molecular subtypes with driver oncogenes and advances in developing targeted treatments such as epidermal growth factor receptor and anaplastic lymphoma kinase inhibitors, current therapeutic approaches for tumors with no driver mutation have achieved a plateau of effectiveness. Thus, the overall outlook of lung cancer survival for most patients remains dismal. Moreover, the inevitable acquisition of resistance to targeted therapies has prompted significant efforts to develop second-generation inhibitors. In recent years, several agents for targeted therapy of lung cancers are rapidly migrating from bench to bedside and multiple small molecule inhibitors with activity against distinct receptors, genes or molecular pathways have been developed.     

Recent advances in targeted advanced lung cancer therapy in the elderly

Introduction: With increasing life expectancy over the last several decades, the incidence of lung cancer is increasing in the elderly population too. In clinical practice about 50% of lung cancers were diagnosed in patients older than 65 years and about 30–40% of lung cancer patients are 70 years old or more. Treatment of elderly patients with non-small-cell lung cancer (NSCLC) represents a challenge in clinical practice, because these patients are not eligible for aggressive therapies for the age-related reduction of functional reserve of many organs and comorbidities.

Areas covered: The activity and safety of small molecules for the treatment of NSCLC harbouring EGFR mutations or ALK rearrangement are reviewed and discussed here, using evidence from clinical trials.

Expert commentary: Age alone should not dictate treatment-related decisions for elderly patients with advanced NSCLC. Some evidence has shown that the only relevant factor for survival outcome in the elderly is performance status and organ functions both with chemotherapy and targeted therapy too. Considering the toxicity profile of tyrosine kinase inhibitors, these small molecules are particularly attractive to treat elderly patients, who could experience potentially more toxicity from chemotherapy. Studies specifically addressed to evaluate the activity of targeted therapy are still more limited.     

New Treatment Options for Lung Adenocarcinoma - in View of Molecular Background

Lung cancer is the leading cause of cancer related mortality all over the world, and a number of developments have indicated future clinical benefit recently. The development of molecular pathology methods has become increasingly important in the prediction of chemotherapy sensitivity and mutation analysis to identify driver mutations as important targets of new therapeutic agents. The most significant changes in the treatment of NSCLC revealed in new pathologic classification and in the introduction of molecularly targeted therapies, which include monoclonal antibodies and small molecule tyrosine kinase inhibitors. The side effects of these agents are generally better tolerated than those of conventional chemotherapy and show higher efficacy. The most important factor follows: histology subtypes, gene mutation status, patients’ selection, drug toxicities and occurence of drug resistance. In the advanced disease, the hope of cure is less than 3 %, but improvements in survival have been clearly achieved. Some years ago the median lung cancer survival rate was 10–12 months, now in case of available specific molecular targets, a significant increase in median survival rates to 24–36 months has been achieved. These agents give an opportunity to provide a new standard of care. Therefore testing EGFR mutations and ALK rearrangements in patients with advanced lung adenocarcinoma should be incorporated into routine clinical practice. This review focuses on the rationale for targeted agents and new treatment possibilities in case of advanced lung adenocarcinoma.     

The role of biologics in stomach cancer

The role for systemic treatment in gastric cancer has become more evident over the past years. Perioperative chemotherapy increases the cure rates in localized stages. At the same time, palliative chemotherapy has shown to prolong survival and maintain the patients’ quality of life in advanced disease. Our comprehension of prognostic and predictive molecular factors in stomach cancer is growing continuously. In parallel, we are making progress in understanding potential targets and pathways for designing molecular therapies against gastric cancer. First promising results have been reported from phase I and phase II studies investigating biologically targeted therapies in advanced gastric cancer. Currently, large randomized trials investigating inhibitors directed against the epidermal growth factor (EGFR) receptor and Her2-neu, against the epithelial cell adhesion molecule (EpCAM) and against vascular endothelial growth factor (VEGF) are being carried out. However, results from these comparative large scale studies are needed before biologically targeted drugs can be used in the clinical routine.     

Angiogenesis inhibitors in lung cancer

Lung cancer is a major public health problem and the leading cause of cancer-related death worldwide. Its survival rates have changed little over the past 20 years. The best clinical benefit (ie, survival rates) with combination cytotoxic therapies in non-small-cell lung cancer (NSCLC) may have been reached. The need for improved survival rates in NSCLC has driven the development of novel, rationally designed, targeted therapies. Inhibitors of angiogenesis have been developed and are increasingly studied. Potential targets for therapy include inhibitors of vascular endothelial growth factor receptor, endogenous angiogenesis inhibitors, and cyclooxygenase inhibitors. Combining targeted molecules with traditional cytotoxic therapies usually results in lower required chemotherapy doses and fewer, less severe side effects. A number of ongoing randomized studies are underway to evaluate this idea. It is anticipated that these new targeted therapies will play an important role, along with cytotoxic and radiation therapies, in the management of metastatic disease.     

Lung cancer after 70: is it a different disease?

Despite the fact that elderly patients comprise over 50% of the nonsmall cell lung cancer (NSCLC) population, our knowledge regarding the efficacy and safety of chemotherapy in this group is suboptimal. The "elderly" (defined as individuals > or = 70 years of age) experience physiologically normal aging of their bone marrow and kidneys, which inherently increases toxicity to therapy. Standard practice has often been to discourage the use of combination chemotherapy in these patients; however, general consensus guidelines emphasize that performance status should primarily guide the choice of treatment. Elderly patients with advanced NSCLC treated with platinum doublet therapy demonstrate similar efficacy (but increased toxicity) to their younger counterparts. Patients with metastatic disease in which a targeted and/or biological agent(s) was added to chemotherapy experienced benefits similar to those treated with standard platinum doublets, but with increased morbidity and mortality. In the future, effective testing of molecular targeted therapies will have to include elderly patients among research cohorts or risk excluding a large population of eligible patients. Overall, elderly patients with advanced NSCLC, while experiencing greater toxicity, demonstrate the same response rates and survival benefits as their younger peers.     

Biomarkers of clinical benefit for anti-epidermal growth factor receptor agents in patients with non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) remains by far the major cause of cancer-related death in the Western world in both men and women. The majority of patients will be diagnosed with metastatic disease, and chemotherapy doublets remain the cornerstone of treatment for these patients. However, chemotherapy has a minimal impact on long-term survival and prognosis remains poor for these patients. Further improvement in treatment is likely to require incorporation of novel targeted therapies. Among these agents, inhibitors of the epidermal growth factor receptor (EGFR) have demonstrated significant activity in the first-, second- or third-line treatment of NSCLC. The purpose of current paper is to present the evidence for using several proposed molecular biomarkers as a tool for selection of NSCLC patients for anti-EGFR treatment. According to current data, EGFR mutation status appears to be the strongest predictor for the selection of NSCLC patients to first-line treatment with EGFR tyrosine kinase inhibitors vs chemotherapy. Use of other biomarkers remains investigational.     

Treatment of elderly patients or patients who are performance status 2 (PS2) with advanced Non-Small Cell Lung Cancer without epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations – Still a daily challenge

Cytotoxic chemotherapy remains the core treatment strategy for patients with advanced non-small cell lung cancer (NSCLC) with tumours that do not have actionable molecular alterations, such as epidermal growth factor receptor (EGFR)-sensitising mutations, anaplastic lymphoma kinase (ALK) translocations or ROS1 translocations. Age and performance status (PS) are two pivotal factors to guide treatment decisions regarding the use of chemotherapy in lung cancer patients. Lung cancer is predominantly a disease of the elderly, with more than two-thirds of patients aged ≥65 years, the current definition of ‘elderly’. The prevalence of poor PS, as estimated by patients themselves, can be as high as 50%. Both the elderly and PS2 patients are underrepresented in clinical trials. Therefore, optimising treatment strategy for the subgroup of elderly or PS2 patients with advanced NSCLC remains challenging as a result of a paucity of clinical trial data. The current review focusses on the elderly or PS2 patients without actionable oncogenic drivers and attempts to summarise current available data on recent treatments trials including angiogenesis inhibitors and immune-checkpoint inhibitors.     

Targeted therapies for lung cancer: clinical experience and novel agents

Although lung cancer remains the leading cancer killer in the United States, recently a number of developments indicate future clinical benefit. These include evidence that computed tomography-based screening decreases lung cancer mortality, the use of stereotactic radiation for early-stage tumors, the development of molecular methods to predict chemotherapy sensitivity, and genome-wide expression and mutation analysis data that have uncovered oncogene "addictions" as important therapeutic targets. Perhaps the most significant advance in the treatment of this challenging disease is the introduction of molecularly targeted therapies, a term that currently includes monoclonal antibodies and small-molecule tyrosine kinase inhibitors. The development of effective targeted therapeutics requires knowledge of the genes and pathways involved and how they relate to the biologic behavior of lung cancer. Drugs targeting the epidermal growth factor receptor, anaplastic lymphoma kinase, and vascular endothelial growth factor are now U.S. Food and Drug Administration approved for the treatment of advanced non-small cell lung cancer. These agents are generally better tolerated than conventional chemotherapy and show dramatic efficacy when their use is coupled with a clear understanding of clinical data, mechanism, patient selection, drug interactions, and toxicities. Integrating genome-wide tumor analysis with drug- and targeted agent-responsive phenotypes will provide a wealth of new possibilities for lung cancer-targeted therapeutics. Ongoing research efforts in these areas as well as a discussion of emerging targeted agents being evaluated in clinical trials are the subjects of this review.     

Molecular targeted agents in non-small-cell lung cancer

Although advances in chemotherapy have provided some improvement in overall survival for patients with advanced non-small-cell lung cancer (NSCLC), outcomes remain poor. Several targeted therapies for lung cancer are in development, and it is hoped that these new approaches will continue to improve survival for patients with advanced NSCLC. These new therapies are targeted specifically to the molecular pathways and processes that characterize tumor growth and progression, including uncontrolled cell growth, invasion, metastasis, angiogenesis, and resistance to apoptosis. Some molecules, such as protein kinase C and the epidermal growth factor receptor-tyrosine kinase, play central roles in cellular activity and are involved in many of the different signaling pathways underlying malignant transformation. Other molecules are dedicated to a specific process, such as the role of vascular endothelial growth factor in angiogenesis. New approaches use a variety of technologies to target these molecules, including small-molecule inhibitors, antibodies, and antisense oligonucleotides, among others. Many of these therapies are currently being tested alone or in combination with each other and with standard treatments for a variety of tumors. This article summarizes data on treatment of NSCLC with some of the agents that are the furthest along in clinical development. It is possible to envision a future in which a combination of therapies treat lung cancer on multiple fronts, significantly enhancing tumor responses and improving survival beyond current expectations.     

Correlation of genes associated with drug response to prognosis of large cell lung carcinoma

Platinum-based chemotherapy remains the main treatment of advanced lung cancer. However, platinum resistance has become a major treatment obstacle. Novel therapies, particularly tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR-TKI) and agents that target vascular endothelial growth factor (VEGF), have improved the treatment. Both chemotherapy and targeted therapy have their molecular mechanisms. This study aimed to determine the mutation, amplification, or expression status and inter...     

非小细胞肺癌脑转移治疗进展

非小细胞肺癌(NSCLC)脑转移的治疗方法包括激素、抗惊厥药物治疗、手术、放疗、化疗.近年来分子靶向治疗如表皮生长因子(EGFR)酪氨酸激酶抑制剂(TKI)成为NSCLC脑转移的新的治疗选择.