Second-line treatment for advanced non-small cell lung cancer: a systematic review

BACKGROUND: Among advanced non-small cell lung cancer (NSCLC) patients, most will resist or relapse after first-line chemotherapy. As a result, second-line therapy has been a major focus for clinical research. MATERIALS AND METHODS: A systematic review was carried out from 1996 to February 2005. RESULTS: Second-line chemotherapy provides pre-treated NSCLC patients with a clear survival advantage. Docetaxel 75 mg/m(2) every 3 weeks is the present standard second-line chemotherapy. Despite promising results regarding efficacy and toxicity in phase III studies, a docetaxel weekly schedule could not be recommended. Pemetrexed recently emerged as an alternative with similar efficacy and less toxicity. Although the combination of two drugs was not associated with a survival benefit when compared with single-agent chemotherapy, such regimens induced a dramatic increase in toxicities and therefore mono-chemotherapy remains the standard as second-line therapy. Finally, few new agents were reported with better results than those used previously and clinical research on second-line therapy currently focuses on combinations with targeted therapies. CONCLUSION: Second-line chemotherapy offers NSCLC patients a small but significant survival improvement. However, this field of clinical research needs further investigations in order to answer certain remaining questions especially concerning targeted therapies.     

Improving patient management in metastatic non-small cell lung cancer

The management of advanced non-small cell lung cancer (NSCLC) has progressed over the last 3 decades. Advances in chemotherapeutic drugs and the use of multi-drug combinations, targeted agents and new management strategies have provided modest survival benefits. However, improving quality of life is equally important, and involves a therapeutic strategy that considers the optimal balance between treatment activity (survival; symptom control) and treatment burden (side effects; duration of hospital stay). There remains room for improvement of therapies today, given that 1-year survival is approximately 35%. The option of adding another cytotoxic agent to a platinum-based doublet does not appear to improve survival but increases toxicity. With the advent of targeted drugs, there is much interest in adding a biological agent such as bevacizumab to the current standard. Another strategy of interest is the use of maintenance treatment with a well-tolerated cytotoxic agent such as gemcitabine after first-line therapy. This has been shown to improve progression-free survival compared with best supportive care alone. Ten years ago, few patients with advanced NSCLC were candidates for second-line treatment for progressive or relapsed disease. However, as response rates and toxicity profiles with first-line therapies improved, relapse therapy has become more important. Several single agent chemotherapies have been evaluated in the second-line setting, including the anti-metabolite pemetrexed, which demonstrates comparable survival outcomes to that of the historical standard docetaxel, but a much better toxicity profile. The targeted therapy erlotinib is also being investigated in this setting. Further studies are required to establish the role of newer agents in the management of advanced NSCLC.     

Optimizing first-line treatment options for patients with advanced NSCLC

The median survival time for advanced non-small cell lung cancer (NSCLC) remains poor, despite years of research into new chemotherapy combinations. Platinum-based chemotherapy has long been the standard of care for the initial treatment of advanced NSCLC. While no one particular platinum-based chemotherapy regimen is definitely superior to the others (as demonstrated in the Eastern Cooperative Oncology Group's E1594 trial), three randomized phase III trials (the Southwest Oncology Group 9509, Italian Lung Cancer Project, and TAX326 trials) have recently demonstrated that taxane-platinum doublets are better tolerated than a combination of vinorelbine and cisplatin (VC). Moreover, a combination of docetaxel and cisplatin produced superior survival and quality of life than VC in the TAX326 study. Nonplatinum combinations, such as a taxane-gemcitabine doublet, appear promising and better tolerated than their platinum-based comparators in other studies. Efforts to evaluate chemotherapy specifically in elderly patients and in those with poor performance status (PS) have increased. Single-agent chemotherapy has been safely administered to these populations, but platinum-based doublet therapy may also be feasible in both elderly patients and patients with PS scores of 2. The addition of the monoclonal antibody against vascular endothelial growth factor, bevacizumab, to standard chemotherapy for patients with non-squamous cell advanced NSCLC significantly extended median survival in the E4599 randomized trial. Each incremental advance demonstrates that progress can be made in first-line treatment of advanced NSCLC.     

The role of docetaxel in N2 locally advanced non-small-cell lung cancer

Patients with locally advanced non-small-cell lung cancer (NSCLC) are a heterogeneous group often treated with multimodality therapy. Docetaxel has an established role in the treatment of advanced-stage NSCLC and has demonstrated promising activity in the locally advanced setting. Herein, we review the available data on the role of docetaxel in locally advanced NSCLC. The phase I/II data regarding the use of docetaxel concomitantly with radiation as a single agent or combined with platinum compounds are reviewed. In addition, we discuss the role of docetaxel induction therapy before surgery or definitive radiation therapy. Additionally, we address the role of docetaxel in consolidation therapy in patients with locally advanced NSCLC.     

Second-line chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC)

An increasing number of patients with advanced non-small cell lung cancer (NSCLC) progressing after front-line chemotherapy are still in good performance status and willing to receive further treatment. Several drugs have been tested in this setting of treatment, but the only agent registered world-wide for second-line chemotherapy of advanced NSCLC is docetaxel. This drug, at dose of 75 mg/m2 every three weeks, has been the standard of care as second-line chemotherapy since 2000, based on two trials that reported improved survival times and quality of life when comparing with best supportive care (TAX 317) and with ifosfamide or vinorelbine (TAX 320). Docetaxel, given at this dose and schedule, resulted in significant haematological toxicity, with many patients at risk for neutropenic fever. Pemetrexed is a novel multitargeted antifolate agent with single-agent activity in first- and second-line treatment of NSCLC. In a phase III study in 571 patients pemetrexed, comparing with docetaxel in second-line chemotherapy, demonstrated clinically equivalent therapeutic outcomes, but a more favourable haematological toxicity profile, with fewer episodes of neutropenia, neutropenic fever, and infections and less use of granulocyte colony-stimulating factor support. Others several agents have been evaluated for the second-line treatment of patients with non-small cell lung cancer, but no comparative phase III studies with docetaxel has been carried out. The epidermal growth factor receptor-tyrosine kinase inhibitors gefitinib (ZD1839, Iressa) and erlotinib (OSI 774, Tarceva) have been evaluated in the second- and third-line setting. Both drugs have demonstrated interesting response rates and toxicity profile and, in particular, erlotinib evidenced a survival advantage of 2 months respect placebo in recent phase III trial. Future developments are likely to value poli-chemotherapy or combination chemotherapy with EGFR tyrosine kinase inhibitors in second-line treatment of advanced NSCLC.     

Prospective randomised phase II study of docetaxel versus paclitaxel administered weekly in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy.

BACKGROUND: Docetaxel and paclitaxel have activity in the second-line treatment of non-small-cell lung cancer (NSCLC), and can be administered as weekly schedules. This phase II randomised study was designed to test the efficacy and toxicity of both taxanes in patients with NSCLC previously treated with platinum-based chemotherapy. PATIENTS AND METHODS: Patients (n = 71) with documented NSCLC were randomised to receive docetaxel (n = 35 patients; 36 mg/m(2)) or paclitaxel (n = 36 patients; 80 mg/m(2)) as a 1 h weekly infusion for 6 weeks followed by a 2-week rest. The cycles were repeated until disease progression or non-acceptable toxicities occurred. RESULTS: Treatment achieved partial response of one versus five patients, median time-to-progression of 74 versus 68 days, and overall survival of 184 versus 105 days, with docetaxel and paclitaxel, respectively. The most common non-haematological toxicities were (docetaxel versus paclitaxel): grade 3/4 pulmonary toxicity in seven versus one patient; grade 2/3 diarrhoea in nine versus five; and grade 3/4 haematological toxicities occurred in two versus four patients. There were no treatment-related deaths. CONCLUSIONS: Docetaxel and paclitaxel administered weekly have discrete efficacy in patients with NSCLC previously treated with platinum-based chemotherapy. The higher non-haematological toxicity of docetaxel, particularly pulmonary toxicity and diarrhoea, is of concern and warrants further investigation.     

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.     

Docetaxel in advanced non-small cell lung cancer

Based on the survival benefit demonstrated in large randomized clinical trials, docetaxel is approved for the treatment of advanced non-small cell lung cancer (NSCLC) in both the first- and second-line settings. The efficacy of docetaxel in combination with cisplatin is equivalent to some, and superior to other, platinum-based doublets for first-line management of NSCLC, and has a manageable toxicity profile. Carboplatin-based regimens and nonplatinum combinations with docetaxel also have proven efficacy in first-line therapy of patients with advanced NSCLC. Combinations of docetaxel with various novel targeted agents have produced encouraging data in Phase II studies. This article reviews recent studies of docetaxel as a single agent and in combination regimens with cytotoxic and more recent targeted agents in the management of advanced NSCLC.     

Docetaxel/platinum in advanced non-small-cell lung cancer: recent randomized trials

The role of docetaxel-containing doublets as first-line chemotherapy for patients with advanced and metastatic non-small-cell lung cancer (NSCLC) was evaluated in a large randomized trial. Docetaxel/cisplatin and docetaxel/carboplatin were compared with the reference regimen of vinorelbine/cisplatin. After adjustment for imbalances in prognostic factors, the overall survival of patients treated with docetaxel/cisplatin was significantly better than that of patients treated with vinorelbine/cisplatin, the reference regimen. Survival for patients on the docetaxel/carboplatin arm was noninferior to the same reference regimen. The major grade 3/4 hematologic toxicity was neutropenia, which affected approximately three fourths of the participants. Overall, the docetaxel/platinum arms were well tolerated. Both docetaxel/carboplatin and docetaxel/cisplatin appear to be effective first-line chemotherapy combinations for advanced NSCLC and are efficacious treatment options in this setting. The future of NSCLC therapy might lie in the development of novel treatment paradigms that involve the integration of targeted agents with traditional cytotoxic chemotherapy.     

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.     

First-line chemotherapy for advanced-stage non-small-cell lung cancer: focus on docetaxel

Systemic chemotherapy results in modest improvements in survival and quality of life for patients with advanced-stage non-small-cell lung cancer (NSCLC). Administration of a platinum compound in combination with a taxane (paclitaxel or docetaxel), gemcitabine, vinorelbine, or irinotecan is considered optimal first-line therapy for patients with advanced-stage NSCLC who have a good performance status. Studies that have compared various platinum agent-based doublet regimens have demonstrated comparable efficacy between these regimens. In addition, non-platinum agent-based regimens have also demonstrated response rates and survival similar to the platinum agent-based combinations. These developments have allowed for tailoring of chemotherapy to individual patients based on factors such as toxicity profile, treatment schedule, and cost. Docetaxel is approved for first-line therapy and salvage treatment of advanced-stage NSCLC. Multiple randomized clinical trials have established the efficacy of platinum-agent/docetaxel regimens for first-line treatment of advanced-stage NSCLC. Improvements in various lung cancer-related symptoms and global quality of life indices have been noted with docetaxel-based regimens. Combination chemotherapy appears to be beneficial even for elderly patients. The current generation of clinical trials is evaluating the incorporation of molecularly targeted agents into existing 2-drug chemotherapy regimens. This article will discuss the role of docetaxel as first-line chemotherapy for patients with advanced-stage NSCLC.     

Concurrent docetaxel and thoracic radiation in non-small-cell lung cancer

Locally advanced (stages IIIA and IIIB) non-small-cell lung cancer (NSCLC) represents approximately 25% of new cases of NSCLC diagnosed annually. The treatment strategy for these patients involves combined-modality therapy with chemotherapy and thoracic radiation. Furthermore, a subset of patients with stage IIIA disease undergo surgical resection. Docetaxel is a chemotherapy agent with activity in both first- and second-line treatment of patients with advanced NSCLC. Several recent studies have also incorporated docetaxel in the treatment of patients with stage III NSCLC as neoadjuvant therapy, alone or in combination with cisplatin or carboplatin and thoracic radiation. Docetaxel has also been used as consolidation therapy. This review will summarize the data to date on the use of docetaxel and thoracic radiation in the treatment of patients with stage III NSCLC.     

Taxanes in the treatment of advanced (stage III and IV) non-small cell lung cancer (NSCLC): recent developments

Taxanes, paclitaxel, and docetaxel have become the cornerstone of both first-line and second-line chemotherapy for advanced non-small cell lung cancer (NSCLC). Recently, several pivotal phase III randomized trials have been published. These studies and phase II trials will be discussed. Additionally, studies utilizing a taxane and radiation therapy for resectable and locally advanced NSCLC will be outlined. The article will end with a discussion on newer strategies being currently explored to improve survival in advanced NSCLC.     

Two cases of advanced gastric cancer in which paclitaxel proved effective after resistance to docetaxel

Docetaxel and paclitaxel are demonstrated to be effective for use as salvage therapy for advanced gastric cancer. Both drugs are taxane derivatives but there is only partial cross-resistance between them. For breast cancer and ovarian cancer, there have been several reports that showed docetaxel is effective for paclitaxel-resistant cancer, and vice versa. We experienced two cases of advanced gastric cancer effectively treated by sequential therapy of docetaxel and paclitaxel. One patient was a 43-year-old woman with a type 4 gastric carcinoma, and the other a 51-year-old woman who had suffered a recurrence of the gastric cancer after a total gastrectomy. At first, chemotherapy failed, so we chose docetaxel/high-dose 5-FU (HDFU) for the second-line therapy. After resistance to Docetaxel/HDFU, paclitaxel was effective for third-line treatment of both patients.     

Chemotherapy regimens in advanced non small-cell lung cancer: recent randomized trials

The four chemotherapy regimens evaluated in Eastern Cooperative Oncology Group study 1594 (paclitaxel/ cisplatin, gemcitabine/cisplatin, docetaxel/cisplatin, and paclitaxel/carboplatin) are effective treatment options for the therapy of advanced non small-cell lung cancer (NSCLC). Only numerical differences have been noted in overall survival with these regimens, probably due to the fact that total therapy received by these patients was the same. There was an improved median time to progression with the gemcitabine/ cisplatin doublet. Choice of a chemotherapy regimen in practice is being based on the tolerability and side-effect profile of these doublets. In the foreseeable future, we will see the use of selective and individualized therapy in addition to chemotherapy in the management of advanced NSCLC.     

Outcome of advanced nonsmall cell lung cancer patients receiving gemcitabine and weekly paclitaxel as first-line treatment

BACKGROUND: Gemcitabine and paclitaxel are both indicated for advanced nonsmall cell lung cancer (NSCLC) patients. Combinations of gemcitabine and paclitaxel with various doses and schedules were shown to be effective treatment for these patients. Nevertheless, the survival outcome of these patients is not clear. PATIENTS AND METHODS: Patients with advanced NSCLC in a phase II study of weekly paclitaxel and gemcitabine as first-line treatment were followed until their death. Second- and further-lines of treatment were recorded. RESULTS: Thirty-seven patients receiving a total of 188 cycles of gemcitabine and paclitaxel treatment were accrued. Toxicities were mild. Twenty-three patients had partial response to treatment (overall response rate, 62%; 95% confidence interval (CI), 46-78%). Median time to treatment failure was 6.0 months. Twenty-seven (73%) patients received second-line anticancer drug treatment. Twenty-three (62%) patients were able to receive platinum doublet as second-line chemotherapy. Median survival after second-line treatment was 10.9 months. Median, 1- and 2-year survivals of 37 patients were 16.8 months, 59% and 27%, respectively. There was a statistically significant difference in median survival between patients who could or could not receive second-line treatment (21.9 vs. 3.1 months, p<0.00001). CONCLUSIONS: Weekly paclitaxel with gemcitabine is effective and well tolerated as first-line treatment for advanced NSCLC patients. The favorable survival may be due to platinum doublet second-line chemotherapy.     

Impact of treatment with bevacizumab beyond disease progression: a randomized phase II study of docetaxel with or without bevacizumab after platinum-based chemotherapy plus bevacizumab in patients with advanced nonsquamous non-small cell lung cancer (WJOG 5910L)

ABSTRACT: BACKGROUND: Bevacizumab, a humanized antibody to vascular endothelial growth factor (VEGF), shows clinical activity against human cancer, with its addition to standard chemotherapy having been found to improve outcome in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). However, there have been no evidence-based studies to support the continued use of bevacizumab beyond disease progression in such patients treated with the drug in first-line therapy. We have now designed a randomized phase II trial to examine the clinical benefit and safety of continued bevacizumab treatment in patients with advanced nonsquamous NSCLC whose disease has progressed after first-line treatment with bevacizumab plus a platinum-based doublet. METHODS: WJOG 5910L was designed as a multicenter, open-label, randomized, phase II trial by the West Japan Oncology Group of docetaxel (arm A) versus docetaxel plus bevacizumab (arm B) in patients with recurrent or metatstatic nonsquamous NSCLC whose disease has progressed after first-line treatment with bevacizumab plus a platinum-based doublet. Patients in arm A will receive docetaxel at 60 mg/m2 and those in arm B will receive docetaxel at 60 mg/m2 plus bevacizumab at 15 mg/kg, with each drug administered on day 1 every 21 days until progression or unacceptable toxicity. The primary endpoint of the study is progression-free survival, with secondary endpoints including response rate, overall survival, and safety, for patients treated in either arm. Trial registration: UMIN (University Hospital Medical Information Network in Japan) 000004715.     

晚期非小细胞肺癌维持治疗的新进展

 目前含铂两药化疗是晚期非小细胞肺癌（NSCLC）患者的一线治疗方案。然而,标准一线化疗方案的疗效已达到了一个平台,晚期NSCLC患者在一线治疗获得了客观缓解或疾病稳定后的维持治疗是目前研究的热点。培美曲塞成为晚期肺癌患者一线治疗达到缓解或稳定后的新的治疗手段,其耐受性好,提高了总体生存时间和无疾病进展时间,并且对于非鳞癌患者疗效显著。厄洛替尼（商品名：特罗凯）与一线化疗序贯治疗能显著延长患者无进展生存期,有研究表明标准治疗后的晚期NSCLC患者,无论病理类型、种族、性别、年龄、吸烟状态,应用厄洛替尼维持治疗均可临床获益且耐受性好。含铂两药一线化疗后使用吉非替尼（商品名：易瑞沙）维持治疗,可以给腺癌患者带来显著的临床获益。