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.     

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.     

The role of irinotecan combined with Cisplatin or Carboplatin in the treatment of advanced non-small-cell lung cancer

Since the 1980s, cisplatin therapy for advanced non-small-cell lung cancer (NSCLC) has shown improvement in patient outcome with respect to overall survival. In the past decade, several new agents, such as the taxanes (paclitaxel and docetaxel), gemcitabine, vinorelbine, and irinotecan, have also shown promising single-agent efficacy in the treatment of advanced NSCLC. Superior efficacy was observed when these 5 agents were used in combination with cisplatin as compared to cisplatin alone for treatment of patients with NSCLC. The toxicity profiles of these 5 agents were found to be largely nonoverlapping with cisplatin. The results of recent randomized trials with different cisplatin-based chemotherapy regimens have shown that platinum-based therapy is still the mainstay for treatment of NSCLC; however, it appears that a chemotherapy efficacy plateau has been reached. Moreover, it has also been shown that for patients unable to tolerate cisplatin, nonplatinum doublets consisting of gemcitabine with either taxanes or vinorelbine are equivalent in efficacy and can be alternatives for first-line treatment of advanced NSCLC. Thus, the development of new and novel strategies is essential for treatment of NSCLC patients. Ongoing trials with vaccines, signal transduction modulators, antiangiogenic agents, and gene therapy in combination with chemotherapy     

The role of weekly docetaxel in the treatment of advanced non-small-cell lung cancer

Docetaxel is one of the most active single agents in the treatment of advanced non-small-cell lung cancer (NSCLC). Weekly administration of docetaxel markedly reduces myelosuppression and also reduces nonhematologic toxicity. Phase II trials with single-agent weekly docetaxel have been completed in first- and second-line treatment of advanced NSCLC; preliminary results of treatment with weekly docetaxel-based combination regimens are also available. In patients who were elderly or had poor performance status, weekly docetaxel produced a 19% response rate, 28% 1-year survival, and was well tolerated. As second-line therapy, response rates to weekly docetaxel were similar to results with administration every 3 weeks, although no direct comparisons exist. Combination regimens, particularly weekly docetaxel/gemcitabine, also appear active and well tolerated and should be further evaluated. Addition of various targeted agents (eg, epidermal growth factor receptor inhibitors, antiangiogenesis agents) also merits evaluation.     

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.     

Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions

Systemic therapy improves the survival and quality of life of patients with advanced stage non-small cell lung cancer (NSCLC). Several new therapeutic options have emerged for advanced NSCLC, incorporating novel cytotoxic agents (taxanes, gemcitabine, pemetrexed) and molecular-targeted agents (erlotinib, bevacizumab). Efforts to improve the outcome of first-line therapy for advanced and metastatic NSCLC have primarily focused on the addition of targeted agents to platinum-based two-drug regimens. Bevacizumab, an antibody against vascular endothelial growth factor, is the first drug to demonstrate superior outcomes when added to systemic chemotherapy in advanced disease. Evaluation of the role of maintenance therapy following four to six cycles of first-line combination chemotherapy is ongoing. Both cytotoxic agents and targeted agents are suitable for evaluation in the maintenance setting. Promising results have been noted with single-agent paclitaxel as maintenance therapy following four cycles of combination therapy with carboplatin and paclitaxel. Phase III studies are now under way to evaluate the roles of gemcitabine, pemetrexed, and erlotinib as maintenance therapies for patients who experience a response or disease stabilization after four cycles of combination chemotherapy. Whether this approach will be successful in extending the survival of a select group of patients remains to be seen.     

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。     

Optimizing chemotherapy and targeted agent combinations in NSCLC

Chemotherapy extends life and provides symptom palliation for patients with advanced non-small cell lung cancer (NSCLC). Numerous trials have been conducted that evaluate a variety of doublet regimens, but the majority of trials have found equal efficacy among the treatment arms. Indeed, a plateau appears to have been reached with respect to survival associated with traditional cytotoxic drug regimens. It was initially hoped that the addition of novel targeted agents to conventional chemotherapy would produce significant survival benefits for patients with advanced NSCLC; however, most trials have failed to show such a benefit. There is no survival benefit associated with adding erlotinib or gefitinib to a chemotherapy regimen, although there is a significant improvement in survival associated with erlotinib monotherapy in the second- and third-line advanced disease setting. In contrast, the results of E4599 clearly demonstrate that the addition of bevacizumab to paclitaxel-carboplatin chemotherapy extends survival in a select group of patients with non-squamous cell NSCLC. E4599 also represents a rational approach to drug development that could be modeled in other trials, namely, the use of a large, well designed, randomized trial prior to beginning a traditional phase II approach. This strategy can lead to the identification of subgroups most likely to benefit, as well as those that might experience increased toxicity, such as patients with squamous cell carcinoma treated with bevacizumab. Another approach to optimizing targeted therapy involves selecting a chemotherapy regimen with the greatest potential for synergy based on preclinical modeling. Because docetaxel has been shown to prolong survival in second-line treatment, a number of novel agents have been combined with docetaxel in order to improve efficacy. Alternatively, investigators have sought to combine novel agents with either carboplatin-paclitaxel or cisplatin-gemcitabine in first-line treatment. A number of trials are underway that combine these agents with inhibitors of the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and the proteasome, as well as COX2 inhibitors, and novel immunomodulators.     

Development of docetaxel in advanced non-small-cell lung cancer

Docetaxel, a semisynthetic taxane initially developed for the treatment of breast cancer, has a high degree of activity in lung cancer. Although the mechanisms of action of the taxanes docetaxel and paclitaxel are identical, docetaxel has almost a twofold higher binding affinity for the target site, beta tubulin. In clinical trials, individuals previously treated with paclitaxel benefited from docetaxel. Docetaxel is the standard of care in second-line therapy of advanced non-small-cell lung cancer (NSCLC) and is effective, alone and in combination, in first-line treatment of advanced NSCLC. The standard in first-line therapy of metastatic NSCLC is a platinum doublet with one of the third-generation chemotherapy agents, docetaxel, paclitaxel, gemcitabine, or vinorelbine. Each of these doublets offers similar therapeutic benefit. In a phase-III study comparing docetaxel-cisplatin and docetaxel-carboplatin with vinorelbine-cisplatin, patients treated in the two docetaxel arms had consistently improved global QoL compared to patients treated with the vinorelbine-cisplatin doublet. This landmark study led to Food and Drug Administration (FDA) approval of cisplatin-docetaxel for the treatment of advanced NSCLC. Non-platinum doublets such as docetaxel-gemcitabine have also demonstrated efficacy and safety. Docetaxel has undergone extensive evaluation and is the only agent approved for use in both first- and second-line therapy of advanced NSCLC.     

Pemetrexed Use in the Adjuvant Setting for Completely Resectable Non–Small-Cell Lung Cancer

Supported by evidence from the LACE (Lung Adjuvant Cisplatin Evaluation) metaanalysis, cisplatin-based adjuvant chemotherapy is now recommended as the standard of care for patients with surgically resected early-stage non–small-cell lung cancer (NSCLC) per American Society of Clinical Oncology and European Society for Medical Oncology clinical practice guidelines. These standard regimens, which principally include cisplatin-etoposide and cisplatin-vinorelbine, are associated with long- and short-term toxicities. Hence, cisplatin-based regimens with an improved therapeutic index and optimal safety and tolerability profile are still needed. Pemetrexed, an antifolate, is currently indicated for first-line, maintenance, and second-line therapy for advanced nonsquamous NSCLC. Pemetrexed-platinum, with or without targeted agents, has proven to be efficacious with an acceptable toxicity profile when given in the first-line metastatic setting. Therefore, it is reasonable that pemetrexed be investigated in the adjuvant setting. This review collates data from January 2000 through August 2012 on the use of pemetrexed-platinum regimens in the adjuvant setting either alone or in combination with targeted agents. To date, more than 1000 patients with early stage NSCLC have been enrolled in adjuvant therapy studies evaluating various pemetrexed-containing treatment regimens, and additional patients are being enrolled in ongoing studies. Current evidence appears to favor the combination with cisplatin over that with carboplatin. We await more robust safety and efficacy data from these ongoing adjuvant trials to define with clarity the role of pemetrexed-containing regimens in this setting.     

Role of cytotoxics in combination with targeted agents

Combining cytotoxics with targeted agents can lead to enhanced efficacy in metastatic breast cancer (MBC). Cytotoxic/targeted agent combinations approved for the treatment of MBC include trastuzumab plus paclitaxel or docetaxel for the first-line treatment in patients presenting with HER2-positive breast cancer. Furthermore, in HER2-negative disease combining bevacizumab with paclitaxel for the first-line treatment of HER2-negative patients is superior compared to monotherapy with either drug. Lapatinib plus capecitabine recently received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) for conditional marketing authorisation in patients with HER2-positive breast cancer following prior therapy with anthracyclines, taxanes and trastuzumab. The novel epothilone ixabepilone is also under investigation in this setting. Preclinical studies have demonstrated synergistic activity in combination with targeted agents including trastuzumab and bevacizumab and early clinical studies have revealed encouraging response rates in combination with trastuzumab and carboplatin in patients with HER2-positive MBC. This article will review recent data on the efficacy of combining cytotoxics with targeted agents for the treatment of MBC.     

Docetaxel: promising and novel combinations in ovarian cancer

Despite considerable progress over the past two decades in the management of advanced ovarian cancer, the majority of patients with this type of malignancy still die from their disease, and the search for new and improved first-line and salvage chemotherapy regimens continues. As part of this work, the antitumour activity and effect on survival of new chemotherapy combinations containing the novel taxane docetaxel are being explored. Dual therapy with docetaxel plus a camptothecin (a topoisomerase inhibitor) has shown promise in second-line treatment, and preliminary data indicate good activity of docetaxel in combination with gemcitabine. Triple-therapy studies have produced mixed results, but encouraging activity has been reported when the anthracycline, epirubicin, is added to docetaxel and carboplatin - sequential therapy with docetaxel, cisplatin and epirubicin is currently being assessed. Combinations of docetaxel, carboplatin and gemcitabine may also be of future interest. Early efficacy and tolerability results with novel combination chemotherapy regimens involving docetaxel thus offer the promise of additional progress in the chemotherapy of advanced ovarian cancer, and further trials should be encouraged.     

Second-line Treatment for Non–Small-Cell Lung Cancer: One Size Does Not Fit All

After progression following first-line treatment, many patients with advanced non–small-cell lung cancer (NSCLC) still have a good performance status and can be considered for further treatments. Based on 2 randomized phase III trials, docetaxel was the first approved second-line therapy associated with longer survival and better quality of life compared with best supportive care alone and vinorelbine or ifosfamide. Since then, other agents have been approved for the second-line treatment of NSCLC (ie, pemetrexed, erlotinib, and gefitinib). Recently, new molecular-targeted agents are being increasingly considered in this setting, above all, bevacizumab and vandetanib. The discovery and validation of predictive markers of efficacy for both chemotherapy drugs and the new targeted therapies is of primary importance for the selection of second-line treatment for all patients with advanced NSCLC.     

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.     

非小细胞肺癌的分子靶向治疗

与传统细胞毒性化疗相比,分子靶向治疗能更特异性作用于肿瘤而毒性反应较轻。新的靶向治疗药物得到发展,并相继在晚期非小细胞肺癌一线、二线治疗中进行临床试验,其中有的药物显示了较好的疗效。本文对近年来关于非小细胞肺癌靶向治疗的临床试验进行回顾。     

Epidermal Growth Factor Receptor Inhibition in the Management of Squamous Cell Carcinoma of the Lung

Molecular therapies targeting epidermal growth factor receptor (EGFR) have had a profound impact on the management of advanced non-small cell lung cancer (NSCLC). EGFR inhibition with EGFR tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR monoclonal antibodies (mAbs) in squamous NSCLC (sqNSCLC) remains controversial in patients whose tumors are not known to harbor EGFR mutations. Recent meta-analyses of EGFR-inhibition randomized trials that are adequately powered for histological subgroup analysis and anti-EGFR trials limited to patients with squamous histology afford the opportunity to revisit EGFR treatment in sqNSCLC. In unselected patients with sqNSCLC who are not eligible for chemotherapy, EGFR-TKI therapy is a valid treatment option over placebo or best supportive care, with improved progression-free survival noted in randomized controlled trials in both the first- and second-line setting and improved overall survival (OS) in the second-line setting. In patients eligible for chemotherapy, first-line combination regimens with anti-EGFR mAbs have been shown to improve OS over chemotherapy alone in patients with squamous histology in meta-analysis and more recently in the SQUIRE sqNSCLC trial (chemotherapy with and without necitumumab). In sqNSCLC patients who respond to induction chemotherapy, maintenance therapy with erlotinib delays disease progression and may improve the survival of patients with stable disease. In the second-line setting, survival outcomes are comparable between chemotherapy and EGFR-TKIs in meta-analysis, with the latter being more tolerable as a second-line therapy. Newer-generation EGFR-TKI therapies may further benefit patients with sqNSCLC who have failed first-line chemotherapy, given the positive trial results from LUX-Lung 8 (afatinib vs. erlotinib). EGFR is a valid therapeutic target in unselected/EGFR wild-type patients with squamous cell carcinoma of the lung. With the recent approval of immune checkpoint inhibitors in the second-line management of advanced sqNSCLC and their adoption as a new standard of care, there exists an opportunity for novel combination therapies to increase therapeutic efficacy and durable tumor control. As more targeted agents are approved, combination regimens that include an anti-EGFR agent should be evaluated, and the optimal sequencing of targeted therapies should be defined.

Implications for Practice:

Anti-epidermal growth factor receptor (EGFR) therapies remain controversial in unselected/wild-type EGFR squamous non-small cell lung cancer (NSCLC). Recent meta-analyses and squamous-only NSCLC EGFR-inhibition trials have overcome the power limitations of early trials and can now inform the management of squamous NSCLC with anti-EGFR therapies. With the approval of immunotherapeutics in the second-line management of squamous NSCLC, there exists an opportunity for novel combination therapies to improve efficacy and durable tumor control. The optimal timing and sequencing of available second-line targeted therapies, however, have yet to be defined. This review analyzes randomized clinical trials of EGFR inhibition in NSCLC and meta-analyses of these trials, with a focus on patients with squamous histology.     

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.     

Future scenarios for the treatment of advanced non-small cell lung cancer: focus on taxane-containing regimens

Despite recent progress in the development of new molecularly targeted agents, the chemotherapy regimens considered standard at the end of the last century—that is, two‐drug combinations consisting of either cisplatin or carboplatin plus a third‐generation agent (docetaxel, paclitaxel, gemcitabine, or vinorelbine)—remain the primary treatment option for advanced non‐small cell lung cancer (NSCLC) patients. Most recently, the existing standard of care has been amended to reflect the significant survival advantage of cisplatin–pemetrexed over cisplatin–gemcitabine as first‐line treatment of nonsquamous NSCLC. The addition of a biological drug (bevacizumab, cetuximab) or the use of a single‐agent epidermal growth factor receptor inhibitor may further improve outcomes in selected patients. It has become increasingly clear, primarily through recent meta‐analyses, that although the therapeutic equivalence of any combination of a platinum agent plus either gemcitabine, vinorelbine, docetaxel, or paclitaxel has been long accepted, each regimen has different side effects and therapeutic outcomes that allow clinicians to select the most appropriate treatment for chemotherapy‐naïve patients with stage IIIB/IV NSCLC. In this review, we evaluate the available evidence and explore the role and importance of various modern chemotherapy regimens, with the aim of optimizing treatment selection and combination with biological agents. Emphasis is placed on the role of taxanes (docetaxel versus paclitaxel) in this changing landscape.