Second–line chemotherapy for non—small–cell lung cancer

Most of the experience with second-line chemotherapy for non-small-cell lung cancer (NSCLC) comes from small phase II trials, which have shown disappointing or inconsistent results. The notable exception has been docetaxel, which has been extensively studied as a second-line therapy for NSCLC. On the basis of consistent phase II activity, two large randomized phase III trials were conducted for patients with advanced NSCLC that had progressed either on or after first-line platinum-based therapy. In one trial, docetaxel, at either 100 or 75 mg/m2, was compared with a regimen of either vinorelbine or ifosfamide. In the second trial, docetaxel 75 to 100 mg/m2 was compared with best supportive care. Both trials showed significant improvement in survival, time to progression, and quality of life in the patients receiving docetaxel versus the control therapy. Based on these two large trials, it appears that the use of second-line therapy with single-agent docetaxel at a dose of 75 mg/m2 every 3 weeks is a reasonable practice in patients who maintain a good performance status.     

Advances in the treatment of second-line non-small-cell lung cancer

Treatment with third-generation chemotherapy agents improves survival and quality of life of patients with non-small-cell lung cancer (NSCLC). Despite these favorable outcomes, most patients receiving front-line therapy experience disease progression. The availability of many new novel agents with activity in NSCLC has prompted investigators to explore second-line chemotherapy options. For many years, docetaxel was the only approved agent for the second-line treatment of NSCLC. More recently, the multi-targeted antifolate pemetrexed has demonstrated activity in patients previously treated with chemotherapy with locally advanced or metastatic NSCLC. The findings of a phase III trial comparing pemetrexed to docetaxel led to the regulatory approval of pemetrexed as monotherapy for the second-line treatment of NSCLC. Several other novel therapies, including molecular targeting agents such as erlotinib, are under development in clinical trials in patients with NSCLC. One of these trials has subsequently led to the approval of erlotinib as second- or third-line therapy in advanced NSCLC.     

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.     

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.     

Single-agent docetaxel (Taxotere) in the treatment of advanced non small-cell lung cancer: clinical concepts and commentary

Chemotherapy in recurrent or metastatic non small-cell lung cancer (NSCLC) has been shown to im-prove quality of life, and to provide a modest prolongation of survival. Docetaxel is a semisynthetic taxane that is an active agent for the treatment of NSCLC, both in previously untreated patients as well as those who have relapsed or progressed following cisplatin-based chemotherapy. After encouraging results in phase II studies, randomized trials have shown that treatment with single-agent docetaxel is superior to best supportive care for advanced NSCLC in both untreated and previously treated patients. This article will review the published data on the use of single-agent docetaxel in the treatment of advanced NSCLC.     

Perspectives on salvage therapy for non-small-cell lung cancer

Platinum-based chemotherapy offers a modest survival advantage over best supportive care in chemotherapy-naive patients with a good performance status and advanced/metastatic non-small-cell lung cancer (NSCLC). Despite the survival benefit associated with first-line chemotherapy, the majority of patients will experience relapse or disease progression. In clinicalpractice, an increasing number of patients maintain a good performance status after first-line treatment and are eligible for further treatments. Docetaxel (Taxotere) at 75 mg/m2 given once every 3 weeks has been the standard of care for second-line chemotherapy since the year 2000. Pemetrexed (Alimta) is a novel multitargeted antifolate agent with single-agent activity in first- and second-line treatment of NSCLC. A large phase 111 study comparing docetaxel to pemetrexed in second-line therapy demonstrated that pemetrexed is equally active and less toxic than docetaxel. Based on these results, pemetrexed is a reasonable second-line chemotherapy option for patients with recurrent, advanced NSCLC. Progress made in the field of molecular biology has led to the identification of drugs active against specific cellular targets. Gefitinib (Iressa) and erlotinib (Tarceva) are both orally active tyrosine kinase inhibitors of the epidermal growth factor receptor. Phase II and III trials have demonstrated that these agents are active particularly in a subgroup of patients with specific biologic characteristics. Both drugs have been approved for the treatment of pretreated NSCLC. Other drugs, such as cetuximab (Erbitux) and bevacizumab (Avastin) have shown promising activity in NSCLC and are currently being tested in clinical trials.     

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.     

Chemotherapy for advanced prostate cancer: Results of new clinical trials and future studies

Our understanding of the role of chemotherapy for advanced prostate cancer has improved considerably in 2004 with the publication of two large randomized phase III trials and the approval by the US Food and Drug Administration of docetaxel and prednisone for metastatic hormone-refractory disease. Although treatment is still considered palliative in nature, studies of chemotherapy for metastatic hormone-refractory prostate cancer (HRPC) have demonstrated improved overall survival compared with older regimens as well as clinically significant improvements in important endpoints, such as quality of life and time to progression. In particular, docetaxel has emerged as first-line therapy on an every-3-week schedule for metastatic HRPC, replacing mitoxantrone, as recently reported in the TAX327 trial. Docetaxel and estramustine combinations have the disadvantage of significant cardiovascular and gastrointestinal toxicity, and further use of estramustine is likely unwarranted as first-line therapy. Future trials examining novel biologic agents and combination therapies should use single-agent docetaxel as the reference standard. The role of chemotherapy for advanced disease in the neoadjuvant or adjuvant setting, in biochemically (PSA) relapsed patients, and as second-line therapy for relapsed disease, remains a subject of active clinical 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.     

Chemotherapy for advanced non-small cell lung cancer

It is well-known that cisplatin-based chemotherapy can prolong the survival of patients with advanced non-small cell lung cancer (NSCLC). This report reviews the recently published clinical trials of chemotherapy for advanced NSCLC. New agents developed in the 1990s such as paclitaxel, docetaxel, gemcitabine, vinorelbine and irinotecan prolonged the survival of patients with advanced NSCLC by single-agent chemotherapy, and combinations of platinum and one of the new agents were superior to existing platinum-based combinations. Accordingly, the current standard chemotherapy for previously untreated patients with advanced NSCLC is considered to be a two-drug combination consisting of cisplatin and one of the new agents. For elderly patients, single-agent chemotherapy using vinorelbine or gemcitabine is recommended. However, the usefulness of platinum-containing chemotherapy for elderly patients has not yet been throughly evaluated. As salvage chemotherapy for patients previously treated with chemotherapy, the effectiveness of docetaxel is confirmed by two randomized trials. However, since many promising agents including pemetrexed and molecular targeting agents such as gefitinib, erlotinib and bevacizumab have been currently developed, we have to evaluate the usefulness of these agents by well-designed clinical trials.     

Recent advances with topotecan in the treatment of lung cancer

Topotecan is a semisynthetic derivative of camptothecin that specifically targets topoisomerase I. It has well-established antineoplastic properties and has been successfully combined with other antineoplastic agents with activity dependent on DNA disruption, such as cisplatin and etoposide. Topotecan is indicated for the treatment of small cell lung cancer (SCLC) sensitive disease after failure of first-line chemotherapy and metastatic ovarian carcinoma after failure of initial or subsequent chemotherapy. Since the approval of topotecan for the second-line treatment of SCLC, studies have been conducted in the first-line setting. Recent studies demonstrate the utility of i.v. topotecan in combination with cisplatin for untreated SCLC. Further, an oral formulation of topotecan is currently under investigation and may provide added convenience for patients. Oral topotecan has been studied in the first- and second-line settings for both SCLC and non-small cell lung cancer (NSCLC). Three recent phase III trials have demonstrated the activity of oral topotecan. In the first study of chemotherapy-na?ve patients with extensive-disease SCLC, oral topotecan plus cisplatin provided efficacy and safety similar to those of etoposide plus cisplatin. In a second study of patients with relapsed SCLC, treatment with oral topotecan showed a statistically significant and clinically meaningful longer overall survival time and improvement in dyspnea and quality of life compared with best supportive care alone in all prognostic groups. Finally, in previously treated patients with NSCLC, single-agent oral topotecan was shown to be noninferior in 1-year survival rate relative to the current standard of i.v. docetaxel. In future studies, oral topotecan will represent a good candidate for combination therapy with other i.v. or oral chemotherapy agents, monoclonal antibodies, and small molecule tyrosine kinase inhibitors.     

2011 Focused Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer

PURPOSE: An American Society of Clinical Oncology (ASCO) focused update updates a single recommendation (or subset of recommendations) in advance of a regularly scheduled guideline update. This document updates one recommendation of the ASCO Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer (NSCLC) regarding switch maintenance chemotherapy. CLINICAL CONTEXT: Recent results from phase III clinical trials have demonstrated that in patients with stage IV NSCLC who have received four cycles of first-line chemotherapy and whose disease has not progressed, an immediate switch to alternative, single-agent chemotherapy can extend progression-free survival and, in some cases, overall survival. Because of limitations in the data, delayed treatment with a second-line agent after disease progression is also acceptable. RECENT DATA: Seven randomized controlled trials of carboxyaminoimidazole, docetaxel, erlotinib, gefitinib, gemcitabine, and pemetrexed have evaluated outcomes in patients who received an immediate, non-cross resistant alternative therapy (switch maintenance) after first-line therapy. RECOMMENDATION: In patients with stage IV NSCLC, first-line cytotoxic chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is stable but not responding to treatment. Two-drug cytotoxic combinations should be administered for no more than six cycles. For those with stable disease or response after four cycles, immediate treatment with an alternative, single-agent chemotherapy such as pemetrexed in patients with nonsquamous histology, docetaxel in unselected patients, or erlotinib in unselected patients may be considered. Limitations of this data are such that a break from cytotoxic chemotherapy after a fixed course is also acceptable, with initiation of second-line chemotherapy at disease progression.     

Second-line chemotherapy for recurrent non-small cell lung cancer: do new agents make a difference?

After a certain degree of nihilism, chemotherapy has become the standard treatment for advanced and metastatic non-small cell lung cancer (NSCLC). The new chemotherapeutic drugs (vinorelbine, taxanes, gemcitabine, and irinotecan) and their associations with cisplatin have shown better response rates and survival in comparison with the standard regimens. This increase of survival is the main motive of the possible consideration of a second-line therapy in NSCLC patients. To this regard, the most promising drug may be docetaxel that, in a randomized trial comprising a best supportive care arm (BSC), documented a response rate of 7.6%, a longer median survival (31 weeks versus 21 of BSC), and a statistically better quality life. Other phase II studies obtained a response rate of 20% and 1-year survival of 40% using docetaxel. Also gemcitabine has shown interesting results in this setting, with a 19% response rate and a median and 1-year survival rate of 34 weeks and 45%, respectively. The activity of paclitaxel is not well defined because of conflicting results and deserves further investigations, while the efficacy of vinorelbine and irinotecan has been dismal. Large randomized trials comparing the treatment arm with best supportive care and a careful analysis of quality of life and cost-effectiveness will be needed to clarify the role of second-line therapy in advanced NSCLC.     

Clinical evidence for second- and third-line treatment options in advanced non-small cell lung cancer

In the U.S. and Europe, the current options for the second- and third-line treatment of advanced non-small cell lung cancer (NSCLC) are cytotoxic drugs and targeted agents. Docetaxel was the first drug approved for second-line treatment after two phase III trials demonstrated its superiority over best supportive care (BSC) alone and single-agent chemotherapy. Pemetrexed was also registered for use as second-line therapy after it was demonstrated to have activity comparable with, and a more favorable toxicity profile than, docetaxel. Erlotinib, an epidermal growth factor receptor inhibitor, is the only biological agent to have been approved in the U.S. and Europe for lung cancer treatment after a study showed its superiority over BSC in recurrent (second-/third-line) NSCLC patients. This review focuses on these drugs, dealing with the results supporting the choice among docetaxel, pemetrexed, and erlotinib in second- and/or third-line treatment.     

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     

Docetaxel (Taxotere) in the treatment of non-small cell lung cancer (NSCLC)--is there a role for a new chemotherapy programme?

Phase II with single-agent docetaxel, in second-line NSCLC, demonstrated an overall response rate of 20%, with a median response duration of 7 months and a median survival time of 9 months. These results suggested that docetaxel had promising activity in patients with platinum-resistant or refractory NSCLC. Phase III studies in this patient population subsequently confirmed this activity; docetaxel prolonged survival when compared to either vinorelbine/ifosfamide or the best supportive care. The phase II studies with docetaxel in first-line NSCLC produced an overall response rate of 30% in evaluable patients, with a median response duration of 6 months and a median survival time of 9 months. A phase III randomized study demonstrated a significant improvement in survival and time to progression with docetaxel, compared to the best supportive care. Based on the activity observed with single-agent docetaxel, combination and multimodality studies with docetaxel have also been conducted. Docetaxel is an active agent in first- and second-line NSCLC. Ongoing studies in the front-line treatment of NSCLC will further define the role of docetaxel in the neo-adjuvant setting.     

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.     

Accelerated second-line or maintenance chemotherapy versus treatment at disease progression in NSCLC

For many decades, the use of chemotherapy as second-line therapy in non-small-cell lung cancer relied upon disease progression. Several studies have shown that four to six cycles of chemotherapy administered as front-line therapy treatment offers a survival advantage to patients; however, further chemotherapy beyond this initial treatment was more associated with side effects and no benefit in survival. Until 2009, second-line treatment for lung cancer was well established for three therapeutic agents: docetaxel, pemetrexed and erlotinib. Currently, the timeframe to use these agents has been challenged by two large randomized clinical trials in which pemetrexed (JMEN trial) and erlotinib (Sequential Tarceva in Unresectable NSCLC [SATURN] trial) were used as ‘maintenance’ therapy and shown to impact progression-free survival and overall survival. This review focuses on the actual dilemma that medical oncologists face in clinical practice in terms of when and to whom maintenance therapy should be applied or if the ‘watch and wait’ approach prior to start second-line therapy is still advisable.     

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.