Gemcitabine-based doublets for advanced non-small-cell lung cancer: beyond gemcitabine/cisplatin

Gemcitabine is one of the most active agents in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). Recent evidence indicates that gemcitabine/cisplatin is among the most active doublets in advanced NSCLC, but the problem of what to give patients who cannot tolerate cisplatin still remains. The combination of gemcitabine/carboplatin is under investigation. Initially thought to be too myelosuppressive, recent schedule modifications have made this a more feasible doublet for NSCLC. Nonplatinum doublets consisting of gemcitabine with the taxanes or vinorelbine are also under investigation. This review covers the most current trials of gemcitabine-based doublets in advanced NSCLC.     

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     

Indications for chemotherapy in stage IV non-small cell lung cancer

Treatment of stage IV NSCLC has been a controversial issue during the last decade. However, there is now clear evidence that cisplatin-containing chemotherapy regimens lead to prolonged survival with an increase of the 1-year survival rates at about 10%. New drugs like gemcitabine, the taxanes (paclitaxel, docetaxel), and vinorelbine have shown very promising single-agent activity and have been included into modern combination chemotherapy regimens achieving response rates of 40 to 50% and 1-year survival rates of between 30 and 40%. In comparison to single-agent cisplatin or cisplatin/etoposide as 'standard treatment approaches', most of these modern combinations could demonstrate advantages in terms of response, survival and improved QOL. Patients with favourable prognostic factors are at the moment frequently treated with platinum-based combination chemotherapy often including one of these newer active drugs. Patients with adverse prognostic factors such as elderly or stage IV patients with a reduced performance status are preferably treated with single agents such as gemcitabine, paclitaxel or vinorelbine.     

First-line chemotherapy for NSCLC: an overview of relevant trials

In advanced non-small cell lung cancer (NSCLC), monotherapy with gemcitabine improves quality of life when compared to best supportive care alone, while single-agent taxanes and vinorelbine also improve survival. Platinum-based combinations achieve benefits in response rate, time to progression and survival compared to single-agent cisplatin. With the introduction of combinations of newer agents, 2-year survival rates of 10-20% are being seen in co-operative group trials. Until recently, the various doublets that have been subjected to randomized comparison appear to have achieved similar rates of response and survival, though toxicities differ considerably depending on the choice of drugs used. However, study TAX 326, the largest trial yet conducted in advanced NSCLC, has now demonstrated that the combination of docetaxel with cisplatin is superior to that of vinorelbine and cisplatin. Controlled trials of platinum-containing vs. non-platinum combinations have yet to demonstrate any superiority of one over the other. Hopes for further improvement in survival are focused on the combination of cytotoxic agents with novel molecularly-targeted drugs such as the anti-angiogenics and EGFR inhibitors.     

Ifosfamide in non-small cell lung cancer

In recent years the role of chemotherapy in advanced non-small cell lung cancer (NSCLC) has been well established. Ifosfamide is an old drug still considered an effective cytostatic agent in the treatment of NSCLC. As a single agent, it has showed a response rate of 20-25%. These results are improved when it is used in combination with cisplatin and mitomycin C. Moreover, in recent years, several new drugs like gemcitabine, taxanes and vinorelbine have been identified, and combinations of two or three drugs have been tested in patients with advanced NSCLC. This paper reviews the main studies recently conducted for the treatment of NSCLC, considering the results obtained by ifosfamide alone and in combination. Three-drug regimens including first-generation cytostatic agents achieve a response rate of about 40% and median survival of 10 months. In combinations with new drugs, ifosfamide shows an improvement in response rate (50%) with a median survival of more than 1 year. Open questions in the treatment of NSCLC are whether three-drug are better than two-drug combinations, and whether cisplatin is still required.     

Irinotecan in non-small-cell lung cancer: status of ongoing trials

Irinotecan possesses significant single-agent activity in non-small-cell lung cancer (NSCLC) and is active in combination with either cisplatin or carboplatin. Two phase III trials completed in Japan have suggested that the combination of irinotecan/cisplatin yields superior survival rates in stage IV NSCLC patients compared to vindesine/cisplatin. The principal toxicities of the irinotecan/cisplatin regimen are neutropenia and diarrhea. This regimen is currently being tested in Japan against regimens commonly used in the United States, such as cisplatin/gemcitabine, cisplatin/vinorelbine, and carboplatin/paclitaxel. These studies include evaluation of monthly as well as weekly schedules of cisplatin in combination with irinotecan as well as a triplet regimen of irinotecan/carboplatin/paclitaxel. Ongoing trials are evaluating these regimens as well as irinotecan/carboplatin and several nonplatinum-based irinotecan-containing doublets in both the first- and second-line treatment of advanced NSCLC. Several ongoing trials are attempting to integrate irinotecan with thoracic radiation therapy in stage III NSCLC. These trials are using irinotecan-containing regimens as induction and concurrent therapy with thoracic radiation therapy. Irinotecan is also being evaluated in the preoperative setting in early-stage resectable NSCLC. Many of these trials are also incorporating celecoxib, a potent inhibitor of the cyclooxygenase-2 pathway, in combination with irinotecan-containing regimens in both advanced as well as early-stage NSCLC. Future trials should focus on the integration of the new targeted agents in combination with irinotecan-containing regimens in all stages of NSCLC.     

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.     

Gemcitabine in the first line therapy of advanced and metastatic non-small-cell lung carcinoma (NSCLC): review of the results of phase III studies

Modern platinum-based combination therapies containing gemcitabine, vinorelbine or taxanes produce response rates of 30-40%, median survival times of 8-10 months and 1-year survival rates of approximately 35% in patients with advanced non-small-cell lung cancer (NSCLC). Of the new drugs available, gemcitabine (Gemzar, Lilly, Bad Homburg, Germany) has been the most extensively researched in clinical trials and exhibits a consistent database. A total of 37 randomized phase III trials involving more than 15,000 patients have been published to evaluate gemcitabine as first-line therapy for treating locally advanced and/or metastatic NSCLC. One trial studied gemcitabine exclusively as a single agent and another four trials investigated the drug in monotherapy and combination therapy. Of the 36 combination treatment studies, 21 included gemcitabine plus cisplatin treatment arms, 6 investigated gemcitabine plus carboplatin, and another 12 evaluated platinum-free gemcitabine combinations with other third generation cytostatic agents (multiple nominations possible). In single-agent treatment, gemcitabine was similarly effective to older platinum-based combinations such as vindesine-cisplatin but was less toxic. Thrombocytopenia was the main dose-limiting toxicity but was rarely clinically relevant. A 3-week cycle with gemcitabine on days 1 and 8 was confirmed as being the most convenient of the gemcitabine-based combinations studied. No other modern platinum-based doublet with vinorelbine or taxanes was superior to gemcitabine plus cisplatin in terms of survival or time to progression in any of the eight phase III studies performed. These results are consistent with previous phase II data and with a recent meta-analysis of 11 phase III and 2 randomized phase II studies involving more than 4,500 patients (1,861 in gemcitabine-based treatment arms). This meta-analysis also demonstrated a statistically significant benefit regarding overall and progression-free survival for gemcitabine-platinum- based regimens compared with other platinum combinations. In summary, currently available data indicate that gemcitabine-platinum 2-agent combinations given in 3-week cycles may at present have the best benefit-risk ratio in the treatment of advanced NSCLC. In contrast, platinum based 3-agent schedules do not offer any survival benefit. In elderly patients with poor performance status single agent treatment with a modern cytotoxic agent should be considered. Furthermore, according to the experiences from phase III studies so far, platinum- free combinations open up the possibility of a more feasible and clinically practical, active and well tolerated treatment which is associated with a positive impact on patient quality of life.     

Efficacy and safety of palliative chemotherapy for patients with advanced breast cancer pretreated with anthracyclines and taxanes: a systematic review

No standard monotherapy or combination palliative chemotherapy currently exists for patients with advanced breast cancer pretreated with anthracyclines and taxanes. In this systematic review we assess the current knowledge on the efficacy and safety of palliative single-agent chemotherapy drugs--capecitabine, vinorelbine, gemcitabine, and liposomal doxorubicin--commonly used in daily clinical practice. We identified 22 studies, of which ten investigated capecitabine, nine investigated vinorelbine, three investigated gemcitabine, and one investigated liposomal doxorubicin. The greatest amount of information was available for capecitabine and vinorelbine. These two drugs showed good efficacy. The disease control rate differed significantly between the four drugs, which is relevant in terms of how well tumour symptoms can be improved and whether quality of life can be maintained or even improved. To obtain more evidence of the efficacy and safety of chemotherapeutic agents used in this pretreated population of advanced breast cancer patients, randomised comparisons of the various drugs, as monotherapy and in combination with targeted agents, are needed.     

Non-cisplatin based chemotherapy in advanced non-small cell lung cancer

Platinum-based, especially cisplatin-based chemotherapy is still the backbone of combination chemotherapy for advanced non-small cell lung cancer (NSCLC). Several combinations of cisplatin-or carboplatin-based chemotherapy are widely used in the treatment of advanced NSCLC. However, cisplatin is associated with considerable toxicity and large amount of fluid infusion that may lead to reluctance on the part of both physicians and patients to accept cisplatin-based chemotherapy for incurable NSCLC. Carboplatin has also been a widely used agent in the treatment of NSCLC instead of cisplatin. However, it is controversial whether carboplatin has the same activity as cisplatin or not. Several reports showed that carboplatin was not superior but almost equal to cisplatin in terms of survival. Third generation agents have been developed in the past decades including gemcitabine, paclitaxel, docetaxel, vinorelbine and irinotecan. All of them have promising levels of anti-tumor activity for NSCLC and the development of non-platinum-based chemotherapy was expected. Several randomized trials and meta-analysis have compared platinum-based combination chemotherapy with non-platinum chemotherapy based on various combinations of these third generation agents. The analysis of these trials indicated that non-platinum based chemotherapy was not superior to platinum-based chemotherapy for survival time but less toxicity. Third-generation-based non-platinum combinations are still treatment options for advanced NSCLC patients who are not eligible for platinum-based chemotherapy.     

Oxaliplatin in First-line Therapy for Advanced Non–Small-Cell Lung Cancer

Platinum doublets are the recommended standard first-line chemotherapy for stage IIIB/IV non–small-cell lung cancer (NSCLC). As efficacy outcomes associated with currently approved agents (cisplatin and carboplatin) are broadly similar, the decision about which platinum-based doublet to use is based on other factors such as toxicity. The goals for new platinum agents are to maintain and perhaps improve current efficacy and to improve toxicity. The aim of this article is to review the available clinical data from studies investigating the third-generation platinum analogue oxaliplatin in patients with advanced NSCLC. Information was obtained from the PubMed database and from recent presentations at national and international meetings. Oxaliplatin has been studied as monotherapy and in combination with a wide range of other chemotherapies (vinca alkaloids, taxanes, gemcitabine, and pemetrexed), mainly in phase II trials. Preliminary results from studies in which oxaliplatin-based doublets have been combined with targeted agents (eg, bevacizumab) are now available. In general, the clinical activity observed with oxaliplatin-based therapy is similar to that seen with other currently used platinum regimens, although outcomes vary between individual trials (response rates, 23%-48%; median progression-free survival, 2.7-7.3 months; median overall survival, 7.3-13.7 months). The toxicity profile of oxaliplatin, particularly when compared with cisplatin, makes it an alternative treatment, especially in patients unable to tolerate cisplatin. However, well-conducted randomized phase III trials will be needed to clarify which particular groups of patients with NSCLC may benefit from oxaliplatin-based therapy.     

Combinations of three chemotherapeutic agents and two chemotherapeutic agents plus a targeted biologic agent in the treatment of advanced non small-cell lung cancer

Lung cancer is the most common cause of cancer death in the world. In the United States, more than 28% of all cancer deaths are from lung cancer. In the past decade, a number of new drugs were introduced into the treatment of lung cancer including taxanes, gemcitabine, vinorelbine, and irinotecan. Combinations of one of these drugs with cisplatin, with carboplatin, or with one another were shown to be superior to best supportive care, to single-agent cisplatin, and in some instances, to a podophyllotoxin and cisplatin. Comparisons of the various two-drug combinations showed that they are equivalent in efficacy although there are differences in convenience, cost, and toxicity. Many of these two-drug combinations are less toxic than older combinations, which allowed for the development of three-drug combinations that could be given in full dose and with acceptable toxicity. Phase II trials of several three-drug combinations including carboplatin/paclitaxel/gemcitabine and cisplatin/vinorelbine/gemcitabine showed response rates and survival rates that were somewhat higher than anticipated with a two-drug combination. These data led to three randomized trials of a doublet combination versus a triplet combination. Each of these trials showed a higher response rate and higher toxicity rates with the triplet combination. The toxicity rates were still acceptable with the triplet combinations. The survival was also superior in the triplet arms of each of the randomized trials. Unfortunately, the sample size in each of these studies was small and the survival differences are not statistically significant. Therefore, additional larger randomized trials are sorely needed. During the past decade, new molecularly targeted agents were introduced into the treatment of lung cancer and completed phase I and II trials. Objective responses were noted with many of these new agents. Several combinations of doublet chemotherapy with a new targeted agent have completed phase II trials with encouraging results. Some of these new triplets are now in phase III randomized trials.     

The value of platinum compounds in non-small-cell lung cancer

The value of platinum compounds has come into question with the advent of newer chemotherapy agents in the management of patients with advanced non-small-cell lung cancer. These newer agents, which include the taxanes, topoisomerase I inhibitors, gemcitabine, and vinorelbine, appear to have higher single-agent response rates and more favorable toxicity profiles when compared to the platinum compounds. However, the toxicity of the platinum compounds is now minimized with the advent of more effective antiemetics. In addition, phase III clinical trials have demonstrated that the strategy of cisplatin dose intensity and prolonged duration of therapy with platinum compounds does not improve overall survival; therefore, moderate doses of cisplatin and a shorter duration of therapy can be given to further decrease toxicity. Furthermore, while phase II trials utilizing nonplatinum-based combination chemotherapy appear to demonstrate superior response rates and survival in comparison to platinum-based doublets, results of phase III trials have demonstrated no improvement in survival. Platinum combination chemotherapy remains the standard approach for stage IV non-small-cell lung cancer. More substantial advances will likely be made with novel molecular targeted therapy, such as the epidermal growth factor receptor inhibitors, which demonstrate synergy with the platinum compounds.     

Gemzar platinum combinations: phase III trials in non-small cell lung cancer

Lung cancer accounts for about 28% of all cancer-related deaths. Non-small cell lung cancer (NSCLC) constitutes 80% of all lung cancer cases, and in 70% of patients, the disease is diagnosed when it is locally advanced or metastatic. In these situations, chemotherapy has played only a minor role in modifying the natural history according to a 1995 meta-analysis. New drugs such as gemcitabine, vinorelbine, and the taxanes have been combined with cisplatin and tested in several phase-II and phase-III clinical trials versus cisplatin alone and different cisplatin/new drug combinations. Overall, the data seem to confirm that, despite a possible increase in response rate, no major difference in long-term survival has been achieved. Moreover, toxicity and cost may be significant with some of the combinations and schedules. While the combination of cisplatin and gemcitabine seems to be fairly active and better tolerated, we all look forward to the results of ongoing studies on the association of these regimens with the new biological drugs.     

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.     

Evolution of non-small cell lung cancer chemotherapy (Review)

Non-small cell lung cancer (NSCLC) is a common malignancy which has been increasing in incidence over the last decades. In the past, these tumors were considered quite resistant to chemotherapy and until the development of cisplatin 30 years ago, the use of cytotoxic drugs was considered palliative. Cisplatin (CDDP) proved to be an active agent and when combined with other cytotoxic drugs, effectiveness in NSCLC increased. Many trials have taken place during the last 30 years with cisplatin combinations. Despite the effectiveness of cisplatin, the renal toxicity and neurotoxicity that are produced obliged researchers and clinicians to create other combinations without CDDP. Carboplatin, an analogue of CDDP and then taxanes, gemcitabine and vinorelbine, a Vinca alkaloid, that proved to be effective in NSCLC, led to substitute combinations for CDDP. In the present article we review the literature on NSCLC chemotherapy in order to visualize the effectiveness of older drug combinations vs. the newer ones. It seems that combinations with or without cisplatin are of similar effectiveness with respect to response rate and median and overall survival but the toxicity is different with a prevalence of myelotoxicity.     

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.     

New drugs in the palliative chemotherapy of advanced non-small-cell lung cancer.

In inoperable advanced non-small-cell lung cancer (NSCLC), palliative chemotherapy is established and aims at palliation of symptoms, improvement of quality of life and prolongation of survival. In the last years, several new drugs with enhanced activity towards NSCLC and improved toxicity profile have been characterised, for example vinorelbine, gemcitabine, paclitaxel and docetaxel. Data from randomised trials suggest that regimens containing new drugs are more active than older combinations. Platin-based combinations of either vinorelbine, gemcitabine or paclitaxel have resulted in better outcome than cisplatin alone and new drugs in combination with platins are more active than the corresponding single agent. Non-platin-based combinations must be considered investigational until their non-inferiority to platin-based protocols has been proven in randomised trials on large patient populations. Patients with good performance status and adequate organ function should receive platin-based chemotherapy that includes the new drugs (vinorelbine, gemcitabine, paclitaxel or docetaxel). New drugs without platins are suitable for elderly patients and patients with poor performance status. Second-line chemotherapy prolongs survival in selected patients and should be particularly offered to patients with good performance status.     

Two- versus three-drug combinations in the chemotherapy of advanced non-small-cell lung cancer

Palliative chemotherapy with three-drug combinations might result in higher efficacy but also enhanced toxicity when compared with two-drug combinations. Italian trials suggested the superiority of cisplatin/gemcitabine/vinorelbine and cisplatin/gemcitabine/paclitaxel over corresponding two-drug combinations. However, a Spanish trial failed to demonstrate an advantage of cisplatin/gemcitabine/vinorelbine over cisplatin/gemcitabine and another multicenter phase III trial did not find differences in response rates and survival between cisplatin/vinorelbine/ifosfamide and cisplatin/vinorelbine. Thus three-drug combinations have not convincingly been demonstrated to be superior to two-drug combinations and should not be considered as standard protocols in advanced NSCLC.     

Vinorelbine and gemcitabine combinations in advanced non small-cell lung cancer

Several new chemotherapeutic agents were developed and tested in advanced non small-cell lung cancer (NSCLC) in the past decade. Vinorelbine and gemcitabine showed consistent single-agent activity in phase II and III trials and have been shown to be superior to older combinations when combined with cisplatin. However, toxicity associated with these regimens remains substantial, and nonplatinum alternatives are currently being explored. Based on the individual activity of vinorelbine and gemcitabine, their distinct mechanisms of action, and their mild, nonoverlapping toxicities, several trials evaluated their use in combination in patients with advanced NSCLC. Therapy has been administered in a convenient outpatient setting over a period of 1 hour. Different weekly schedules have been tested, but in general, toxicity is mild and the regimen is well tolerated, even in elderly patients or those with a poor performance status. Efficacy seems to be at least comparable to traditional platinum-based regimens, with respect to overall response rate and survival. In summary, vinorelbine/gemcitabine is an active and well-tolerated regimen and represents an option for the treatment of patients with advanced NSCLC. Randomized studies comparing this combination to reference platinum- or taxane-based regimens are needed to further evaluate the role of this combination in advanced NSCLC.