Treatment of unresectable non-small-cell lung cancer

Current progress in the treatment of unresectable non-small-cell lung cancer (NSCLC) is reviewed. Several new agents including vinorelbine, paclitaxel, docetaxel, gemcitabine, and irinotecan have been shown to have distinct activity for NSCLC. Combinations of a new agent with cisplatin or carboplatin were highly active for advanced NSCLC, and randomized trials are in progress to establish the standard chemotherapy regimen for advanced NSCLC. The effectiveness of concurrent chemoradiotherapy has been established in Japan, while that of induction chemotherapy has yet to be confirmed. Induction chemoradiotherapy may be useful and randomized trials comparing chemotherapy alone with chemoradiotherapy as an induction therapy are needed.     

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.     

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.     

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.     

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.     

Management of non-small cell lung cancer in elderly patients

Non-small cell lung cancer (NSCLC) may be considered typical of advanced age. More than 50% of NSCLC patients are diagnosed over the age of 65 and approximately one-third of all patients with non-small cell lung cancer (NSCLC) are over the age of 70. Elderly patients tolerate chemotherapy poorly compared to their younger counterpart because of the progressive reduction of organ function and comorbidities related to age. For this reason, these patients are often not considered eligible for aggressive cisplatin-based chemotherapy, the standard medical treatment of advanced NSCLC. At present, for early stages there are no indications for adjuvant and neoadjuvant chemotherapy. Combined chemo-radiotherapy in locally advanced disease, particularly with concurrent approach should be investigated in specific trials before to be preferred in clinical practice to radiation therapy alone. In advanced disease, prospective phase II trials have demonstrated suitable toxicity profile and good antitumor activity for single agent chemotherapy with the recently developed drugs vinorelbine, gemcitabine and taxanes. Moreover, vinorelbine, compared to best supportive care in a phase III randomized trial, has proven to improve survival and quality of life. A phase III randomized trial showed that polychemotherapy with gemcitabine and vinorelbine does not improve any outcome as compared to single agent chemotherapy with vinorelbine or gemcitabine. In clinical practice, single agent chemotherapy should remain the standard treatment. Feasibility of cisplatin-based polychemotherapy remains an open issue and has to be proven prospectively. The two main research-lines to explore in the near future are the introduction of biological agents in the treatment schemes and the development of specifically designed schedules of platin-based regimens. However, practicing a multidimensional geriatric asessment for individualized treatment choice in NSCLC elderly patients is mandatory.     

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.     

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.     

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.     

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.     

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.     

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.     

Chemoradiation paradigm for the treatment of lung cancer

For the treatment of locoregional advanced stage III non-small-cell lung cancer, when chemotherapy is added sequentially to radiotherapy it acts systemically and is aimed at reducing distant metastases. Concurrent chemotherapy and radiation, however, is intended to enhance the locoregional efficacy of this modality. Combined effects of these modalities are based on their different toxicity profiles, leading to a reduced toxicity : efficacy ratio of the combination. Controlled trials investigating this additive approach indicate that concurrent application of chemotherapy and radiotherapy results in a small but significant benefit for locoregional control, which translates into a small but measurable survival benefit. This benefit is most evident when looking at 3-year or 5-year overall survival rates, when it is of clinical significance. The use of single-agent cisplatin has already demonstrated major radiosensitizing effects whereas the radiosensitizing properties of concurrent application of the single-agent carboplatin have not been observed in controlled trials. Newer drugs such as vinorelbine, the taxanes and gemcitabine might enhance this effect, although no improvement has been observed in randomized controlled trials comparing such regimens with single-agent cisplatin. New 'targeted' agents might synergize with ionizing irradiation and provide an interesting rationale concerning combined modality therapy, but this hypothesis awaits prospective clinical evidence from randomized controlled trials.     

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.     

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.     

Chemotherapy in Patients with Anthracycline and Taxane-Pretreated Metastatic Breast Cancer: An Overview

Anthracyclines and taxanes are cytotoxic agents commonly used for treatment of breast cancer, including in adjuvant, neoadjuvant, and metastatic settings. Each drug class is associated with cumulative and potentially irreversible toxicity, including cardiomyopathy (anthracyclines) and neuropathy (taxanes). This may either limit the duration of therapy for advanced disease, or prevent retreatment for recurrence if previously used as component of adjuvant or neoadjuvant therapy. Several classes of cytotoxic agent have been evaluated in patients with anthracycline and taxane-pretreated metastatic breast cancer (MBC), including other antitubulins (vinorelbine, ixabepilone, eribulin), antimetabolites (capecitabine, gemcitabine), topoisomerase I inhibitors (irinotecan), platinum analogues (cisplatin, carboplatin), and liposomal doxorubicin preparations. No trials have shown an overall survival advantage for combination chemotherapy in this setting, indicating that single cytotoxic agents should usually be used, expect perhaps for patients with rapidly progressive disease and/or high tumor burden.     

Combined chemotherapy and radiation in locally advanced non-small-cell lung cancer

The efficacy of radiotherapy in locally advanced non-small-cell lung cancer is limited. One attempt to improve survival uses a combination of radiation and chemotherapy. These two modalities can be applied in sequence or concurrently, but results from phase III trials of combined therapy versus radiation alone have been inconsistent. Early studies were mostly negative, but more recent trials using platinum-based regimens have shown some survival benefit for combined treatments. The positive impact of chemotherapy has also been shown in a meta-analysis. In recent studies, concurrent chemotherapy and radiation appears better than sequential application. However, the benefit of the combined approach is modest and should be balanced against increased early and late toxicity. The role of new agents such as taxanes, vinorelbine, gemcitabine, and topoisomerase inhibitors in combined modality therapy of non-small-cell lung cancer warrants further clinical investigation.     

Gemcitabine hydrochloride is a new anti-cancer agent which will be available in the patients with non-small cell lung cancer (NSCLC) in Japan]

Gemcitabine hydrochloride is a novel anti-cancer drug which is marketed as an indication for non-small cell lung cancer (NSCLC). This drug is already on the market and has been done many clinical trials. In order to evaluate its efficacy in treating NSCLC, many studies of gemcitabine by combination chemotherapy using agents such as cisplatin, which is a key drug in treating NSCLC, and paclitaxel, docetaxel and vinorelbine, which are novel anti cancer agents, were conducted. Although the efficacy of this drug was confirmed in terms of the combination therapy from the results, the optimal dosage schedule of this drug was not established because each study showed a different result in terms of the dosage as well as the dosage interval, thus, it is necessary to discuss and establish the optimal dosage schedule. Also comparative studies between the single therapy of gemcitabine and the existing combination therapy were conducted and it was reported that the single therapy was as effective as the conventional combination therapy. Based upon the results, it is considered that gemcitabine is a potential option in the chemotherapy for NSCLC. Gemcitabine has been already approved as indications for NSCLC as well as pancreatic cancer abroad and now there have been discussions on its efficacy against other kinds of cancer such as breast cancer. Clinical trials in order to evaluate its efficacy for pancreatic cancer have been conducted here in Japan and it is also expected to expand develop the efficacy against other kinds of cancer.     

Status and trends of chemotherapy for advanced NSCLC

With a response rate of 20%, cisplatin has been considered the key-drug in the treatment of NSCLC since 1980 and the combination of cisplatin-etoposide, cisplatin-vinblastine and cisplatin-vindesine have been considered standard regimens for NSCLC up to the mid 1990s. In the last 10 years, several new drugs have emerged; the most promising are vinorelbine, taxanes, gemcitabine and irinotecan which all have showed response rates of 20–30% among previously untreated patients. These agents have also been evaluated in combination with cisplatin, carboplatin or other drugs with encouraging results. There is not a single gold-standard doublet but cisplatin-based chemotherapy along with vinorelbine, taxanes or gemcitabine are the established standards in this setting. Carboplatin can replace cisplatin in selected patients but is not obviously as active in terms of survival impact. Triplets have not showed superiority over doublets in the vast majority of randomised studies. Genetic characteristics of the tumour are also important sources of prognostic information, and pharmacogenetic approaches, such as the tumoral detection of tumour specific mutations, that can predict chemoresistance to specific drugs, represent an area of great hope. Finally, the better understanding of the biology of lung cancer has led to the development of novel therapies directed at tumour-specific targets. Most of these targets are tumour growth factor signal pathways but tumour proliferation, angiogenesis or apoptosis may also be targeted. Several new agents have already demonstrated a promising activity. Nevertheless, most phase III studies have been disappointing and the combination of cytotoxic doublets and targeted agents have also failed to demonstrate any substantial improvement up to now.     

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.